Number 71 - November 2016 - Heart and Metabolism · the suspicion of senile amyloid (caused by...

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Heart failure with preserved ejection fraction (HFpEF): what’s the problem?

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Number 71 - November 2016

Heart and Metabolism


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Mario Marzilli, MD, PhD, Italy

Luis Henrique W. Gowdak, MD, PhD, BrazilDerek J. Hausenloy, PhD, UKGary D. Lopaschuk, PhD, CanadaMichael Marber, MB (BS), PhD, UK

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Heart and Metabolism is a journal published three times a year, focusing on the management of cardiovascular diseases. Its aim is to inform cardiologists and other specialists about the newest findings on the role of metabolism in cardiac disease and to explore their potential clinical implications. Each issue includes an editorial, followed by articles on a key topic. Experts in the field explain the metabolic consequences of cardiac disease and the multiple potential targets for phar-macotherapy in ischemic and nonischemic heart disease.

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Contents

EDITORIALHFpEF, is it more than just the sum of its parts? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2M. Marber

ORIGINAL ARTICLESHeart failure with preserved ejection fraction (HFpEF): a basic and clinical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4A. Shah, P. C. Chowienczyk

How to diagnose heart failure with preserved ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9T. H. Marwick

Treatment of HFpEF: why we have no evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14M. Marber

Imaging fibrosis in heart failure with preserved ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18A. N. Bhuva, R. Schofield, R. T. Lumbers, C. H. Manisty, J. C. Moon

Trimetazidine in the new 2016 European guidelines on heart failure and beyond . . . . . . . . . . . 23Y. Lopatin

CASE REPORT HFpEF or just multiple comorbidities? The challenges of making a definitive diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27J. Webb

REFRESHER CORNERHeart failure with preserved ejection fraction–where is the problem: heart or arteries? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32S. Ewen, M. Böhm

HOT TOPICSThe failing heart: an engine operating on “bad” fuel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37V. Sequeira, J. van der Velden

GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40G. D. Lopaschuk

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Heart Metab. (2016) 71:2-3Editorial - Michael Marber

This issue of our journal focuses on the highly topical subject of heart failure with preserved left ventricular ejection fraction (HFpEF). It is

clear from congresses and journals that HFpEF’s popularity is on the rise. This is hardly surprising given that its high prevalence, morbidity, and mortality com-bine with a lack of effective therapy. This combination provides the “perfect storm,” whipping up academic and commercial interest. Against such backdrop, the articles in this issue provide a balanced view of this field, which often attracts polarized opinion. A good place to start is the “basic and clinical perspective” provided by Ajay Shah and Philip Chow-ienczyk. This article highlights the varied pathologies that drive HFpEF and makes the point that current guidelines recommend nothing other than the treat-ment of comorbidities because there is no clear mechanism of disease causation. Without a domi-nant mechanism driving disease, it’s difficult to cre-ate animal models that recapitulate the phenotype(s) seen in patients. The question is Why are patients with HFpEF so heterogeneous? One of the key causes of heterogeneity in HFpEF is the difficulty in diagnosing this condition. This issue is tackled by Thomas Marwick in his article on how to diagnose HFpEF. The article makes the point that there are two main modes by which patients present: with acute pulmonary edema in the acute care set-ting and with more insidious disease with progressive

breathlessness and fatigue in the ambulatory care setting. Acute presentation with documented pulmo-nary edema that rapidly resolves with diuresis pro-vides enhanced diagnostic specificity, provided that other triggers such as dynamic mitral regurgitation and tachyarrythmia are excluded. The problem lies in those who present with chronic symptoms, which constitutes the majority of patients. Here, the diag-nosis relies on demonstrating abnormal myocardial relaxation; however, as Thomas Marwick discusses, current noninvasive methods lack specificity because with age many of the measured parameters change in the same direction as in HFpEF. Consequently, dif-ferentiating HFpEF from “healthy” aging is more art than science. Newer echocardiographic techniques that use speckle tracking to measure myocardial strain may offer improvements in specificity, as may other imaging modalities. The article by James Moon and colleagues dis-cusses some of these newer imaging techniques but focuses on the use of cardiac magnetic resonance imaging (cMRI). The advantage of cMRI is its ability to quantify myocardial extracellular volume through use of contrast agents and native T1. The above-men-tioned “basic and clinical perspective” article by Ajay Shah and Philip Chowienczyk discusses the physiol-ogy of diastole, which is divided into an active phase determined by actin-myosin crossbridge detachment and a passive phase determined by the restoration

HFpEF, is it more than just the sum of its parts?Michael Marber, PhDBHF Center of Research Excellence, Cardiovascular Division, The Rayne Institute, St Thomas’ Hospital, London, UK

Correspondence: Michael Marber, BHF Center of Research Excellence, Cardiovascular Division, The Rayne Institute, St Thomas’ Hospital, London, SE1 7EH, UKE-mail: [email protected]

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of elastic components within the myocardium that were distorted during systole. Diffuse myocardial fi-brosis will alter passive myocardial relaxation. Thus, as argued by James Moon, cMRI is one of the few techniques that can actually provide some insight into the pathology causing abnormal relaxation. This ability to look “upstream” also enables cMRI to raise the suspicion of senile amyloid (caused by myocardial deposition of wild-type transthyretin), which is almost certainly underdiagnosed and for which specific treat-ments may soon be available. This focus on passive relaxation is complement-ed by the Hot Topics article by Vasco Sequeira and Jolanda van der Velden, which concentrates on ab-normal active relaxation. The underlying premise is that healthy relaxation requires fast detachment of the actin-myosin crossbridges and that this in turn is energetically demanding, relying on adenosine tri-phosphate (ATP) to drive the sarcoplasmic reticulum calcium ATPase to clear the systolic calcium transient and also to replace adenosine diphosphate (ADP) on myosin. Effectively, both these processes are depen-dent on a high concentration of ATP but also on a low concentration of ADP (ATP/ADP ratio). Thus, a high concentration of ADP pollutes the fuel driving con-traction, fostering the concept that the failing heart is an engine running on bad fuel and that this manifests as impaired relaxation. This raises the obvious ques-tion of what can be done to remedy the situation. The article by Yury Lopatin summarizes the new European Society of Cardiology (ESC) heart fail-ure guidelines and points out that trimetazadine is now given a class IIbA recommendation for use in the treatment of angina in heart failure patients on a β-blocker or who are unable to tolerate a β-blocker. Mirroring the Hot Topics article, Yury Lopatin postu-lates that trimetazadine may have additional benefits on the heart failure process itself by increasing the

efficiency of conversion of ADP to ATP. As pointed out by most of the contributors, there are no specific therapies that alter mortality in HFpEF. This topic is discussed in detail in the article by Sebas-tian Ewen and Michael Böhm who summarize all the main past and forthcoming trials of drugs and devices in HFpEF. The article makes sobering reading because it highlights the substantial investment already made in HFpEF, often treading a path that has proven success-ful in HFrEF. Although ongoing studies may provide a light at the end of the tunnel; the question still re-mains, why have past trials failed? In this issue, I have attempted to answer this question in my article entitled “Treatment of HFpEF: why we have no evidence.” Finally, this issue’s Case Report article by Jes-sica Webb summarizes a patient with a constellation of symptoms, signs, and imaging findings that were consistent with HFpEF. To finalize the diagnosis, the patient underwent right and left heart catheterization, including pressure-volume analysis of the left ventricle. The case report illustrates the ability of invasive stud-ies to characterize key parameters of diastolic compli-ance and clarify the diagnosis. It also reminds us that elevated left ventricular filling pressure is the hallmark of HFpEF. Unfortunately, there is only one way to di-rectly measure pressure, but invasive studies are not appropriate in the majority of patients with HFpEF due to their age and comorbidities. In addition, making the diagnosis will not dramatically alter therapy. I found editing this issue both stimulating and depressing! It brought home to me that we still un-derstand little about the complex and heterogeneous conditions that lead to the HFpEF syndrome. At the moment, all we can do is identify and treat its predis-posing risk factors and hope that ultimately there will be a specific therapy that suggests it is more than just a sum of these parts. L

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Heart Metab. (2016) 71:2-3 Marber

HFpEF, is it more than just the sum of its parts?

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Introduction

Chronic heart failure (CHF) affects nearly 6 mil-lion people in the United States and similar proportions in other industrialized countries.1

The prevalence is projected to rise substantially over

the next 15 years, particularly in the >65 age group. It causes substantial mortality and morbidity and represents a major disease and socioeconomic bur-den. CHF is a systemic syndrome involving the heart, vasculature, kidneys, and other organs, but it de-velops primarily as a result of diverse acquired and/

Heart failure with preserved ejection fraction (HFpEF): a basic and clinical perspective

Ajay M. Shah, MD, FMedSci1; Philip C. Chowienczyk, FRCP2

Departments of 1Cardiology and 2Clinical Pharmacology and Therapeutics, Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, UK

Correspondence: Professor Shah, Cardiovascular Division, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK

E-mail: [email protected]

AbstractUp to 50% of patients with heart failure have a relatively normal ejection fraction; this is called “heart failure with preserved ejection fraction” or HFpEF. These patients are more likely to be older, female, hypertensive, obese, or to have metabolic syndrome or atrial fibrillation. They suffer substantial mortality and morbidity, but there are currently no treatments available proven to improve outcomes. Abnormal left ventricular diastolic function is thought to be a major feature of HFpEF, and its detection (or the detection of cardiac structural abnormalities that predispose to diastolic dysfunction) is a requirement for positive diagnosis in most diagnostic guidelines. However, noninvasive detection of left ventricular diastolic dysfunction and its distinction from normal cardiovascular aging may be difficult. Clinical assessment of patients during exercise or similar stress can be very valuable. The clinical pathophysiol-ogy of HFpEF is heterogeneous and involves not only diastolic dysfunction but also abnormalities in heart rate, heart rhythm, microvascular resistance, aortic stiffness, and ventricular-vascular coupling, resulting in impaired systolic and diastolic reserve capacity upon exercise. The mechanisms underlying these abnormalities are poorly understood. The phenotype bears similarity to normal cardiovascular aging and could involve similar abnormalities in inflammation and oxidative stress levels. Abnormalities in nitric oxide/cyclic guanosine monophosphate (cGMP) signaling also possibly contribute. To develop effective therapies for HFpEF, more rigorous clinical phenotyping and classification are probably needed to facilitate a better understanding of the disease pathophysiology and the development of more per-sonalized treatments. L Heart Metab. 2016;71:4-8

Keywords: diastolic dysfunction; HFpEF; ventricular-vascular coupling

Heart Metab. (2016) 71:4-8Original Article

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Heart Metab. (2016) 71:4-8 shah and chowienczyk

HFpEF—basic and clinical perspective

or genetic structural and functional abnormalities of the heart. Forty percent to 50% of CHF patients have a form of heart failure in which left ventricular (LV) systolic function, as assessed by ejection frac-tion (EF) at rest, is relatively well preserved. This type of heart failure has come to be termed heart failure with preserved EF (HFpEF). The outcome of patients with HFpEF is on average slightly better than for those with reduced EF (HFrEF), but they still have substantial morbidity and mortality, eg, 23% mortal-ity over 3 years in a large meta-analysis.2 Further-more, the prevalence of HFpEF relative to HFrEF is rising. Although many trials have had limited power, treatments used for patients with HFrEF (eg, inhibi-tors of the renin-angiotensin-aldosterone system, β-adrenergic blockers, biventricular pacemakers, and implantable defibrillators) have not been shown to reduce mortality in HFpEF. Current treatment is thus focused on comorbidities.3,4 To develop effec-tive specific treatments, there is a compelling need to better understand the pathophysiology of this type of heart failure.

Diagnosis of HFpEF

The diagnosis of HFpEF is more difficult than HFrEF and more likely to be inaccurate. It is generally ac-cepted that abnormal LV diastolic function (with or without other cardiovascular pathology, as discussed later) is a fundamental component of HFpEF. Current American Heart Association (AHA) guidelines require the presence of signs or symptoms of heart failure, a preserved EF (EF≥50%), and objective evidence of LV diastolic dysfunction to diagnose HFpEF.3 Because symptoms may be nonspecific and difficult to distin-guish from those related to aging and comorbidities, such as obesity, and because EF is preserved, the demonstration of LV diastolic dysfunction becomes critical, especially in those without definitive signs (such as pulmonary edema). However, noninvasive

assessment of LV diastolic function is not always easy. Assessment during exercise—when diastolic abnormalities are more evident—is particularly valu-able though not routinely performed. The most recent European Society of Cardiology (ESC) guidelines have added the presence of elevated natriuretic pep-tide (NP) levels as an essential requirement for the diagnosis of HFpEF.4 However, not all patients with HFpEF (including those characterized by definitive in-vasive assessment) have elevated NP levels5; the use of these new criteria may therefore exclude important subsets of patients with HFpEF. Risk factors and heterogeneity

Whether HFpEF and HFrEF are distinct conditions or part of a spectrum has been debated, but it is clear that patient characteristics differ between the groups. HFpEF is especially common in the elderly. Patients with HFpEF are more likely to be female, have hyper-tension, obesity, metabolic syndrome, diabetes, atrial fibrillation, and to lead a sedentary lifestyle than those with HFrEF, and they are less likely to have ischemic heart disease. Transition of HFpEF to HFrEF may largely occur only in those who develop myocardial infarction. There is significant phenotypic and probably pathophysiologic heterogeneity among patients with HFpEF. An important question is whether defining more homogeneous subpopulations might allow a better understanding of the underlying pathophysiol-ogy and identification of groups that respond favor-ably to specific therapies. This idea is supported by a recent unbiased clustering analysis of nearly 400 carefully diagnosed HFpEF patients; in the analy-sis, three distinct patient groups could be identified, which differed in clinical and cardiac structural/func-tional characteristics as well as outcomes.6

Clinical pathophysiology

HFpEF was historically considered primarily to be a disorder of LV diastolic function (so-called “diastolic heart failure”). Although this is undoubtedly a major feature, it is now evident that HFpEF results from a complex and variable interplay of multiple defects in LV hemodynamic and reserve function, including ab-normalities of heart rate and rhythm, vascular stiffness and resistance, and ventricular-vascular coupling.

AbbreviationscGMP: cyclic guanosine monophosphate; CHF: chronic heart failure; EF: ejection fraction; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; HYVET: HYpertension in the Very Elderly Trial; LV: left ventricular; NO: nitric oxide; NOS: nitric oxide synthase

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shah and chowienczyk Heart Metab. (2016) 71:4-8HFpEF—basic and clinical perspective

LV diastolic dysfunction in HFpEF usually com-prises both an impairment of active LV relaxation and an increase in passive (late diastolic) stiffness that to-gether increase LV filling pressures. The latter may be especially evident during exercise, highlighting that the problem is essentially one of reserve capacity (as in CHF more generally).7 The left ventricle is typi-cally concentrically remodeled and hypertrophied but rarely dilated. Concentric LV remodeling and intersti-tial fibrosis contribute to elevated diastolic stiffness in HFpEF, but an important additional factor may be an increased cardiomyocyte sarcomeric stiffness, influ-enced by the giant elastic protein titin and its phos-phorylation status.8 In diabetic patients, increased stiffness related to advanced glycation end products may be important. Impairment of the myocardial en-ergetic state on exercise, knowing that energy me-tabolism is crucial for active myocardial relaxation, may also contribute to diastolic dysfunction.9 Chronic elevation in LV filling pressure leads to pulmonary hypertension in many HFpEF patients, especially upon exercise. An associated impairment of right ventricular function predicts worse outcomes. Elevated filling pressures also predispose to atrial fi-brillation, which is poorly tolerated because HFpEF patients are highly dependent on normal left atrial function to adequately fill the left ventricle. Many pa-tients with HFpEF have an inadequate increase in heart rate upon exercise, related to abnormalities in autonomic balance, which impairs cardiac output and exercise capacity. Vascular dysfunction is an important feature of HF-pEF. An increase in aortic stiffness and central aortic pressure increases vascular hydraulic load on the left ventricle, adversely affects LV relaxation, and contrib-utes to chronically increased wall stress that may drive concentric LV remodeling.10 Myocardial perfusion re-serve is often reduced, independent of coronary artery disease, which may in part be related to the increased vascular load. The potential importance of hyperten-sion in HFpEF is illustrated by findings from the HYVET (HYpertension in the Very Elderly Trial) study, where in-dapamide (either with or without perindopril) compared with placebo reduced fatal or nonfatal heart failure events by 64% in patients with preexisting hyperten-sion who were aged 80 years or more (but did not sig-nificantly reduce cardiac deaths).11 Although the type of heart failure was not specifically defined in this study, the characteristics of the patients were such that a

substantial proportion of the heart failure would have been HFpEF. Patients with HFpEF also have reduced vasodilatation during exercise, which impairs their abili-ty to increase stroke volume.12 A defining characteristic of HFpEF is therefore vascular dysfunction and abnor-mal ventricular-vascular coupling, which compromises optimal hemodynamic function. Although EF at rest is normal or only mildly re-duced in HFpEF, the preceding discussion indicates that there is significant systolic impairment during ex-ercise. Indeed, more sensitive indices of contractile function than EF readily identify subtle abnormalities of systolic function even at rest. However, there is a clear difference between HFpEF and HFrEF, with the left ventricle typically being concentrically remodeled and nondilated in HFpEF, whereas HFrEF is charac-terized by substantial LV thinning, dilatation, and sys-tolic impairment at rest. Disease mechanisms

The underlying mechanistic basis for the multisystem abnormalities in patients with HFpEF is unknown and may vary among patients. Hypertension is an impor-tant factor in many patients. The in vivo dissection of potential disease mechanisms is quite challenging; at the same time, there are few reliable animal models of HFpEF. Many pathophysiologic abnormalities found in typical HFpEF resemble those observed in normal aging (which is a dominant risk factor for HFpEF), al-beit much more exaggerated. HFpEF could therefore be considered a form of premature cardiovascular aging.13 The mechanisms underlying cardiovascular aging are complex and incompletely understood.13,14 However, there is a consensus that there is a general disorder of multiple aspects of the signaling cascades and molecular pathways required to maintain cellu-lar and organ homeostasis, driven for example by increasingly dysfunctional cellular defense pathways and by increased oxidative stress. It has been sug-gested that the cardiovascular aging phenotype is the consequence of inflammatory defenses generated by cells in an attempt to limit this molecular and signaling disorder.14 From this perspective, a proinflammatory aging-related milieu may be an important aspect of the underlying mechanism in HFpEF. Recently, it has been proposed that dysregulated nitric oxide (NO) signaling is an important contributor

to HFpEF pathophysiology.15 NO generated by NO synthases (NOSs) regulates multiple aspects of car-diovascular function, including vascular tone, myo-cardial function, growth, energetics, and autonomic function. Endothelial NOS (eNOS) is expressed in endothelial cells and to a lesser extent in cardiomy-ocytes, whereas neuronal NOS (nNOS) is found in nerves, cardiomyocytes, and potentially in vascular smooth muscle. NO signaling involves the elevation of cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG) activity or the S-nitrosylation of specific protein targets. The potential of PKG to modulate cardiomyocyte stiff-ness via titin phosphorylation may be particularly rel-evant to HFpEF.8 Interestingly, recent studies in small groups of highly selected HFpEF patients identified increased cardiomyocyte stiffness in myocardial biopsies, which was related to a reduced PKG-mediated phosphorylation of titin.16 These authors proposed that HFpEF involves systemic endothelial dysfunction (most risk factors predisposing to HF-pEF impair endothelial function) involving impaired bioactivity of endothelium-derived NO, for example, due to increased oxidative stress. It should be noted that randomized clinical trials of agents that enhance NO release (eg, the β-blocker nebivolol) or prevent cGMP breakdown (eg, the phosphodiesterase type 5 inhibitor sildenafil) were unsuccessful in HFpEF.17,18 However, ongoing trials are assessing agents that directly stimulate cGMP formation (eg, vericiguat; NCT01951638). Table I shows the potential pathophysiologic ab-normalities that may be influenced by antihyperten-sive agents or by agents that target the NO-cGMP pathway.

Summary and future perspective

The effective treatment of HFpEF represents a major unmet clinical need. Accurate diagnosis of the condi-tion is difficult, and the mechanisms underlying the pathophysiology are poorly understood. HFpEF ap-pears to be a highly heterogeneous condition in which different subgroups may require different therapeutic strategies. Although large randomized clinical trials have validated many new therapies for cardiovascular disease and prevention over the last 30 years, includ-ing new CHF treatments, they have relied on a sim-plicity of diagnosis and inclusion criteria that appar-ently has not worked well for the HFpEF population. We suggest that a more rigorous and detailed clinical phenotyping, diagnosis, and classification of HFpEF into more homogeneous subtypes is required in order to advance basic understanding of the pathophysiol-ogy and develop effective personalized therapies. L

REFERENCES

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38-e360.

2. Meta-analysis Global Group in Chronic Heart Failure (MAG-GIC). The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Eur Heart J. 2012;33(14):1750-1757.

3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-e327.

4. Ponikowski P, Voors AA, Anker SD, et al; The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Fail-ure of the European Society of Cardiology (ESC); developed with the special contribution of the Heart Failure Association (HFA) of the ESC. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37(27):2129-2200.

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HFpEF—basic and clinical perspective

Mechanism Effects of antihypertensive treatment Effects of NO-cGMP pathway modulation

Increased filling pressures Reduced by diuretics Some diuretic effect

Increased passive diastolic stiffness (structural)

Reduced by regression of LVHPossible specific effect of spironolactone

Reduced titin phosphorylation

Impaired LV relaxation Improved by reduction in afterload Improved relaxation

Systolic dysfunction Improved by reduction in afterload Possibly improved by reduction in afterload

Increased aortic stiffness Reduced Possible specific effect of spironolactone

Minor effects

Increased wave reflection from conduit arteries

Reduced reflection (minor) Reduced reflection

Microvascular dysfunction Reduced peripheral resistance Endothelium-derived NO beneficial

Skeletal muscle dysfunction Possible effect Improved mitochondrial respiration

Table I Pathophysiologic mechanisms in heart failure with preserved ejection fraction (HFpEF) and potential benefits of antihypertensive treatments and manipulation of the nitric oxide–cGMP pathway. Abbreviations: cGMP, cyclic guanosine monophosphate; LV, left ventricular; LVH, left ventricular hypertrophy; NO, nitric oxide.

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5. Anjan VY, Loftus TM, Burke MA, et al. Prevalence, clinical phenotype, and outcomes associated with normal B-type na-triuretic peptide levels in heart failure with preserved ejection fraction. Am J Cardiol. 2012;110(6):870-876.

6. Shah SJ, Katz DH, Selvaraj S, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131(3):269-279.

7. Borlaug BA, Olson TP, Lam CS, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection frac-tion. J Am Coll Cardiol. 2010;56(11):845-854.

8. Linke WA, Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res. 2014;114(6):1052-1068.

9. Phan TT, Abozguia K, Nallur Shivu G, et al. Heart failure with preserved ejection fraction is characterized by dynamic impair-ment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol. 2009;54(5):402-409.

10. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and dia-stolic reserve limitations. Circulation. 2003;107(5):714-720.

11. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hyper-tension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-1898.

12. Borlaug BA, Melenovsky V, Russell SD, et al. Impaired chro-notropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006;114(20):2138-2147.

13. Loffredo FS, Nikolova AP, Pancoast JR, Lee RT. Heart failure with preserved ejection fraction: molecular pathways of the ag-ing myocardium. Circ Res. 2014;115(1):97-107.

14. Lakatta EG. So! What’s aging? Is cardiovascular aging a dis-ease? J Mol Cell Cardiol. 2015;83:1-13.

15. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dys-function and remodeling through coronary microvascular endo-thelial inflammation. J Am Coll Cardiol. 2013;62(4):263-271.

16. van Heerebeek L, Hamdani N, Falcão-Pires I, et al. Low myo-cardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012;126(7):830-839.

17. Conraads VM, Metra M, Kamp O, et al. Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. Eur J Heart Fail. 2012;14(2):219-225.

18. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phospho-diesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268-1277.


How to diagnose heart failure with preserved ejection fraction

Thomas H. Marwick, MBBS, PhD, MPHBaker IDI Heart and Diabetes Research Institute, Melbourne, Australia

Correspondence: Dr Thomas Marwick, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia


AbstractThe current clinical and echocardiographic steps required for the recognition of heart failure with pre-served ejection fraction (HFpEF) have contributed to the heterogeneity of this diagnostic group. There are three clinical manifestations—acute pulmonary edema, and exertional dyspnea with and without raised filling pressure. Additional steps in the characterization of HFpEF might include documentation of impaired functional capacity, the use of alternative systolic function parameters including global longitudinal strain, and new markers of left ventricular filling pressure and diastolic dysfunction. The diastolic stress test—performed invasively or noninvasively—may be particularly valuable for improving the attribution of dyspnea to raised left ventricular filling pressure in patients with normal filling pressure at rest. L Heart Metab. 2016;71:9-13

Keywords: diagnosis; diastolic dysfunction; heart failure with preserved ejection fraction

Introduction

Heart failure with preserved ejection fraction (HFpEF) remains enigmatic. The combination of a clinical diagnosis of heart failure (itself

inexact) with a rather inexact imaging measurement has engendered a heterogeneous entity. The vari-ability of this disease goes some way to explain the failure of an effective therapeutic strategy.

Clinical diagnosis

Although the presence of diastolic dysfunction (DD) in the absence of clinical symptoms may represent stage B heart failure (SBHF; discussed below), the recognition of HFpEF begins with clinical symptoms. There are two presentations—acute and chronic. The

acute clinical presentation of diastolic heart failure involves a presentation of acute pulmonary edema in a patient with a normal-sized heart.1 If pulmonary edema resolves (or responds to therapy) within a short time interval, then HFpEF should be considered rather than other causes of pulmonary edema, such as myocardial ischemia and mitral valve disease.2 HFpEF patients presenting in this way tend to have hypertensive heart disease with increased left ven-tricular (LV) mass.3 However, such presentations are rare; probably around 5% of patients presenting with pulmonary edema have a preserved ejection fraction and remain stable after the presentation. The second mode of presentation that is often la-beled as HFpEF involves the patient with apparently normal systolic function who complains of exertion-al dyspnea. Few of these patients present with an

9

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acute episode of heart failure, and most have normal LV filling pressure at rest. They tend to be old, and have comorbidities that may also explain their symp-toms, most commonly pulmonary disease, obesity, anemia, and/or deconditioning.4 This is not a group well served by current definitions. An elderly patient presenting with exertional dyspnea and abnormal diastolic filling would have only one of the minor cri-teria for heart failure; so, according to this definition, patients in this situation should not be described as having heart failure. Indeed, there have been numer-ous efforts to create a specific definition for diastolic heart failure, which I now summarize: Standardized diagnosis.5 With standardized diag-nosis, three groups are possible: those with definite, probable, or possible heart failure. A diagnosis of defi-nite diastolic heart failure is based on proof of abnor-mal diastolic function upon left heart catheterization. Unfortunately, use of such a procedure is impractical for a community-based problem involving the elderly. Probable diastolic heart failure does not require left heart catheterization, but such diagnosis does require documentation of a normal ejection fraction within 72 hours of acute presentation. Possible diastolic heart failure requires a normal ejection fraction, although not at the time of the acute presentation. American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.6 These guidelines emphasize the shortcomings of a diagnosis of exclu-sion. They propose integration of clinical signs or symptoms of heart failure with evidence of preserved or normal LV ejection fraction (LVEF) and evidence of abnormal LV DD by Doppler echocardiography or cardiac catheterization, as proposed in the standard-ized diagnosis. European Diastolic Heart Failure Study group.7 This group’s definition of diastolic heart failure com-bines signs/symptoms of heart failure (exertional dys-pnea is admissible in the most recent update) with treatment response and either systolic dysfunction or echo Doppler criteria of diastolic abnormalities. How-ever, of 27% of patients with confirmed heart failure who had preserved systolic function and no valvular

heart disease, only 43% were confirmed as having diastolic heart failure using the initial European crite-ria. Whereas these findings may have been partly due to imperfect recognition of pseudonormal LV filling patterns and/or a delay in acquiring these data after admission, in many cases, they reflect a problem with the diagnosis of heart failure. Current European Society of Cardiology guide-lines.8 These guidelines emphasize the LV morphol-ogy associated with HFpEF (Table I), and they iden-

tify most as having DD. They propose a “midrange” group (ejection fraction of 40% to 49%) as being separate from HFpEF, which is a step further than the ACC/AHA guidelines’ recognition of this group as a subgroup of HFpEF.6

Standard echocardiography

As HFpEF is most commonly a concern among el-derly patients in the community, a widely available and noninvasive test is required for diagnosis, and echocardiography is generally the most suitable. The echocardiographic report involves three compo-nents—assessment of ejection fraction, estimation of filling pressure, and characterization of the stage of DD.

Ejection fraction

The estimation of ejection fraction is inexact. A num-ber of the problems of echocardiographic estimation of ejection fraction pertain to image quality, image orientation, and geometric assumptions, and these can be addressed by the use of echocardiographic

AbbreviationsBNP: B-type natriuretic peptide; DD: diastolic dysfunc-tion; HFpEF: heart failure with preserved ejection frac-tion; LV: left ventricular

LV morphology and other properties

Patients with HFpEF

Patients with HFrEF

Systolic dysfunction (other than EF)

+ ++

Diastolic dysfunction ++ ++

LV remodeling Concentric LVHConcentric remodeling

Eccentric remodeling

Aortic stiffness ++ +

Disturbances of LV relaxation or compliance

++ +

Table I Comparison of left ventricular morphology and other prop-erties among patients with heart failure and preserved or reduced ejection fraction. Abbreviations: EF, ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; LVH, left ventricular hypertrophy.

Marwick Heart Metab. (2016) 71:9-13Diagnosis of HFpEF

11

Heart Metab. (2016) 71:9-13 Marwick

Diagnosis of HFpEF

contrast agents and/or three-dimensional imaging.9 However, ejection fraction obtained by any modality is susceptible to changes related to altered loading conditions. A 10% test-retest variation in ejection fraction is common, implying that an ejection frac-tion of 45% today could be under 35% or over 55% tomorrow, possibly with no change in myocardial performance. It is therefore not clear if the “interme-diate” level of ejection fraction—between reduced and preserved—is a discreet group resulting from a true biologic variation or from variation in measure-ment.6,8

The entity of HFpEF has previously been inter-preted to imply normal systolic function, but this is untrue. There is a gradation in not only diastolic, but also systolic, tissue velocity in normal individuals, in those with HFpEF and in those with HFrEF. Several new parameters of systolic function, especially global longitudinal strain (GLS), appear to offer more robust measurement and greater prognostic value than ejec-tion fraction.10 It is disappointing that the guidelines remain focused on ejection fraction because GLS may be a preferable parameter.

Estimation of filling pressure

Although useful, the noninvasive evaluation of LV fill-ing pressure remains approximate. The most widely available marker of LV diastolic pressure is the ratio of the passive mitral filling wave and the tissue Doppler wave corresponding to LV relaxation (E/e’). Although this test forms one of the cornerstones of the dia-stolic function assessment guidelines,11 it should be recognized that it is not feasible to carry out in many common scenarios (eg, the presence of mitral annu-lar calcification)12 and is not particularly accurate.13

Diastolic dysfunction (DD)

The three major categories of DD—delayed relaxation (mild), and pseudonormal (moderate) and restrictive filling (severe)—have differing prognostic implications. In the Olmsted County study, moderate or severe DD was present in 5% to 6% of the population, although even in these subjects fewer than half had a diagnosis of heart failure. Nonetheless, both mild and moder-ate-to-severe DD predicted all-cause mortality over a subsequent follow-up of 5 years, even in the absence of clinical heart failure.14

Although DD is prognostically relevant, it is also extremely common, especially with advancing age. The reported prevalence of DD in the population has varied between 11% and 36% in studies in the United States, Europe, and Australia. This variation corresponds to differing ages of the studied popula-tions, as well as to different degrees of complexity of assessing transmitral flow. The Australian study examined the impact of age on transmitral flow: the prevalence of abnormal LV filling in the presence of normal ejection fraction varied from 1% to 4% in the 60-64–year age group, increasing to 10% or more in the over 80 age group.15 Thus, although DD is prog-nostically sinister, it is common with increasing age, and there is a risk of overdiagnosis of HFpEF, espe-cially if the symptoms attributed to heart failure are nonspecific.

Additional steps

The traditional approach to diagnosis of HFpEF is based upon symptoms, estimated ejection fraction, and diastolic evaluation, all of which seem inexact. Further categorization will produce a more homoge-neous diagnostic group (Figure 1).

Symptoms

As in other conditions, symptoms may be mislead-ing. Deconditioned individuals may express exercise intolerance in the presence of normal exercise ca-pacity, and conversely, symptoms may be trivialized in patients who are inactive. Some form of functional testing is useful in order to objectify impaired exercise capacity. Coronary artery disease remains common in the population, and significant disease may be associ-

Nonacute HFNormal �lling

pressure

Exclude unrecognizedcauses:

Ischemia Mitral valve disease

Atrial �brillation Renal artery stenosis Exclude coronary

disease Consider

comorbidities

Tissuecharacterization

Diastolic stress test

Nonacute HFRaised �lling

pressure

Exclude coronarydisease Consider

comorbidities

Additional veri�cation ofraised �lling pressure

Con�rm impairedfunctional status

Acute HF

Fig. 1 Additional steps that might facilitate the characterization of patients with preserved ejection fraction and acute or chronic dyspnea.Abbreviations: HF, heart failure.

12

Marwick Heart Metab. (2016) 71:9-13Diagnosis of HFpEF

ated with minimal or no angina. Atypical symptoms are most common in women, who are also prone to HFpEF. The exclusion of myocardial ischemia should be incorporated in the evaluation of HFpEF. Comorbidities are common in HFpEF. Pulmonary disease, renal impairment, and anemia should be checked for as they may be the primary source of symptoms. Although these diagnoses do not exclude the coexistence of HFpEF, it would seem prudent to exclude them from intervention trials.

Ejection fraction

The limitations of estimated ejection fraction have been discussed above. The results from evaluation of myocardial strain are often abnormal when ejection fraction is normal; perhaps this should form part of the diagnosis.

Diastolic function

Both the filling pressure and diastolic class compo-nents of the HFpEF diagnosis have limitations. More specific markers of raised filling pressure together with more accurate tissue characterization may assist in the recognition of HFpEF. The use of a myocardial deformation (eg, strain or strain-rate),16 rather than an annular, measurement (eg, e’) may improve diagnos-tic feasibility as it allows testing in patients with mitral annular calcification. Likewise, assessment of atrial strain may provide additional evidence about filling pressure.17 As discussed above, presentation of the HFpEF patient with pulmonary edema is uncommon and poses much less of a diagnostic challenge than the dyspneic patient with a small heart. In this setting, DD provides increased resistance to filling of the left ven-tricle under conditions of increased flow, leading to an inappropriate rise in the diastolic pressure-volume relationship and causing symptoms of pulmonary congestion during exercise. Provocative testing in this situation potentially distinguishes the HFpEF patient from one with “bystander” mild DD and nonspecific symptoms. The value of measuring the B-type natriuretic pep-tide (BNP) level in this situation is questionable. The patients most likely to have elevated BNP levels are those with elevated LV filling pressure or a pseudo-normal filling pattern, who do not pose the greatest

diagnostic challenge. Nonetheless, about one-third of HFpEF patients do not have elevated BNP levels,18 and this is associated with obesity. For those without elevated filling pressure, resting BNP is usually nor-mal, but exercise intolerance related to increased LV filling pressure in response to exercise might be iden-tifiable from the BNP response to stress.19

Other testing

Tissue characterization using cardiac magnetic reso-nance imaging may help to distinguish patients ac-cording to their underlying disease. Such a process may help us to move away from the heterogeneity of the HFpEF construct and to instead characterize pa-tients according to the contributions of disturbances in myocardial relaxation, interstitial fibrosis, chrono-tropic incompetence, increased pulmonary vascular resistance, and right ventricular dysfunction.20

Conclusion

What used to be labeled as “diastolic heart failure” in elderly dyspneic patients was in many cases neither diastolic nor heart failure. DD is common with increas-ing age, which is associated with exercise intolerance and adverse outcome. However, its confusion with heart failure has led to mislabeling, inappropriate ex-pectations about its epidemiology and outcome, and the obscuring of underlying treatable etiologies. The additional testing for functional capacity, comorbid-ity, and diastolic responses to exercise, and the intro-duction of new measures to characterize myocardial function may reduce the heterogeneity of the diastolic heart failure diagnosis. L

REFERENCES

1. Dodek A, Kassebaum DG, Bristow JD. Pulmonary edema in coronary-artery disease without cardiomegaly. Paradox of the stiff heart. N Engl J Med. 1972;286:1347-1350.

2. Rimoldi SF, Yuzefpolskaya M, Allemann Y, Messerli F. Flash pul-monary edema. Prog Cardiovasc Dis. 2009;52:249-259.

3. Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med. 2001;344:17-22.

4. Fukuta HL, Little WC. Diastolic heart failure: general principles, clinical definition, and epidemiology. In: Klein AL, Garcia MJ, eds. Diastolic Heart Failure. Burlington, UK: Elsevier; 2007.

5. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation. 2000;101:2118-2121.

6. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation, American Heart Association Task

13

Heart Metab. (2016) 71:9-13 Marwick

Diagnosis of HFpEF

Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Associa-tion Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147-e239.

7. European Study Group on Diastolic Heart Failure. How to diag-nose diastolic heart failure. Eur Heart J. 1998;19:990-1003.

8. Ponikowski P, Voors AA, Anker SD, et al; Authors/Task Force Members; Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;18(8):891-975.

9. Jenkins C, Moir S, Chan J, Rakhit D, Haluska B, Marwick TH. Left ventricular volume measurement with echocardiography: a comparison of left ventricular opacification, three-dimension-al echocardiography, or both with magnetic resonance imag-ing. Eur Heart J. 2009;30:98-106.

10. Kalam K, Otahal P, Marwick TH. Prognostic implications of global LV dysfunction: a systematic review and meta-anal-ysis of global longitudinal strain and ejection fraction. Heart. 2014;100:1673-1680.

11. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommenda-tions for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardio-vascular Imaging. J Am Soc Echocardiogr. 2016;29:277-314.

12. Park JH, Marwick TH. Use and limitations of E/e’ to assess left ventricular filling pressure by echocardiography. J Cardiovasc Ultrasound. 2011;19:169-173.

13. Sharifov OF, Schiros CG, Aban I, Denney TS, Gupta H. Di-

agnostic accuracy of tissue doppler index E/e’ for evaluating left ventricular filling pressure and diastolic dysfunction/heart failure with preserved ejection fraction: a systematic review and meta-analysis. J Am Heart Assoc. 2016;5(1). doi:10.1161/JAHA.115.002530.

14. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bai-ley KR, Rodeheffer RJ. Burden of systolic and diastolic ven-tricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003;289:194-202.

15. Abhayaratna WP, Marwick TH, Smith WT, Becker NG. Charac-teristics of left ventricular diastolic dysfunction in the commu-nity: an echocardiographic survey. Heart. 2006;92:1259-1264.

16. Wang J, Khoury DS, Thohan V, Torre-Amione G, Nagueh SF. Global diastolic strain rate for the assessment of left ventricular relaxation and filling pressures. Circulation. 2007;115:1376-1383.

17. Cameli M, Mandoli GE, Loiacono F, Dini FL, Henein M, Mon-dillo S. Left atrial strain: a new parameter for assessment of left ventricular filling pressure. Heart Fail Rev. 2016;21:65-76.

18. Anjan VY, Loftus TM, Burke MA, et al. Prevalence, clinical phenotype, and outcomes associated with normal B-type na-triuretic peptide levels in heart failure with preserved ejection fraction. Am J Cardiol. 2012;110:870-876.

19. Mottram PM, Haluska BA, Marwick TH. Response of B-type natriuretic peptide to exercise in hypertensive patients with sus-pected diastolic heart failure: correlation with cardiac function, hemodynamics, and workload. Am Heart J. 2004;148:365-370.

20. Shah SJ, Katz DH, Selvaraj S, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131:269-279.

14

Introduction

The treatment of heart failure remains one of the “wild” frontiers of cardiology, where prevalence, morbidity, and mortality are all still sufficiently

high to drive academic and commercial investment. This attraction persists despite the very many suc-cessful trials in heart failure with reduced ejection frac-tion (HFrEF), which have clearly shown the benefit of angiotensin-converting enzyme inhibitors, 1-adreno-ceptor blockers, mineralocorticoid receptor antago-nists, cardiac resynchronization therapy (biventricular pacemakers), implantable cardioverter-defibrillators, and most recently, angiotensin-receptor blockers combined with neprilysin inhibitors. Furthermore, these drugs/devices seem to work irrespective of

the etiological cause of HFrEF (ischemic vs other). Many of these same therapies have been tested in studies of similar design in heart failure with preserved ejection fraction (HFpEF), but without success. The question is why?

Selection based on left ventricular ejection fraction

Heart failure is a nebulous syndrome with nonspecif-ic symptoms (fatigue, breathlessness, ankle edema) and signs that lack diagnostic sensitivity (elevated jugular venous pressure, lung crackles, third heart sound). For this reason, the clinical suspicion needs to be supported by investigations that have high sensitivity and specificity. The attraction of measur-ing left ventricular ejection fraction (LVEF) to aid di-

Treatment of HFpEF: why we have no evidence

Michael Marber, PhDBHF Center of Research Excellence, Cardiovascular Division, The Rayne Institute, St Thomas’ Hospital,

London, UK

Correspondence: Michael Marber, BHF Center of Research Excellence, Cardiovascular Division, The Rayne Institute, St Thomas’ Hospital, London, SE1 7EH, UK


AbstractThe treatment of heart failure with reduced ejection fraction (HFrEF) is relatively straightforward, with guidelines from the European Society of Cardiology (ESC) and the American Heart Association (AHA)/American College of Cardiology providing numerous class 1 recommendations, supported by evidence at level A. In stark contrast, the same guidelines do not offer a single recommendation with level A evidence for management of heart failure with preserved ejection fraction (HFpEF). This difference is due to a failure of clinical trials to provide a reliable evidence base in HFpEF, for complex and multifactorial reasons. This review highlights how uncertainties surrounding the importance of left ventricular ejection fraction, the mechanisms driving HFpEF, and the burden of comorbidities have probably frustrated efforts thus far. L Heart Metab. 2016;71:14-17

Keywords: HFpEF; left ventricular ejection fraction


15


Treatment of HFpEF: why no evidence?

agnosis is that values are easily obtained by echo-cardiography and, although prone to measurement error, when LVEF is below 40% it is very probable that left ventricular dysfunction is the cause for the patient’s symptoms. Furthermore, if doubt remains, measurement of circulating N-terminal pro–B-type natriuretic peptide (NT-proBNP) provides further di-agnostic power. These simple investigations provide a stable foundation on which to make a diagnosis of HFrEF and have been the basis of enrolment into successful clinical trials. In contrast, these powerful diagnostic filters are not available in HFpEF because, by definition, LVEF is above 40% (see below) and NT-proBNP is often not markedly elevated. Conse-quently, there is a real danger of labeling nebulous syndromes, in which the heart may not drive symp-toms or events, as HFpEF. Furthermore, very large registries suggest that the power of LVEF to predict both total mortality and cardiovascular events is lost once it exceeds 40%,1 intimating a biological boundary above which cardio-vascular interventions may struggle to reduce risk, as excess risk doesn’t exist! Thus, trials in HFrEF have used an LVEF of 40% as the selection cutoff, below which exists a clear inverse risk gradient between LVEF and events.1

The exact LVEF cutoff value to distinguish be-tween HFpEF and HFrEF in an individual with heart failure symptoms is controversial and has varied between trials from 40% (and greater) to 50% (and greater).2 Those with an LVEF between 40% and 50% lie in a so-called gray zone between definite HFrEF and definite HFpEF. This gray zone is likely

to encompass varied pathologies, including indi-viduals that at some point had an LVEF under 40% that has improved/recovered. Thus, one would ex-pect interventions of proven value in HFrEF to show their greatest chance of success in trials recruiting HFpEF patients within this gray zone (trial selection criterion LVEF>40% or >45%). However, despite in-cluding patients in the gray zone, well-established HFrEF therapies have failed to have an impact on HFpEF (eg, spironolactone in TOPCAT [Treatment Of Preserved Cardiac function heart failure with an Aldosterone antagonist Trial], carvedilol in J-DHF [Japanese Diastolic Heart Failure Study], candesar-tan in CHARM-PRESERVED [Effects of Candesartan in Patients With Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction], and perindopril in PEP-CHF [Perindopril in Elderly People with Chronic Heart Failure]). These failures have occurred despite additional selection criteria designed to include pa-tients at increased risk, such as recent hospitaliza-tion with a diagnosis of heart failure. Even when such additional selection criteria are used, the nebu-lous nature of HFpEF means that trials still enroll pa-tients with poorly defined syndromes and, therefore, the study population encompasses a broad range of cardiovascular risk. This is very well illustrated by TOPCAT, where despite identical selection criteria (LVEF>45% and recent hospital admission due to “heart failure”) there was a four-fold higher event rate in patients enrolled in the Americas versus those en-rolled in Russia and Georgia.3 A possible solution to ensure that those with an LVEF above 40% really have HFpEF is to measure left atrial filling pressure (LAP). By definition, this is abnor-mally elevated in left heart failure of any cause. The difficulty is that invasive hemodynamic measurements are inappropriate for the vast majority of patients with suspected HFpEF because of their age and mul-tiple comorbidities (see below). In addition, because symptoms occur on exertion, ideally, LAP should be acquired during exercise. Thus, invasively acquired LAP should aid HFpEF diagnosis and guide enrol-ment into clinical trials. However, in practice, data are difficult to interpret. For example, asymptomatic el-derly patients frequently have a mean LAP above 20 mm Hg on exercise.4 What is needed, therefore, is a widely accepted gold standard noninvasive measure of an elevated LAP. Unfortunately, at present, no such measure exists (see Omar et al5 for recent review).

AbbreviationsCHARM-PRESERVED: Effects of Candesartan in Pa-tients With Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; J-DHF: Japanese Diastolic Heart Failure Study; LAP: left atrial filling pressure; LVEF: left ventricular ejection fraction; MAGGIC: Meta-Analysis Global Group In Chronic heart failure; NT-proBNP: N-terminal pro–B-type natriuretic peptide; PEP-CHF: Perindopril in Elderly People with Chronic Heart Failure; TOPCAT: Treatment Of Preserved Car-diac function heart failure with an Aldosterone an-tagonist Trial

16

Marber Heart Metab. (2016) 71:14-17Treatment of HFpEF: why no evidence?

Identifying the mechanism(s) driving HFpEF

One possible reason why therapies in HFpEF have failed is that the relatively crude way in which trials have selected patients (see above) means that the “net has been cast too wide” and that we have in-advertently captured a number of different diseases. This seems extremely probable because the comor-bidities (see Figure 1) associated with HFpEF are un-

likely to mediate damage through a single common pathway. Fundamentally, HFpEF is caused by a left ventricle that fails to relax normally in diastole. This can result from abnormalities within and/or outside cardiac myocytes. Within cardiac myocytes, active relaxation requires the actin and myosin cross-bridges to detach and this in turn needs cytosolic calcium concentrations to fall, adenosine triphosphate (ATP) concentration to be high, and adenosine diphosphate (ADP) concentra-

tion to be low. Calcium and energy balance are in turn influenced by the availability of metabolic substrates, pH, and mitochondrial energetics, all of which have been reported as being perturbed in HFpEF through a variety of mechanisms. Similarly, passive relax-ation needs the cytoskeletal structures that are com-pressed during systole to quickly decompress/relax in diastole. Abnormalities in passive relaxation have been ascribed to changes in titin isoforms and/or its phosphorylation state. These processes are in turn regulated by upstream signaling cascades, including kinases such as protein kinase G (PKG), which have also been shown to be disordered in HFpEF (as de-picted in Figure 1). Abnormalities outside cardiac myocytes have also been associated with the ventricular stiffening caus-ing HFpEF. These changes include the collagen sub-types that make up the extracellular matrix, as well as abnormal cross-linking between collagen fibers. Once again, these processes are controlled by up-stream signals that control fibroblast and inflamma-tory cell activity. Finally, abnormalities outside the heart have been shown to contribute to HFpEF. These include ab-normal coupling between the left ventricle and sys-temic arteries, deconditioning of skeletal muscle, and changes in heart rate associated with atrial fibrillation and chronotropic incompetence. In summary, the processes responsible for cardi-ac relaxation are complex and intertwined. Generally, their individual contributions to HFpEF in a particular patient are not assessed before a treatment is start-ed. Instead, “a one-size-fits-all” approach has been taken to HFpEF treatment. In the absence of person-alized therapy, one could argue that the clinical trials conducted to date are equivalent to treating all forms of anemia with vitamin B12!

The problem of comorbiditiesIt’s unusual for HFpEF to occur in isolation, and com-monly there are antecedent risk/causative factors (eg, diabetes, hypertension, renal disease) and other coin-cident conditions that may also aggravate symptoms (eg, obesity, lung disease, skeletal muscle decon-ditioning) (see Figure 1). Furthermore, HFpEF patients are older than those with HFrEF, and normal aging is associated with decrements in cardiac, skeletal, and respiratory performance that are difficult to dissociate from the HFpEF phenotype. So much so, that some

Collagen subtypes

Collagen Xlinks

Chronotropicincompetence

Ventricular-vascular coupling

Vascular stiffening

Dynamic mitral regurgitation

Concentric hypertrophy

Capillary rarefaction

Atrial�brillation

Obstructive sleep apnea

Obstructive pulmonary disease

Diabetes

Renal impairment

Oxidative stress

Aging

Obesity

In�ammation

Hypertension

Coronary artery

disease

Sarcopenia

Anemia

Iron de�ciency

Deconditioning

Depression

De�cient NO

[ATP]:[ADP] Sarcomeric

PTMs PKG/PKA/p38 PKC/CAMK

Titin isoforms

Titin Phos

Diastolic Ca2+

Fig. 1 The complexity of heart failure with preserved ejection fraction (HFpEF). The figure depicts the processes that have been implicated in either causing HFpEF or coexisting with HFpEF and aggravating the symptom of exertional breathlessness. At the cen-ter are processes within the cardiac myocyte responsible for active (uppermost) or passive (lowermost) relaxation. Bounded by the innermost red circle are other myocardial abnormalities implicated in HFpEF that lie outside cardiac myocytes. The gray circle and text include cardiovascular pathologies that are thought to contribute to HFpEF but lie outside the myocardium. Finally, the outermost blue circle and text includes systemic changes that are thought to influence HFpEF.Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ca2+, calcium; CAMK, calcium and calmodulin-regulated kinase; NO, nitric oxide; P38, p38 mitogen-activated protein kinase; Phos, phosphorylation; PK, protein kinase; PTMs, posttranslational modifications; Xlinks, cross-links.

17


Treatment of HFpEF: why no evidence?

have likened HFpEF to “presbycardia.” The difficulty with the comorbidities is that they are in themselves major predictors of mortality and are unlikely to be modified by the drugs used to treat heart failure. For example, in the MAGGIC meta-registry (Meta-Analysis Global Group In Chronic heart failure), which included almost 40 000 patients with heart failure (HFpEF and HFrEF) and 16 000 deaths, the top five predictors of mortality were age, lower EF (below 40%), New York Heart Association class, serum creatinine level, and diabetes.1 The predictive effect of age was even more pronounced in those with HFpEF than with HFrEF; but, unfortunately, age is not modifiable! In common with the discussion above on the mechanisms driving HFpEF, the multiple comorbidi-ties suggest it comprises more than one disease. In an attempt to dissect out these diseases, math-ematical algorithms were applied to a cohort of ex-tremely well-phenotyped HFpEF patients in whom 67 variables were recorded.6 The result of this unbiased analysis suggested that certain characteristics tend to cosegregate more frequently than expected by chance. Features clustered into three distinct groups (phenogroups) between which existed significant dif-ferences in age and sex and prevalence of diabetes, hypertension, obesity, kidney disease, obstructive sleep apnea, and atrial fibrillation.6 Although this seg-regation does not touch on the underlying mecha-nism, it may allow the recruitment of more homoge-neous patient groups into future clinical trials.

Conclusion

In conclusion, it is probable that the heterogeneous nature of the patient population with HFpEF together with the high burden of life-limiting, but noncardiac, comorbidities have frustrated clinical trials to date and diminished their chance of success. These limitations can only be overcome through a more detailed un-derstanding of this diverse condition and more careful selection of patients to ensure they share a dominant underlying pathology that can be altered by the study intervention. L

REFERENCES

1. Pocock SJ, Ariti CA, McMurray JJ, et al; Meta-Analysis Global Group in Chronic Heart Failure. Predicting survival in heart fail-ure: a risk score based on 39 372 patients from 30 studies. Eur Heart J. 2013;34:1404-1413.

2. Kelly JP, Mentz RJ, Mebazaa A, et al. Patient selection in heart failure with preserved ejection fraction clinical trials. J Am Coll Cardiol. 2015;65:1668-1682.

3. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation. 2015;131:34-42.

4. Wright SP, Esfandiari S, Gray T, et al. The pulmonary artery wedge pressure response to sustained exercise is time-variant in healthy adults. Heart. 2016;102:438-443.

5. Omar AM, Bansal M, Sengupta PP. Advances in echocardio-graphic imaging in heart failure with reduced and preserved ejection fraction. Circ Res. 2016;119:357-374.

6. Shah SJ, Katz DH, Selvaraj S, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131:269-279.

18


Introduction

The management of heart failure with reduced systolic function (also known as heart failure with reduced ejection fraction [HFrEF]) has

progressed over the last few decades with the abil-ity to dramatically enhance life span by treatment with angiotensin-converting enzyme (ACE) inhibi-tors, β-blockade, and mineralocorticoid receptor antagonists. However, in heart failure where ejection fraction is preserved (called HFpEF), mortality rates have remained static, and management has relied on symptomatic treatment, with no prognostic therapies available despite numerous trials.1 This is largely because HFpEF represents an amalgam of

different underlying etiologies, and we are currently unable to accurately stratify the disease according to underlying mechanism. In turn, this limits the scope for innovation of targeted therapies that reduce the considerable morbidity and mortality associated with this condition. Increased interstitial myocardial fibrosis is thought to be a major determinant of the reduced myocardial compliance that characterizes HFpEF. Until recent-ly, cardiac imaging methods have not been able to quantify fibrosis and have been limited to downstream measures of remodeling and ventricular dysfunction.2 Quantification of myocardial fibrosis may provide im-portant prognostic information in HFpEF and permit disease stratification to guide therapy.

Imaging fibrosis in heart failure with preserved ejection fraction

Anish N. Bhuva, MRCP1,2; Rebecca Schofield, MRCP2; R. Tom Lumbers, PhD1,2; Charlotte H. Manisty, PhD1,2; James C. Moon, MD1,2

1Institute of Cardiovascular Science, University College London, London, UK, WC1E 6BT2Barts Heart Center, St Bartholomew’s Hospital, West Smithfield, London, UK, EC1A 7BE

Correspondence: Professor James Moon, Barts Heart Center, St Bartholomew’s Hospital, West Smithfield, London, UK, EC1A 7BE


AbstractIncreased myocardial fibrosis is considered to be a key underlying pathological mechanism in heart failure with preserved ejection fraction (HFpEF), with increased myocardial stiffness resulting in left ventricular dysfunction. Direct measurement of fibrosis via histology is not feasible; however, noninvasive imaging approaches now offer the potential for quantification. Improved fibrosis assessment in HFpEF should facilitate earlier disease detection, targeted treatment, and improved prognostication. This review high-lights the importance of fibrosis in HFpEF and introduces the various contemporary multimodality imaging technologies available for quantification. We focus on T1 mapping and extracellular volume quantification by cardiac magnetic resonance imaging and outline the current evidence and potential future applica-tions. L Heart Metab. 2016;71:18-22

Keywords: HFpEF; myocardial fibrosis; T1 mapping

19

Heart Metab. (2016) 71:18-22 bhuva and others


Patterns of fibrosis in disease and imaging correlates

Myocardial fibrosis can be reparative or reactive. Both lead to increasing stiffness and ultimately to ventricular dysfunction. There are different patterns of fibrosis, dependent on the underlying disease pa-thology, but in all there is extracellular matrix (ECM) remodeling with excess collagen (predominantly types I and III). Focal replacement fibrosis is pres-ent in myocardial infarction and many other non-ischemic pathologies and correlates with clinical outcome. In contrast, with HFpEF, changes occur in the ECM due to a number of different metabolic and hemodynamic factors, including hypertension, dia-betes, and renal failure,3 leading to reactive diffuse interstitial fibrosis.4 Endomyocardial biopsy is the gold standard for as-sessing fibrosis; however, it is prone to sampling er-ror and because it is invasive, is rarely performed. Al-though interstitial fibrosis is reversible5 and a key target for several current and pending therapies,6 its diffuse nature makes it hard to identify noninvasively. There-fore, until recently, diagnosis of fibrosis in HFpEF relied on assessing the functional consequences.

Functional imaging for evidence of fibrosis in HFpEF

Increased mass and chamber geometry is a common structural abnormality of the heart in HFpEF, and sen-sitivity has improved from M-mode, two-dimensional, and now three-dimensional technology (which appre-ciates regional changes). Mitral valve blood flow as-sessed by Doppler echocardiography, combined with pulmonary vein assessment and left atrial size, is ab-normal in virtually all patients with HFpEF and relative-ly easily measured. Tissue velocities (tissue Doppler) help in borderline patients, and new parameters such as strain imaging or speckle tracking have potential use as a more reproducible measure, independent of tethering and translational cardiac motion.7

Studies suggest that diastolic dysfunction due to hy-pertension and left ventricular hypertrophy may be reversible with treatment,8 yet these findings have not been replicated more generally in clinical HFpEF. Fur-thermore, echocardiographic measures of diastolic function are often observed in patients without heart failure and are variable within each individual, being influenced dynamically by other physiological factors, such as loading conditions. In part, this is because functional measurements only capture the down-stream effects of fibrosis. Techniques have been developed to directly image the pathways of collagen metabolism and regulation, such as radiolabeled losartan, matrix metalloprotein-ases in animal models, and collagen-specific contrast agents.9–11 Such technology shows promise in animal models and after myocardial infarction but has not been translated into clinical practice. Therefore, the current functional biomarkers need to be supported by imaging methods for tissue characterization in or-der to detect and quantify fibrosis.

Noninvasive methods for quantitative assessment of myocardial fibrosis

Echocardiography: integrated backscatter

Ultrasonographic tissue characterization uses fre-quency-dependent attenuation and dispersion as a correlate of fibrosis, known as “integrated backscat-ter” (IBS). Validation work has been performed both against histology and serological markers of fibrosis,12 and the technique has been shown to differentiate controls from patients with muscular dystrophy and scleroderma, and it correlates with myocardial biopsy in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).13 Yet larger studies are elu-sive, and the technique appears unreliable despite early promise,14 with limitations by acoustic windows and influences from other factors such as angiogen-esis.

Nuclear medicine: perfusable tissue index

The perfusable tissue index (PTI) offers a way to as-sess fibrosis by evaluating the ratio of perfusable to total tissue using radioisotope tracers imaged with positron emission tomography.15 It correlates with

AbbreviationsECM: extracellular matrix; ECV: extracellular volume; GBCA: gadolinium-based contrast agent; HFpEF: heart failure with preserved ejection fraction

cardiovascular magnetic resonance (CMR) tissue tag-ging suggesting an association with fibrosis, though more recent work has concentrated on viability as-sessment.16

Cardiovascular magnetic resonance imaging: T1 mapping and extracellular volume quantification

Gadolinium-based contrast agents (GBCA) are ex-tracellular contrast agents that passively persist in infarcted tissue and have been used extensively to image scar tissue. Such tissue can be imaged using the late gadolinium enhancement (LGE) technique, with normal myocardium artificially “nulled” to ap-pear black by operator manipulation of the magnetic resonance sequence. The utility of LGE imaging is limited in HFpEF both because of the global nature of the pathology and the fact that the degree of fibro-sis is generally below the limits of detection for the technique. T1 mapping may help. T1 (longitudinal relaxation time, expressed in milliseconds) and also T2 (“true” transverse relaxation time) and T2* (“ob-served” T2) are magnetic properties of tissue. These change with pathology, and of these, mapping of T1 is the most promising. These relaxation times can be calculated on a voxel by voxel basis and represented on a clinically intuitive color map. There are a num-ber of different sequences that vary inversion pulses and readout timings, originating from modified Look-Locker inversion recovery (MOLLI).17 Each sequence has variable precision, repeatability, and theoretical accuracy, as well as varying tradeoffs in breath-hold duration and resolution. Attempts to standardize T1 mapping techniques are ongoing and important for widespread uptake.18,19

As GBCA does not pass through intact cell mem-branes, it provides a way to dichotomize the intra- and extracellular myocardium using T1 mapping. This therefore provides promise for application in HFpEF where fibrosis accumulates in the ECM, meaning that there will be GBCA accumulation and shortening of T1. Comparing T1 values before and after introduc-tion of GBCA negates some of the issues of repro-ducibility and standardization, as it is the change in T1 values, rather than absolute value, that is measured. The extracellular volume (ECV) fraction can then be calculated by correcting for the volume of distribution through hematocrit sampling, thus reflecting changes in the ECM. It can now be performed without blood

testing (blood T1 approximates hematocrit) and cal-culated on the scanner itself, significantly simplifying the technique.

ECV and post-contrast T1 both have potential ap-plication in HFpEF. ECV expansion correlates with both invasive and noninvasive measures of diastolic function and filling pressures20–24 and directly tracks changes that result in a noncompliant heart.25 More-over, it predicts outcome in HFpEF and correlates with ECM on histology.26 Kammerlander et al27 found that in 473 patients (246 with HFpEF), ECV predicted prognosis the most strongly of all imaging biomark-ers and remained in multivariate models when com-bined with clinical variables (unlike ejection fraction or B-type natriuretic peptide [BNP]). Before widespread application in HFpEF, these techniques need to be demonstrated to robustly track disease in clinical tri-als; many are currently in progress (see Table I).

Fibrosis quality or quantity?

In early disease, T1 mapping could be useful for risk stratification and to direct therapy. However, the road is not without difficulty. Differences between normal and abnormal tissue can be small,28 and therefore fibrosis detection may be limited by precision and overlap between healthy and patient populations. Moreover, the quality rather than the quantity of ECM change per se may be important. Collagen cross-linking has recently been shown to have an important role in determining left ventricular stiffness,29 as do other structural proteins such as titin.30 In the context of HFpEF though, T1 mapping has an additional role in identifying rare causes of HFpEF due to infiltrative disease. Gross expansion of the extracellular space in amyloidosis is readily detected (high pre-contrast T1), as is intracellular accumulation of iron (hemochromatosis) or glycosphingolipid (Ander-son-Fabry disease) deposition, both causing low T1. As ECV also permits analysis of myocyte volume, a low ECV may also distinguish adaptive from maladaptive pathology in athletes who have myocyte hypertrophy.31

Cardiac amyloidosis

Senile wild-type transthyretin amyloidosis (wtATTR) is underrecognized in HFpEF. One HFpEF autopsy study showed moderate or severe infiltration in 5%

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Heart Metab. (2016) 71:18-22 bhuva and others


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of patients and mild infiltration in 12%.32 wtATTR de-mands recognition as a different disease with poor prognosis but potential new treatment options.33 It shares a common pathway in diastolic dysfunction with HFpEF; however, relatively speaking, there is massive ECM expansion due to amyloid fibril deposi-tion (rather than fibrosis). This is easily picked up both by pre-contrast T1 mapping and ECV; the latter is el-evated up to 45% in amyloid versus 25% in control populations (only a few percent higher in diffuse fibro-sis). Importantly, occult amyloid may be a disease in a broader elderly population than HFpEF, and when present, it appears to drive outcomes in aortic steno-sis more than valve stenosis itself.34

Conclusion

Preventing or reversing interstitial fibrosis is a thera-peutic target in HFpEF; however, accurate and re-producible noninvasive methods for detection and quantification are needed. Imaging offers a potential solution, with both functional and quantitative tech-niques available; T1 mapping and ECV quantifica-tion using cardiac magnetic resonance imaging are currently the most promising. Incorporating these markers into clinical trials may be a necessary step in development of better therapies and ultimately in pro-viding pathophysiology-based disease stratification in this population. L

Trial Abbreviated trial names

Identifier Number Primary end point Secondary end point

Renal Denervation in Heart Failure Patients With Preserved Ejection Fraction

RESPECT-HF NCT02041130 144 Changes in left atrial volume index; left ven-tricular mass index on CMR imaging

The biomarkers of car-diac interstitial fibrosis as assessed by plasma assays, imaging mar-kers of cardiac fibrosis

Left Ventricular Stiffness vs Fibrosis Quantification by T1 Mapping in Heart Failure with Preserved Ejection Fraction

STIFFMAP NCT02459626 36 Correlation of extracel-lular volume [MRI] and myocardial stiffness [p-v-loops)

n/a

Understanding and Treating Heart Failure With Preser-ved Ejection Fraction: Novel Mechanisms. Diagnostics and Potential Therapeutics

Alberta HEART NCT02052804 700 Percent of patients meeting new diagnostic criteria for HFpEF

CMR markers: ECV, T2mapping phase contrast, taggingBiomarker analysis of the extracellular matrix

Women’s lschemia Study Evaluation

WISE NCT02582021 220 Cardiovascular events Blood proteomic bio-markers of extracellular matrix remodeling and fibrosis; Exercise CMR; LGE

New Echocardiographic Parameters for Assessment of Longitudinal Left Ventricular Function

LAX study NCT01275963 160 Left ventricular longitu-dinal systolic strain (LV-LSS] in all patients

n/a

Noninvasive Evaluation of Myocardial Stiffness by Elasto-graphy

Elasto-Cardio NCT02537041 100 Myocardial stiffness (by kPa) via novel device

n/a

Myocardial Perfusion, Oxidative Metabolism, and Fibrosis in HFpEF

HFpEF-PRoF NCT02589977 60 Myocardial blood flow by CMR and PET; ECV

n/a

Assessment of Efficacy of Mira-begron, a New beta3-adrener-gic Receptor in the Prevention of Heart Failure

Beta3_LVH NCT02599480 297 Echo change in left ventricular mass and diastolic function

Cardiac fibrosis by CMR;Galectin,GDF15

Myocardial Performance at Rest and During Exercise in Heart Failure With Preserved Ejection Fraction

X-HF-SPECKLE NCT01747785 21 Rest and stress strain, strain rate and torsion (two-dimensional echo]

n/a

Table I Currently recruiting HFpEF trials that use interstitial fibrosis biomarkers as end points. Abbreviations: CMR, cardiac magnetic resonance; ECV, extracellular volume; GDF15, growth differentiation factor 15; HFpEF, heart failure with preserved ejec-tion fraction; kPa, kilopascal; LGE, late gadolinium enhancement; MRI, magnetic resonance imaging; n/a, not applicable; PET, positron emission tomography.

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bhuva and others Heart Metab. (2016) 71:18-22Imaging fibrosis in heart failure with preserved ejection fraction

REFERENCES

1. Tribouilloy C, Rusinaru D, Mahjoub H, et al. Prognosis of heart failure with preserved ejection fraction: a 5 year prospective population-based study. Eur Heart J. 2008;29(3):339-347.

2. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Com-mittee for Practice Guidelines. ESC Guidelines for the dia-gnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardio-logy. Developed in collaboration with the Heart Failure Associa-tion (HFA) of the ESC. Eur Heart J. 2012;33(14):1787-1847.

3. López B, González A, Querejeta R, Larman M, Díez J. Altera-tions in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol. 2006;48(1):89-96.

4. Weber KT, Brilla CG. Pathological hypertrophy and cardiac in-terstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation. 1991;83(6):1849-1865.

5. Treibel TA, Fontana M, Kozor R, et al. Diffuse myocardial fibrosis - a therapeutic target? Proof of regression at 1-year following aortic valve replacement: the RELIEF-AS study. J Cardiovasc Magn Reson. 2016;18(suppl 1):O37. doi:10.1186/1532-429X-18-S1-O37.

6. Schelbert EB, Fonarow GC, Bonow RO, Butler J, Gheorghiade M. Therapeutic targets in heart failure: refocusing on the myo-cardial interstitium. J Am Coll Cardiol. 2014;63(21):2188-2198.

7. Paulus WJ, Tschöpe C, Sanderson JE, et al. How to diag-nose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Asso-ciations of the European Society of Cardiology. Eur Heart J. 2007;28(20):2539-2550.

8. Díez J, Querejeta R, López B, González A, Larman M, Martínez Ubago JL. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation. 2002;105(21):2512-2517.

9. Sahul ZH, Mukherjee R, Song J, et al. Targeted imaging of the spatial and temporal variation of matrix metalloproteinase activity in a porcine model of postinfarct remodeling: relation-ship to myocardial dysfunction. Circ Cardiovasc Imaging. 2011;4(4):381-391.

10. Verjans JW, Lovhaug D, Narula N, et al. Noninvasive imaging of angiotensin receptors after myocardial infarction. JACC Car-diovasc Imaging. 2008;1(3):354-362.

11. Helm PA, Caravan P, French BA, et al. Postinfarction myocardial scarring in mice: molecular MR imaging with use of a collagen-targeting contrast agent. Radiology. 2008;247(3):788-796.

12. Kosmala W, Przewlocka-Kosmala M, Wojnalowicz A, Mysiak A, Marwick TH. Integrated backscatter as a fibrosis marker in the metabolic syndrome: association with biochemical evi-dence of fibrosis and left ventricular dysfunction. Eur Heart J Cardiovasc Imaging. 2012;13(6):459-467.

13. Fujimoto S, Mizuno R, Nakagawa Y, et al. Ultrasonic tissue characterization in patients with dilated cardiomyopathy: com-parison with findings from right ventricular endomyocardial bi-opsy. Int J Card Imaging. 1999;15(5):391-396.

14. Prior DL, Somaratne JB, Jenkins AJ, et al. Calibrated integrat-ed backscatter and myocardial fibrosis in patients undergoing cardiac surgery. Open Heart. 2015;2(1):e000278.

15. Knaapen P, Boellaard R, Götte MJ, et al. Perfusable tissue in-dex as a potential marker of fibrosis in patients with idiopathic dilated cardiomyopathy. J Nucl Med. 2004;45(8):1299-1304.

16. Timmer SA, Teunissen PF, Danad I, et al. In vivo assessment of myocardial viability after acute myocardial infarction: a head-to-head comparison of the perfusable tissue index by PET and delayed contrast-enhanced CMR. J Nucl Cardiol. 2016 Feb 2. Epub ahead of print. doi:10.1007/s12350-015-0329-7.

17. Messroghli DR, Radjenovic A, Kozerke S, Higgins DM, Sivana-nthan MU, Ridgway JP. Modified Look-Locker inversion recov-ery (MOLLI) for high-resolution T1 mapping of the heart. Magn Reson Med. 2004;52(1):141-146.

18. Moon JC, Messroghli DR, Kellman P, et al. Myocardial T1 map-ping and extracellular volume quantification: a Society for Car-diovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus state-ment. J Cardiovasc Magn Reson. 2013;15:92.

19. Captur G, Gatehouse P, Kellman P, et al. A T1 and ECV phan-tom for global T1 mapping quality assurance: The T1 mapping and ECV standardisation in CMR (T1MES) program. J Cardio-vasc Magn Reson. 2016;18(suppl 1):W14. doi:10.1186/1532-429X-18-S1-W14.

20. Su MY, Lin LY, Tseng YH, et al. CMR-verified diffuse myocar-dial fibrosis is associated with diastolic dysfunction in HFpEF. JACC Cardiovasc Imaging. 2014;7(10):991-997.

21. Iles L, Pfluger H, Phrommintikul A, et al. Evaluation of dif-fuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol. 2008;52(19):1574-1580.

22. Jellis C, Wright J, Kennedy D, et al. Association of imaging markers of myocardial fibrosis with metabolic and functional disturbances in early diabetic cardiomyopathy. Circ Cardio-vasc Imaging. 2011;4(6):693-702.

23. Neilan TG, Mongeon FP, Shah RV, et al. Myocardial extracel-lular volume expansion and the risk of recurrent atrial fibrilla-tion after pulmonary vein isolation. JACC Cardiovasc Imaging. 2014;7(1):1-11.

24. Marzluf B, Bonderman D, Tufaro C, et al. Diffuse myocardial fi-brosis by post-contrast T1-time predicts outcome in heart fail-ure with preserved ejection fraction. J Cardiovasc Magn Reson. 2013;15(suppl 1):M6. doi:10.1186/1532-429X-15-S1-M6.

25. Rommel KP, von Roeder M, Latuscynski K, et al. Extracellu-lar volume fraction for characterization of patients with heart failure and preserved ejection fraction. J Am Coll Cardiol. 2016;67(15):1815-1825.

26. Mascherbauer J, Marzluf BA, Tufaro C, et al. Cardiac magnetic resonance postcontrast T1 time is associated with outcome in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging. 2013;6(6):1056-1065.

27. Kammerlander AA, Marzluf BA, Zotter-Tufaro C, et al. T1 map-ping by CMR imaging from histological validation to clinical im-plication. JACC Cardiovasc Imaging. 2016;9(1):14-23.

28. Treibel TA, Zemrak F, Sado DM, et al. Extracellular volume quantification in isolated hypertension - changes at the de-tectable limits? J Cardiovasc Magn Reson. 2015;17(1):74. doi:10.1186/s12968-015-0176-3.

29. López B, Ravassa S, González A, et al. Myocardial collagen cross-linking is associated with heart failure hospitalization in patients with hypertensive heart failure. J Am Coll Cardiol. 2016;67(3):251-260.

30. Zile MR, Baicu CF, Ikonomidis J, et al. Myocardial stiffness in pa-tients with heart failure and a preserved ejection fraction: con-tributions of collagen and titin. Circulation. 2015;131(14):1247-1259.

31. McDiarmid AK, Swoboda PP, Erhayiem B, et al. Athletic cardi-ac adaptation in males is a consequence of elevated myocyte mass. Circ Cardiovasc Imaging. 2016;9(4):e003579.

32. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventric-ular amyloid deposition in patients with heart failure and pre-served ejection fraction. JACC Heart Fail. 2014;2(2):113-122.

33. Richards DB, Cookson LM, Berges AC, et al. Therapeutic clearance of amyloid by antibodies to serum amyloid P com-ponent. N Engl J Med. 2015;373(12):1106-1114.

34. Sperry BW, Jones BM, Vranian MN, Hanna M, Jaber WA. Rec-ognizing transthyretin cardiac amyloidosis in patients with aor-tic stenosis: impact on prognosis. JACC Cardiovasc Imaging. 2016;9(7):904-906.

23


Introduction

The spring of 2016 was marked by the issu-ance of two guidelines devoted to heart failure. The first document, the European Society

of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic heart failure, was developed with the special contribution of the Heart Failure Association of the ESC.1 The second one was produced by the American College of Cardiology, the American Heart Association, and the

Heart Failure Society of America in collaboration with the International Society for Heart and Lung Transplantation.2 Whereas the American guidelines are focused only on the update of pharmacological therapy, for example, about agents used in the United States, such as angiotensin receptor–neprilysin inhibi-tor (valsartan/sacubitril) and If inhibitor (ivabradine), the 2016 ESC guidelines for the diagnosis and treat-ment of acute and chronic heart failure represent a complete update of their 2012 version.3

Trimetazidine in the new 2016 European guidelines on heart failure and beyond

Yury Lopatin, MD, PhD , FHFAVolgograd Medical State University, Volgograd Regional Cardiology Center, Volgograd, Russian Federation

Correspondence: Yury Lopatin, Professor and Head of Cardiology Department, Volgograd Regional Cardiology Center, 106, Universitetsky prospekt, Volgograd, Russian Federation


AbstractThis article focuses on the management of concomitant angina in patients with heart failure, as described in the 2016 European guidelines for the diagnosis and treatment of acute and chronic heart failure. Trimetazidine has been included in this new guideline because it is considered an effective and safe antianginal treatment in patients with angina and heart failure. It is well-known that impairment of cardiac metabolism plays an important role in the pathophysiology of heart failure. Trimetazidine shifts the myocardial energy metabolism from fatty acid β-oxidation toward glucose oxidation, resulting in a greater production of high-energy phosphates. Adding trimetazidine to a β-blocker (or to an alternative treatment to β-blocker), is considered as an effective and safe step to eliminate angina. Along with this, trimetazidine improves New York Heart Association functional capacity, delays or reverses left ven-tricular remodeling, and reduces B-type natriuretic peptide levels in heart failure patients. Trimetazidine improves exercise duration, left ventricular function, and quality of life in patients with heart failure with reduced ejection fraction. The rationale and perspectives of using this agent in patients with heart fail-ure with midrange and preserved ejection fraction are also discussed. L Heart Metab. 2016;71:23-26

Keywords: heart failure; guidelines; myocardial metabolism; trimetazidine

24

It is well-known that impairment of cardiac metabolism plays an important role in the pathophysiology of heart failure. Therefore, there is nothing surprising in the fact that the list of new therapies targeting cardiac metabo-lism is constantly expanding; however, most of these new therapies are not yet available in clinical practice. Studies of mitochondria-targeted peptides (coenzyme Q10, Szeto-Schiller peptides, especially elamipretide), manganese superoxide dismutase mimetics, hormone replacement therapy, and iron chelators attract partic-ular attention. The place of these agents in the guide-lines on heart failure needs to be determined by further experimental and clinical research. However, one of the changes made by the 2016 European guidelines on heart failure1 was the addition of trimetazidine in the guideline’s section devoted to the pharmacologi-cal management of angina in patients with heart failure (class IIb, level of evidence A recommendation).

Trimetazidine’s clinical benefits in patients with heart failure

Trimetazidine has been demonstrated to act directly at the level of the cardiomyocyte by blocking long-chain 3-ketoacyl coenzyme A thiolase, the key enzyme in the β-oxidation pathway and, therefore, inhibiting free fatty acid oxidation. Trimetazidine shifts the myocar-dial energy metabolism from fatty acid β-oxidation toward glucose oxidation, resulting in a greater pro-duction of high-energy phosphates. The beneficial ef-fect of trimetazidine in heart failure is also attributed to improvement in endothelial function, reduction in calcium overload and free radical–induced injury, and inhibition of cell apoptosis and cardiac fibrosis.4-7 Us-ing 31P-magnetic resonance spectroscopy to measure the cardiac phosphocreatine/adenosine triphosphate (PCr/ATP) ratio, investigators showed that trimetazi-dine preserves myocardial high-energy phosphate lev-els in patients with heart failure.8 Thus, trimetazidine

acting at the cellular level in the failing heart provides a significant improvement in functional class and left ventricular function in heart failure patients.8 It has also been observed that trimetazidine improves skeletal muscle metabolism.9 The effects of trimetazidine on symptoms, exercise capacity, and left ventricular func-tion in patients with heart failure are concordant in all clinical studies. Moreover, several studies have dem-onstrated the ability of trimetazidine to prevent car-diovascular events and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF).10-12 Four meta-analyses have been performed to estimate the effects of trimetazidine in patients with heart fail-ure. All of them concluded that trimetazidine improves functional capacity and left ventricular ejection fraction, delays or reverses left ventricular remodeling, and re-duces B-type natriuretic peptide level in heart failure patients.13-16

Management algorithm for the treatment of stable angina pectoris with symptomatic (NYHA class II-IV) HFrEF

According to the new ESC guidelines for the diagno-sis and treatment of acute and chronic heart failure, the management algorithm for the treatment of stable angina pectoris with symptomatic (New York Heart Association [NYHA] class II-IV) HFrEF may be repre-sented as follows1: A β-blocker (class I, level of evidence A) is rec-ommended as the preferred first-line treatment to relieve angina because of the associated benefits of this treatment, such as reduction in the risks of heart failure hospitalization and premature death. On top of β-blocker or in case a β-blocker is not tolerated, ivabradine (class IIa, level of evidence B) should be considered as an antianginal drug in HFrEF patients with sinus rhythm and a heart rate at or above 70 beats per minute. For additional angina symptom relief, there are several drugs recommended, as fol-lows: Short- and long-acting nitrates: Long-acting ni-trates, despite being an effective antianginal treatment, have not been extensively studied in heart failure. Trimetazidine (class IIb, level of evidence A): Trimeta-zidine has been recognized in new 2016 heart failure guidelines as an effective antianginal therapy and safe in heart failure; thus, it is recommended when angina persists despite treatment with a β-blocker or alter-

AbbreviationsESC: European Society of Cardiology; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; NYHA: New York Heart Association; PCr/ATP: phosphocreatine/adenosine triphosphate; RALI-DHF: RAnoLazIne for the treatment of Diastolic Heart Failure [study]

lopatin Heart Metab. (2016) 71:23-26Trimetazidine in the 2016 European guidelines on heart failure and beyond

25

Heart Metab. (2016) 71:23-26 lopatin Trimetazidine in the 2016 European guidelines on heart failure and beyond

native. Along with this, trimetazidine improves NYHA functional capacity, exercise duration, left ventricular function, and quality of life in patients with HFrEF.17,18 Amlodipine (class IIb, level of evidence B): Amlodip-ine has been studied in sizeable numbers of patients with HFrEF/left ventricular dysfunction and shown to be effective and safe. Other antianginals: The safety of other antianginal agents in HFrEF, such as ranolazine and nicorandil, are uncertain, so they received a class IIb, level of evidence C recommendation. In heart failure patients, ranolazine and nicorandil may be considered only in those unable to tolerate a β-blocker to relieve angina. This is unlike the previous version of the ESC guide-lines on heart failure,3 where ranolazine was consid-ered as an alternative to β-blockers or a second-line antianginal agent (class IIb, level of evidence C). Furthermore, with regard to ranolazine, new ESC guidelines have once again emphasized that its safety in heart failure patients is unclear. It is currently ap-proved as an antianginal agent; however, the impact of ranolazine on heart failure has only been investigated in a few clinical trials.19,20 Ranolazine has been shown to significantly increase left ventricular ejection fraction in patients with systolic and diastolic heart failure. The RALI-DHF study (RAnoLazIne for the treatment of Dia-stolic Heart Failure)20 revealed that ranolazine improves measures of hemodynamics; however, there were no significant effects on relaxation parameters or N-ter-minal pro–B-type natriuretic peptide concentration in patients with heart failure with preserved ejection frac-tion (HFpEF). Apparently, the value of ranolazine in the management of heart failure itself has yet to be clari-fied. It is very important to mention that other drugs, specifically diltiazem and verapamil, are thought to be unsafe in patients with HFrEF. Myocardial revascularization: Percutaneous and surgical revascularization are complementary ap-proaches for symptomatic relief of angina in HFpEF, but whether these interventions improve outcomes is not entirely clear. Myocardial revascularization is rec-ommended when angina persists despite treatment with antianginal drugs.

Further perspectives in the treatment of HFpEF and HFmrEF patients

Is it possible to extend the use of trimetazidine to HFpEF patients and to those with heart failure

with midrange ejection fraction (HFmrEF)? It seems quite logical to consider use of trimetazidine to manage angina in these categories of patients. However, the impact of this agent on the disease course itself for HFmrEF and HFpEF needs to be clarified. Whereas the term HFmrEF first appeared in the 2016 European guidelines on heart failure, the term HFpEF has long been in the spotlight of such guidelines. Nevertheless, despite the irrefut-able clinical significance of HFpEF—its morbid-ity and mortality rates on par with HFrEF—a wide range of issues about underlying pathophysiology and clinical management remain controversial, as discussed in this issue. Phan et al have investigated the association be-tween exercise-related changes in left ventricular relaxation, vasculoventricular coupling, and myo-cardial energy deficiency in patients with HFpEF.21 The study included 37 patients with HFpEF and 20 control subjects. Vasculoventricular coupling and left ventricular relaxation were assessed via radio-nuclide ventriculography while patients were at rest and during exercise. Cardiac energetic status (PCr/ATP ratio) was measured using 31P-magnetic reso-nance spectroscopy. At rest, both time to peak filling normalized for R-R interval and vasculoventricular coupling were similar in HFpEF patients and control subjects. On the other hand, the cardiac PCr/ATP ratio was significantly lower in HFpEF patients than in control subjects, indicating lower energy reserves. The relative changes in stroke volume and cardiac output during submaximal exercise were significant-ly lower in HFpEF patients than in control subjects. The time to peak filling normalized for R-R interval decreased during exercise in control subjects but increased in HFpEF patients. Vasculoventricular coupling decreased on exercise in control subjects but was unchanged in HFpEF patients. The authors stressed that patients with HFpEF manifest a sig-nificant reduction in PCr/ATP ratio at rest, indicating impairment of myocardial energy reserves. More-over, during exercise, the energetically demanding active phase of relaxation during diastole length-ened and there was also a failure of the normal in-crease in contractile function on exercise in patients with HFpEF. These data suggest that trimetazidine treatment, due to its improvement in the energetic status in HFpEF, might be considered as a promising strategy to manage this category of patients.

26

lopatin Heart Metab. (2016) 71:23-26Trimetazidine in the 2016 European guidelines on heart failure and beyond

Conclusion

Finally, the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure have established the position of trimetazidine as a new therapeutic strategy for the management of patients with angina and HFrEF. Future research should reveal whether agents targeting cardiac metabolism can be used in HFmrEF and HFpEF patients without angina, as well as in patients with nonischemic etiology of heart failure. L

REFERENCES

1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guide-lines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975.

2. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart fail-ure: an update of the 2013 ACCF/AHA Guideline for the Man-agement of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2016;134(13):e282-e293.

3. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guide-lines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14:803-869.

4. Park KH, Park WJ, Kim MK, et al. Effects of trimetazidine on endothelial dysfunction after sheath injury of radial artery. Am J Cardiol. 2010;105:1723-1727.

5. Renaud JF. Internal pH, Na+, and Ca2+ regulation by trimeta-zidine during cardiac cell acidosis. Cardiovasc Drugs Ther. 1988;1:677-686.

6. Maridonneau-Parini I, Harpey C. Effects of trimetazidine on membrane damage induced by oxygen free radicals in human red cells. Br J Clin Pharmacol. 1985;20:148-151.

7. Liu X, Gai Y, Liu F, et al. Trimetazidine inhibits pressure over-load-induced cardiac fibrosis through NADPH oxidase–ROS–CTGF pathway. Cardiovasc Res. 2010;88:150-158.

8. Fragasso G, De Cobelli F, Perseghin G, et al. Effects of meta-bolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J. 2006;27:942-948.

9. Ferraro E, Giammarioli AM, Caldarola S, et al. The metabolic modulator trimetazidine triggers autophagy and counteracts stress-induced atrophy in skeletal muscle myotubes. FEBS J. 2013;280:5094-5108.

10. El-Kady T, El-Sabban K, Gabaly M, et al. Effects of trimetazi-dine on myocardial perfusion and the contractile response of chronically dysfunctional myocardium in ischemic cardiomyop-athy: a 24-month study. Am J Cardiovasc Drugs. 2005;5:271-278.

11. Di Napoli P, Di Giovanni P, Gaeta MA, et al. Trimetazidine and reduction in mortality and hospitalization in patients with isch-emic dilated cardiomyopathy: a post hoc analysis of the Villa Pini d’Abruzzo trimetazidine trial. J Cardiovasc Pharmacol. 2007;50:585-589.

12. Fragasso G, Rosano G, Baek SH, et al. Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multi-center retrospective cohort study. Int J Cardiol. 2013;163:320-325.

13. Huang C, Dong B. Effects of trimetazidine for coronary heart failure: a systematic review. Chin J Evid Based Med. 2007;7:37-44.

14. Gao D, Ning N, Niu X, et al. Trimetazidine: a meta-analy-sis of randomized controlled trials in heart failure. Heart. 2011;97:278-286.

15. Zhang L, Lu Y, Jiang H, et al. Additional use of trimetazi-dine in patients with chronic heart failure. J Am Coll Cardiol. 2012;59:913-922.

16. Zhou X, Chen J. Is treatment with trimetazidine beneficial in patients with chronic heart failure? PLoS One. 2014;9:e94660.

17. Vitale C, Wajngaten M, Sposato B, et al. Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease. Eur Heart J. 2004;25:1814-1821.

18. Marazzi G, Gebara O, Vitale C, et al. Effect of trimetazidine on quality of life in elderly patients with ischemic dilated cardiomy-opathy. Adv Ther. 2009;26:455-461.

19. Murray GL, Colombo J. Ranolazine preserves and improves left ventricular ejection fraction and autonomic measures when added to guideline-driven therapy in chronic heart failure. Heart Int. 2014;9:66-73.

20. Maier LS, Layug B, Karwatowska-Prokopczuk E, et al. RAno-LazIne for the treatment of diastolic heart failure in patients with preserved ejection fraction: the RALI-DHF proof-of-concept Study. JACC Heart Fail. 2013;1:115-122.

21. Phan TT, Abozguia Kh, Shivu GN, et al. Heart failure with pre-served ejection fraction is characterized by dynamic impair-ment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol. 2009;54:402-409.

27

Heart Metab. (2016) 71:27-31case report

A 71-year-old Afro-Caribbean woman was seen in the heart failure clinic with shortness of breath (New York Heart Association functional class

III) and fatigue. She was known to have long-standing hypertension, diabetes, mild chronic obstructive pul-monary disease (she was an ex smoker), obstructive sleep apnea (OSA), and bilateral adrenal nodules. Three years previously, this patient had a coronary angiogram that confirmed unobstructed coronary ar-teries, and a Reveal device was inserted, which did not detect any malignant arrhythmias. This patient,

reviewed by the hypertension service and thought not to have Conn syndrome, was advised to continue her antihypertensive medications. Two years later, the patient was admitted with pulmonary edema, hyper-tension, and acute kidney injury. Then, three months before the latest visit, the patient was admitted to hospital to treat her edema and to rationalize her medications, as she was suffering with postural hy-potension and deranged electrolytes. Since that ad-mission, the patient’s symptoms deteriorated and she began waking every hour during sleep, struggling to

HFpEF or just multiple comorbidities? The challenges of making a definitive diagnosis

Jessica Webb, BM BCh, MA, MRCP, FHEADivision of Imaging Sciences and Biomedical Engineering, King’s College London, SE1 7EH, UK; Department of

Cardiology, Princess Royal University Hospital, BR6 8ND, UK

Correspondence: Dr Jessica Webb, Division of Imaging Sciences and Biomedical Engineering, 4th floor Lambeth Wing, King’s College London, SE1 7EH, UK


AbstractHeart failure is a complex clinical syndrome resulting from the inability of the heart to meet the metabolic needs of the body at normal ventricular filling pressures. The clinical manifestations are breathlessness, fatigue, and fluid retention. It is a progressive disease, characterized by high rates of hospitalization that tend to increase over time. Studies have suggested that approximately half of the estimated 1 million people with heart failure in the United Kingdom have heart failure with preserved ejection fraction (HFpEF). Imaging is clearly critical in identifying patients with heart failure symptoms and a normal ejection fraction, although imaging parameters of diastolic dysfunction do not always correlate with the gold standard diagnostic test, invasive pressure-volume loop analysis. The updated 2016 European Society of Cardiology (ESC) guidelines have simplified the diagnosis of HFpEF; nevertheless, diagnosis remains challenging in patients with multiple comorbidities. As this case report highlights, there is an unmet need for access to advanced imaging techniques to accurately identify these patients. L Heart Metab. 2016;71:27-31

Keywords: cardiac magnetic resonance imaging; HFpEF; pressure-volume loop analysis

28

use her continuous positive airway pressure (CPAP) machine, and sleeping with two pillows. In addition, she complained of generalized body pains, a poor appetite, and presyncope on standing, which was as-sociated with palpitations lasting up to 30 seconds. There were no episodes of loss of consciousness. On her most recent examination, her weight was 80.2 kg, her height was 152 cm, and her body mass index (BMI) was 34.7 kg/m2. Her pulse was 60 beats per minute and regular, with a supine blood pressure of 160/80 mm Hg and a standing blood pressure of 140/80 mm Hg. There was no peripheral edema, her jugular venous pressure (JVP) was not raised, and auscultation of her chest confirmed vesicular breath sounds with air entry equal bilaterally. This patient’s medications included bisoprolol 10 mg, nifedipine 20 mg, and frusemide 20 mg, taken at 8am and at 12 noon. In addition, she took warfarin, gli-clazide, simvastatin, co-codamol, and used asthma inhalers (tiotropium, salbutamol). She was intolerant of angiotensin-converting enzyme (ACE) inhibitors. The electrocardiogram showed sinus rhythm with left bundle branch block and a QRS duration of 126 ms. Blood analysis confirmed an elevated N-terminal pro–B-type natriuretic peptide level (NT-proBNP; 2439

ng/L), stage 4 renal dysfunction (glomerular filtration rate [GFR], 20 mL/min), and associated anemia (he-moglobin level, 93 g/L). Sodium and potassium were both within normal limits. Echocardiography confirmed preserved biventricular systolic function with normal left ventricular (LV) size. There was severe concentric remodeling (LV hypertrophy) and left atrial enlargement with grade 1 diastolic dysfunction (Figure 1). These findings are consistent with increased LV filling pres-sures. The lateral e’ velocity was 4.5 cm/s and E/e’ was 20. Longitudinal right ventricular function was normal, and there was mild tricuspid regurgitation (TR velocity, 3.15 m/s) with an estimated pulmonary artery systolic pressure (PASP) of 40 mm Hg. Cardiac magnetic resonance (CMR) imaging was performed and confirmed normal LV volumes and a mildly reduced LV ejection fraction (LVEF, 55%). There was increased LV wall mass with increased wall thick-ness, maximal in the mid septal segment at 21 mm (Figure 2A). The left atrial size was 26 cm2 (Figure 2B). After the administration of gadolinium, there was no late enhancement, and native T1 (longitudinal relax-ation time) was increased at 1118.3 ms (normal range in the 1.5-Tesla scanner, 900-1000 ms).

AbbreviationsBMI: body mass index; BNP: B-type natriuretic peptide; COPD: chronic obstructive pulmonary disease; EDPVR: end-diastolic pressure-volume relationship; HFpEF: heart failure with preserved ejection fraction; LV: left ventricular; LVEF: left ventricular ejection fraction; OSA: obstructive sleep apnea

Fig. 1 Mitral valve pulse wave Doppler confirming grade 1 diastolic dysfunction.Abbreviations: DecT, deceleration time; Dec Slope, deceleration slope; E/A ratio, ratio of peak early to late diastolic velocities; E Vel, E velocity; HR, heart rate; MV, mitral valve.

Fig. 2 (A) Cardiac magnetic resonance imaging of the mid left ventricle (short axis) showing increased left ventricular wall thick-ness. (B) Cardiac magnetic resonance imaging four-chamber view showing increased left ventricular wall thickness and mildly enlarged left atrial size.

webb Heart Metab. (2016) 71:27-31Challenges in making a definitive HFpEF diagnosis

29

Heart Metab. (2016) 71:27-31 webb

Challenges in making a definitive HFpEF diagnosis

Discussion

This elderly Afro-Caribbean patient has multiple comorbidities: hypertension, diabetes, OSA, and chronic obstructive pulmonary disorder, and has had admissions with heart failure in the context of a nor-mal LV size and mildly impaired LV dysfunction. The diagnosis of heart failure with preserved ejection frac-tion (HFpEF) is challenging in the elderly, as signs and symptoms are often nonspecific, although it is the most likely unifying diagnosis in this patient. Practi-cally, clinicians rely on echocardiographic measures of diastolic dysfunction to assist in making this diag-nosis, and according to the recent American Society of Echocardiography/European Association of Car-diovascular Imaging (ASE/EACVI) guidelines, this pa-tient has definite diastolic dysfunction (the patient has more than two of the four requirements, which are average E/e’ >14, lateral e’ velocity <10 cm/s, TR ve-locity >2.8 m/s, and left atrial volume index >34 mL/m2).1 The newly updated 2016 European Society of Cardiology (ESC) guidelines on the diagnosis of heart failure with preserved ejection fraction (HFpEF)2 have separated HFpEF from heart failure with middle-range LV ejection function in the hope of simplifying the di-agnostic process. The current guidelines recommend that the following four conditions must be satisfied to diagnose HFpEF: presence of symptoms and signs typical of heart failure, LVEF >50%, elevated biomark-ers, and either structural (left atrial enlargement >34 mL/m2 or LV mass index >115 g/m2 in males or >95 g/m2 in females) or functional changes (average E/e’ >13 or average e’ velocity <9 cm/s). The 2013 Ameri-can College of Cardiology/American Heart Associa-tion (ACC/AHA) consensus statement based the di-agnosis of HFpEF on typical symptoms and signs of heart failure in a patient with a normal or near normal LVEF and no significant valvular abnormalities detect-ed by echocardiography.3 Thus, by both diagnostic criteria, this patient has HFpEF. The exact pathophysiology of HFpEF remains uncertain, although increased LV passive stiffness is consistently reported.4,5 Patients often have overlap-ping comorbidities, and it has only recently been con-vincingly demonstrated that HFpEF represents more than a sum of all its comorbidities and is a condition in its own right.6,7 HFpEF is probably caused by a com-bination of the following: (i) diastolic dysfunction; (ii) impaired systolic function on exercise; (iii) abnormal

ventricular-arterial coupling; (iv) inflammation and en-dothelial dysfunction; (v) chronotropic incompetence; (vi) altered myocardial and peripheral skeletal muscle metabolism and perfusion; (vii) pulmonary hyperten-sion; and (viii) renal insufficiency.5 It has recently been proposed that within the het-erogeneous HFpEF population there are three distinct phenogroups.8 Using unbiased hierarchical clustering analysis of phenotypical data and penalized model-based clustering, it has been possible for Shah et al8 to categorize patients who were identified via the following criteria: having received a diagnosis of heart failure, the presence of the words “heart failure” in the discharge notes, having a B-type natriuretic peptide (BNP) level >100 pg/mL, or having received more than two doses of intravenous diuretics. Fol-lowing discharge, patients needed to have an LVEF >50%, significant diastolic dysfunction (grade 2 or 3) on echocardiography, evidence of elevated LV filling pressures on invasive hemodynamic testing (demon-strating increased LV filling pressures), or a BNP level >100 pg/mL. Phenogroup 2 is described as having the highest prevalence of obesity, diabetes, hyperten-sion, OSA, and the worst LV relaxation (defined as lower e’ velocities); phenogroup 3 is described as be-ing elderly with chronic kidney disease (CKD), having the highest BNP levels, and having more severe elec-trical and myocardial remodeling. This patient does not fit neatly into either phenogroup 2 or 3 and is best described as lying between the two. It remains to be seen how clinically useful these phenogroups are and if clustering can be used to predict outcome or response to therapy. Previous large epidemiological studies have found that HFpEF patients are more like-ly to be older females with a history of hypertension, diabetes mellitus, atrial fibrillation, and coronary artery disease9-11; also, renal impairment, chronic lung dis-ease, liver disease, hypothyroidism, and anemia have been reported in the HFpEF population.12 In addition, it has recently been suggested that there are differ-ent geographical populations of HFpEF, which further contributes to the challenges in accurately diagnos-ing HFpEF.5 Despite this, Shah’s phenogroup-based classification represents a significant development in understanding the HFpEF population, but further work is needed to ensure that it is universally appli-cable. As part of this patient’s assessment, she was re-ferred for invasive pressure-volume studies, which are

30

considered the gold standard for HFpEF diagnosis. Burkhoff et al provide an overview of the principles behind such analysis,13 summarized here. The LV end-diastolic pressure-volume relationship (EDPVR) defines the passive physical properties of the LV chamber and reflects the net effects of all facets of myocardial material properties, chamber structural properties, and the extracellular matrix. Changes in EDPVR may reflect myocardial fibrosis, ischemia, and edema, or they may be caused by physiological (nor-mal growth) or pathological (hypertrophy, chamber enlargement) remodeling. In the low pressure-volume range, there is only a small increase in pressure for a given increment in volume. The stiffness is thought to be due to compliant elastin fibers and stretched my-ocytes constrained by sarcomeric titin. With further volume increases, the pressure rises more steeply as stretch is resisted by the stiff elements (the slack lengths of collagen fibers and titin are exceeded). Be-cause the EDPVR is nonlinear, the chamber stiffness varies with filling pressures. The chamber-stiffness constant, β (1/mL), allows diastolic chamber proper-ties to be indexed; by multiplying β by LV wall vol-ume (Vw), a dimensionless chamber-stiffness index is obtained (βw). This allows different heart sizes to be compared. In addition, elastance can be measured, which is defined as the change in pressure for a given change in volume within a chamber. So, the higher the elastance, the stiffer the chamber wall. Patients with HFpEF have a prolonged tau (τ), which is the isovolumic relaxation constant. In 2007, Kasner et al investigated 43 clinically symptomatic patients; diastolic dysfunction was considered present if τ was prolonged (>48 ms), the LV end-diastolic pres-sure (LVEDP) was elevated (>12 mm Hg), and/or β was elevated (>0.015 mL-1) despite normal ejection fraction.14 These cutoff values were defined as values corresponding to the 90th percentiles of their control patients. According to these criteria and on the basis of the pressure-volume study, our patient has diastol-ic dysfunction. Figure 3 shows the pressure-volume loops for baseline readings (red loop) and reduced preload and afterload readings (blue loop), with mini-mal change shown for leg raise (increased preload). There are still many challenges in managing pa-tients with HFpEF, not least because there are no current treatments, and patients have multiple co-morbidities that can make imaging challenging (poor acoustic windows due to increased BMI, and for

CMR difficulty with breath holding, atrial fibrillation, and raised BMI). Moreover, it is not always appropri-ate to send all patients to the catheter laboratory for invasive pressure-volume studies. Nonetheless, as illustrated by this case, it does provide further assur-ance of diagnosis based on noninvasive imaging. L

REFERENCES

1. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommenda-tions for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardio-vascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277-314.

2. Ponikowski P, Voors AA, Anker SD, et al; Authors/Task Force Members. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC). Devel-oped with the special contribution of the Heart Failure As-sociation (HFA) of the ESC. Eur Heart J. 2016;37(27):2129-2200.

3. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Associa-tion Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.

4. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure—ab-normalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004;350(19):1953-1959.

5. Sharma K, Kass DA. Heart failure with preserved ejection frac-tion: mechanisms, clinical features, and therapies. Circ Res. 2014;115(1):79-96.

6. Mohammed SF, Borlaug BA, Roger VL, et al. Comorbidity and ventricular and vascular structure and function in heart failure with preserved ejection fraction: a community-based study.

400

20

60Volume (mL)

BaselineNitratesLeg raise

Pres

sure

(mm

Hg)

40

60

80

100

120

140

160

180

80 100 120 140 160

Fig. 3 Pressure-volume loops with changing preload. The red loop shows baseline readings; the blue loop shows readings after treat-ment with nitrates, a preload- and afterload-reducing drug; and the black loop shows readings with leg raise. Pressures and volumes are reduced with nitrates. Load-independent measurements of relaxation confirm heart failure with preserved ejection fraction (HFpEF). See text for additional details.

webb Heart Metab. (2016) 71:27-31Challenges in making a definitive HFpEF diagnosis

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Heart Metab. (2016) 71:27-31 webb

Challenges in making a definitive HFpEF diagnosis

Circ Heart Fail. 2012;5(6):710-719.7. Campbell RT, Jhund PS, Castagno D, Hawkins NM, Petrie

MC, McMurray JJ. What have we learned about patients with heart failure and preserved ejection fraction from DIG-PEF, CHARM-preserved, and I-PRESERVE? J Am Coll Cardiol. 2012;60(23):2349-2356.

8. Shah SJ, Katz DH, Selvaraj S, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131(3):269-279.

9. Lenzen MJ, Scholte op Reimer WJ, Boersma E, et al. Differ-ences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey. Eur Heart J. 2004;25(14):1214-1220.

10. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med.

2006;355(3):251-259. 11. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with

preserved ejection fraction in a population-based study. N Engl J Med. 2006;355(3):260-269.

12. Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection frac-tion. Eur J Heart Fail. 2011;13(1):18-28.

13. Burkhoff D, Mirsky I, Suga H. Assessment of systolic and dia-stolic ventricular properties via pressure-volume analysis: a guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol. 2005;289(2):H501-H512.

14. Kasner M, Westermann D, Steendijk P, et al. Utility of Doppler echocardiography and tissue Doppler imaging in the estima-tion of diastolic function in heart failure with normal ejection fraction: a comparative Doppler-conductance catheterization study. Circulation. 2007;116(6):637-647.

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Heart Metab. (2016) 71:32-36Refresher Corner

Introduction

Chronic heart failure (CHF) is one of the most common chronic diseases worldwide, and its prevalence and incidence are increasing. CHF

with preserved systolic function (HFpEF) accounts for 40% to 50% of all patients with CHF.1 Approximately half of the patients with acute decompensated heart failure in emergency wards present with a normal ejection fraction (EF) of ≥50%. However, in contrast to heart failure with reduced EF (HFrEF; EF<50%), there is no therapeutic strategy currently available that prevents cardiovascular death and hospitaliza-tion.2 Nearly two-thirds of the patients with HFpEF die from cardiovascular causes,3 corresponding to an annual mortality rate between 10% and 30%.4 The

postdischarge prognosis for patients with HFpEF seems to be slightly superior to that in patients with HFrEF. However, rates of long-term mortality and hos-pitalization because of CHF are comparable.4,5 HFpEF is distinct from HFrEF, with different pathophysiology and etiology, comorbidities, clinical and demographic characteristics, and response to therapy (Figure 1).6,7 Crucial risk factors for developing HFpEF include age, female sex, hypertension, metabolic syndrome, diabetes mellitus, obesity, microalbuminuria, high waist-to-hip ratio, and physical inactivity.1

HFpEF represents the cumulative expression of the above risk factors and comorbidities, which in-duce a systemic inflammatory state with increased plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, soluble ST2 (sST2), and pentraxin 3.

Heart failure with preserved ejection fraction–where is the problem: heart or arteries?

Sebastian Ewen, MD; Michael Böhm, MDDepartment of Internal Medicine III, Cardiology, Angiology, and Intensive Care, Saarland University Hospital,

Homburg/Saar, Germany

Correspondence: Dr Sebastian Ewen, Department of Internal Medicine III, Cardiology, Angiology, and Intensive Care, Saarland University Hospital, Kirrberger Str., Geb. 40, 66421 Homburg/Saar, Germany


AbstractChronic heart failure is one of the most common chronic syndromes worldwide, with increasing preva-lence and incidence. Heart failure with preserved ejection fraction seems to have a different epidemiol-ogy and etiology than heart failure with reduced ejection fraction. The present review aims to provide an overview of heart failure with preserved ejection fraction based on the current guidelines of the European Society of Cardiology. First, pathophysiologic concepts will be explained. Second, trials in patients with heart failure with preserved ejection fraction using evidence-based therapies from heart failure with reduced ejection fraction will be presented. Finally, new pharmacological developments, such as angiotensin–neprilysin inhibition and If-channel inhibition with ivabradine, will be discussed. L Heart Metab. 2016;71:32-36

Keywords: chronic heart failure; ESC guidelines; heart failure with preserved ejection fraction

33

Heart Metab. (2016) 71:32-36 ewen and böhM HFpEF—where is the problem: heart or arteries?

These lead to increased expression of vascular cell adhesion molecule 1 and activate the cardiac endo-thelium, with a consequent decrease in the produc-tion of nitric oxide, an agent known to exert direct antifibrotic effects through the cyclic guanosine mo-nophosphate pathway (Figure 2).1,8,9 Diastolic stiffness is attributed to excessive myocardial collagen deposi-tion and cardiomyocyte stiffness, of which the latter is

necessary to induce HFpEF without any involvement of the extracellular matrix.10 In addition, coronary mi-crovascular disease is involved in the pathophysiol-ogy of the development of HFpEF.9 This new concep-tual paradigm has shifted the emphasis from excess left ventricular overload to coronary microvascular pathology. This hypothesis was supported by find-ings of an association between microvascular density and left ventricular fibrosis in autopsy specimens from subjects with an antemortem diagnosis of HFpEF.11 Numerous pathophysiologic mechanisms for coro-nary microvascular dysfunction, including endothelial, smooth muscle, and sympathetic dysfunction; micro-vascular spasm; extramural rarefaction; and luminal obstruction, have been hypothesized (Figure 3).12 Further understanding of the underlying pathogenesis of HFpEF is necessary to find novel treatment options and improve the prognosis of these patients.

Clinical trials

The current guideline states that “no treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFpEF.”2 The current recommendation is to use diuretics to control sodium and water retention and reduce dyspnea and edema. Furthermore, hypertensive therapy should include

HypertensionDiabetesROS production

Psychiatric disordersDepresssion

ObesitySarcopenia

AgingDeconditioning

Renal dysfunctionVolume overload

Iron de�ciencyAnemia

Lung diseaseCOPD

Ventricular dysfunction- Impaired relaxation- Impaired �lling- Systolic dysfunction

Arterial dysfunction

Heart failurewith

preserved EF

Autonomic dysfunctionChronotropic incompetence

Vascular dysfunctionVascular stiffeningVentriculo-arterial coupling

Elevated blood pressureInadequate BP response to exercisePulmonary hypertension

Valvular dysfunctionDynamic mitral regurgitation

Fig. 1 Heart failure with preserved ejection fraction. Schematic showing potential cardiovascular risk factors, cardiovascular abnormalities, and other comorbidities that may be present.Abbreviations: BP, blood pressure; COPD, chronic obstructive pulmonary disease; EF, ejection fraction; ROS, reactive oxygen species. After reference 7: Senni et al. Eur Heart J. 2014;35(40):2797-2815. © 2014, The Author. Published on behalf of the European Society of Cardiology. All rights reserved.

Overweight/obesityHypertension

Diabetes mellitus COPD

Iron de�ciency

IL-6TNF-α sST2

Pentraxin 3

Endothelium

Cardiomyocytes

ROS

NO

Peroxynitrite

(ONOO-)

PKG

Resting tension of cardiomyocytes

Hypertrophy

sGC

cGMP

VCAM E-selectin

Collagen

Myo�broblasts

Leukocytes

Fibroblasts TGF-β

Fig. 2 Myocardial remodeling in heart failure with preserved ejec-tion fraction.Abbreviations: cGMP, cyclic guanosine monophosphate; COPD, chronic obstructive pulmonary disease; IL-6, interleukin 6; NO, nitric oxide; PKG, protein kinase G; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; sST2, soluble ST2; TGF-b, transforming growth factor b; TNF-a, tumor necrosis factor a; VCAM, vascular cell adhesion molecule. After reference 9: Paulus and Tschope. J Am Coll Cardiol. 2013;62(4):263-271. © 2013, American College of Cardiology Foundation.

AbbreviationsCHF: chronic heart failure; CHAMPION: CardioMEMS Heart sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA class III heart failure patients; EDIFY: Preserved Left Ventricular Ejection Fraction Chronic Heart Failure with Ivabradine Study; HFpEF: heart failure with preserved ejection fraction; I-PRESERVE: Irbesartan patients with heart failure and PRESERVEd systolic function; LV: left ventricu-lar; PARAGON-HF: Efficacy and Safety of LCZ696 Compared to Valsartan on Morbidity and Mortality in Heart Failure Patients with Preserved Ejection Fraction; SENIORS: Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure; SOCRATES: SOluble guany-late Cyclase stimulatoR heArT failurE Studies; TOPCAT: Treatment Of Preserved Cardiac function heart failure with an Aldosterone antagonist Trial

34

ewen and böhM Heart Metab. (2016) 71:32-36HFpEF—where is the problem: heart or arteries?

β-blockers and angiotensin-converting enzyme (ACE) inhibitors (or angiotensin II receptor blockers [ARBs]); in case of myocardial ischemia, β-blocker therapy is obligatory; and in case of atrial fibrillation, the heart rate should be controlled in order to improve symp-toms. Over the past few years, a number of estab-lished treatments for HFrEF have been tested in pa-tients with HFpEF. However, even pharmacological therapies that had a reliable evidence base in HFrEF achieved only neutral results in randomized clinical tri-als in HFpEF. β-Blocker trials have failed to provide conclusive results in HFpEF. Subgroup analysis of the results from the SENIORS trial (Study of Effects of Nebivo-lol Intervention on Outcomes and Rehospitalization in Seniors with heart failure) showed that the efficacy of nevibolol in patients with HFpEF (mean EF, 49%) was similar to its efficacy in those with HFrEF (mean EF, 29%) in reduction of all-cause and cardiovascu-lar mortality.13 However, a meta-analysis of 15 ob-servational studies and two randomized controlled trials including more than 27 000 patients reported that whereas β-blockers were beneficial in terms of mortality in observational studies, this was not shown in the randomized controlled trials.14 Meta-analysis of the observational trial results indicated that β-blocker treatment reduced all-cause mortality, but not hospi-talization for CHF. On the other hand, the randomized

controlled trial results indicated no significant effect of the use of β-blocker on either end point. The authors of the meta-analysis concluded that further random-ized clinical trials with β-blockers for HFpEF are cer-tainly warranted. There is also no evidence of any clinical benefit associated with the use of ACE inhibitors, ARBs, endothelin antagonists, or metalloproteinase inhibi-tors in HFpEF from randomized controlled trials.15,16 Even spironolactone, which is known to have a posi-tive effect on left ventricular mass and aortic stiff-ness,17 failed to demonstrate a benefit in the TOP-CAT study (Treatment Of Preserved Cardiac function heart failure with an Aldosterone antagonist Trial; NCT00094302).18 TOPCAT included 3445 patients with HFpEF and compared the effect of spironolac-tone (15-45 mg/day) with that of placebo. After 72 months, there was no significant difference in the primary end points of cardiovascular death, cardiac arrest, or hospitalization for CHF.18 Only hospitaliza-tion for CHF as an individual component achieved a significant improvement in the spironolactone group (P=0.04). The overall neutral results of the trial might be explained by methodological problems, including enrolment based on clinical symptoms and hospital-ization or B-type natriuretic peptide (BNP) levels. An-other factor may have been the regional variations, since patients from the Americas (USA, Canada, Brazil, and Argentina) appeared to be at a five times higher risk for the primary end points than patients in Russia or Georgia. A post hoc analysis of the TOP-CAT data indicated that there were greater potassium and creatinine changes with spironolactone in the pa-tients from the Americas, and this may well translate into greater clinical benefit.19 Experimental data suggested that the phospho-diesterase-5 inhibitor sildenafil prevents cardiac and myocyte remodeling in advanced hypertrophy20 and would, therefore, be beneficial in the treatment of HFpEF. However, a randomized double-blind, pla-cebo-controlled clinical trial in 216 outpatients with a median left ventricular EF (LVEF) of 60% failed to demonstrate improvements in exercise capacity or clinical status over 24 weeks of treatment.21 There are a number of treatments currently under exploration for HFpEF, of which at least some may lead to an evidence-based management strategy for this con-dition. One avenue for research involves advanced glycation end products, which may play a role in

Conduction

Transmuralpressure

Shearstress

Convection

Metabolicstimuli

Fig. 3 Model for vascular diameter adaptation in microvascular networks. Such adaptation occurs through the response of microvascular vessels to signals that are transmitted upstream by conduction through gap junctions in the vessel wall, signals transmitted by convection of substances with blood flow down-stream, metabolic stimuli, and local hemodynamic signals–such as transmural pressure and wall shear stress. After reference 12: Pries and Reglin. Eur Heart J. 2016 Feb 2. Epub ahead of print. doi:10.1093/eurheartj/ehv760. © 2016, The Author. Published by Oxford University Press on behalf of the European Society of Cardiology.

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Heart Metab. (2016) 71:32-36 ewen and böhM HFpEF—where is the problem: heart or arteries?

the development and progression of CHF and have, therefore, been considered as potential targets in HF-pEF.22 Another treatment showing great promise is the angiotensin receptor–neprilysin inhibitor LCZ696, which reduced N-terminal-proBNP in a phase 2 trial in 300 patients with HFpEF (LVEF≥45%).23 LCZ696 is currently being tested on a large scale in the phase 3 trial PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan on Morbidity and Mortality in Heart Failure Patients with Preserved Ejection Frac-tion; NCT01920711). The first results of PARAGON-HF are expected by the start of 2019. Molecules that stimulate the soluble guanylate cyclase pathway are also undergoing phase 2 testing in patients with HF-pEF. The agent vericiguat is currently being investigat-ed in the SOCRATES trial (SOluble guanylate Cyclase stimulatoR heArT failurE Studies; NCT01951638), which intends to recruit a mixed population of pa-tients with HFpEF (470 patients to be randomized) and HFrEF (410 patients).24

Another topic of interest is the use of pharmaco-logical heart rate reduction, other than by β-blockers. This is particularly relevant because elevated rest-ing heart rate is known to predict mortality in HFpEF. An analysis in the I-PRESERVE (Irbesartan patients with heart failure and PRESERVEd systolic func-tion; NCT0095238) database of patients with HFpEF (LVEF>45%) showed that every 12-beats-per-minute increase in heart rate was associated with a 13% increase in risk for a composite of cardiovascular death or hospitalization for CHF.25 Preliminary and experimental results with the If inhibitor ivabradine indicated potential for heart rate reduction in HF-pEF.26,27 Ivabradine is currently undergoing further phase 2 testing for HFpEF in the ongoing EDIFY trial (Preserved Left Ventricular Ejection Fraction Chronic Heart Failure with Ivabradine Study; EUCTR2012-002742-20-DE). According to the concept that heart rate reduction might be important in HFpEF, novel devices and treatments with this target, such as va-gal and carotid artery simulation, are under investiga-tion. Another avenue that is being actively explored is wireless pulmonary artery pressure monitoring as a guide for management. In the single-blind, random-ized CHAMPION trial (CardioMEMS Heart sensor Al-lows Monitoring of Pressure to Improve Outcomes in NYHA class III heart failure patients; NCT00531661), microelectromechanical pressure sensors were im-planted during right heart catheterization in patients

with HFpEF.28 Participants were then randomly allo-cated to either receive treatment guided by daily re-corded pressures or normal treatment. Over nearly 18 months of follow-up, those in the guided-treatment group were 50% less likely to be hospitalized for HF.28 Further studies of this approach are required. In ad-dition to the formal treatment with pharmacological agents or other interventions, the effect of lifestyle changes on HFpEF is also being explored. A recent trial on endurance exercise training showed positive results in 40 patients with HFpEF, with improvements in peak oxygen consumption and exercise capacity after 4 months.29

Conclusion and perspectives

HFpEF is a complex disorder caused by multifacto-rial stresses secondary to comorbidities. To date, only the prevention of HFpEF through treatment of risk factors has been effective.30 Finding new multidirec-tional strategies to abrogate endothelial dysfunction and subsequent cardiac remodeling will be challeng-ing. Further randomized controlled trials are needed to prove the hint of positive results in phase 2 trials and achieve an evidence-based treatment for this dif-ficult-to-treat disease. HFpEF—where is the problem: the heart or the arteries? Probably both! L

REFERENCES

1. Ferrari R, Böhm M, Cleland JG, et al. Heart failure with pre-served ejection fraction: uncertainties and dilemmas. Eur J Heart Fail. 2015;17(7):665-671.

2. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Commit-tee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787-1847.

3. Senni M, Gavazzi A, Oliva F, et al. In-hospital and 1-year out-comes of acute heart failure patients according to presentation (de novo vs. worsening) and ejection fraction. Results from IN-HF Outcome Registry. Int J Cardiol. 2014;173(2):163-169.

4. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355(3):260-269.

5. Brouwers FP, de Boer RA, van der Harst P, et al. Incidence and epidemiology of new onset heart failure with preserved vs. re-duced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J. 2013;34(19):1424-1431.

6. Komajda M. Current challenges in the management of heart failure. Circ J. 2015;79(5):948-953.

7. Senni M, Paulus WJ, Gavazzi A, et al. New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes. Eur Heart J. 2014;35(40):2797-2815.

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ewen and böhM Heart Metab. (2016) 71:32-36HFpEF—where is the problem: heart or arteries?

8. Tschöpe C, Van Linthout S. New insights in (inter)cellular mechanisms by heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2014;11(4):436-444.

9. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263-271.

10. Chung CS, Hutchinson KR, Methawasin M, et al. Shortening of the elastic tandem immunoglobulin segment of titin leads to diastolic dysfunction. Circulation. 2013;128(1):19-28.

11. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rar-efaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015;131(6):550-559.

12. Pries AR, Reglin B. Coronary microcirculatory pathophysiol-ogy: can we afford it to remain a black box? Eur Heart J. 2016 Feb 2. Epub ahead of print. doi:10.1093/eurheartj/ehv760.

13. van Veldhuisen DJ, Cohen-Solal A, Böhm M, et al; SENIORS Investigators. Beta-blockade with nebivolol in elderly heart fail-ure patients with impaired and preserved left ventricular ejec-tion fraction: data from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol. 2009;53(23):2150-2158.

14. Bavishi C, Chatterjee S, Ather S, Patel D, Messerli FH. Be-ta-blockers in heart failure with preserved ejection fraction: a meta-analysis. Heart Failure Rev. 2015;20(2):193-201.

15. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in pa-tients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359(23):2456-2467.

16. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ven-tricular ejection fraction: the CHARM-Preserved trial. Lancet. 2003;362(9386):777-781.

17. Edwards NC, Steeds RP, Stewart PM, Ferro CJ, Townend JN. Effect of spironolactone on left ventricular mass and aortic stiff-ness in early-stage chronic kidney disease: a randomized con-trolled trial. J Am Coll Cardiol. 2009;54(6):505-512.

18. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-1392.

19. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOP-CAT) trial. Circulation. 2015;131(1):34-42.

20. Nagayama T, Hsu S, Zhang M, et al. Sildenafil stops progres-sive chamber, cellular, and molecular remodeling and improves

calcium handling and function in hearts with pre-existing ad-vanced hypertrophy caused by pressure overload. J Am Coll Cardiol. 2009;53(2):207-215.

21. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phospho-diesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268-1277.

22. Hartog JW, Voors AA, Bakker SJ, Smit AJ, van Veldhuisen DJ. Advanced glycation end-products (AGEs) and heart fail-ure: pathophysiology and clinical implications. Eur J Heart Fail. 2007;9(12):1146-1155.

23. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejec-tion fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851):1387-1395.

24. Pieske B, Butler J, Filippatos G, et al. Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES). Eur J Heart Fail. 2014;16(9):1026-1038.

25. Böhm M, Perez AC, Jhund PS, et al. Relationship between heart rate and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-Pre-serve). Eur J Heart Fail. 2014;16(7):778-787.

26. Kosmala W, Holland DJ, Rojek A, Wright L, Przewlocka-Kos-mala M, Marwick TH. Effect of If-channel inhibition on hemo-dynamic status and exercise tolerance in heart failure with pre-served ejection fraction: a randomized trial. J Am Coll Cardiol. 2013;62(15):1330-1338.

27. Reil JC, Hohl M, Reil GH, et al. Heart rate reduction by If-inhibi-tion improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with pre-served ejection fraction. Eur Heart J. 2013;34(36):2839-2849.

28. Adamson PB, Abraham WT, Bourge RC, et al. Wireless pulmo-nary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection frac-tion. Circ Heart Fail. 2014;7(6):935-944.

29. Haykowsky MJ, Brubaker PH, Stewart KP, Morgan TM, Egg-ebeen J, Kitzman DW. Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction. J Am Coll Cardiol. 2012;60(2):120-128.

30. Schocken DD, Benjamin EJ, Fonarow GC, et al. Prevention of heart failure: a scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisci-plinary Working Group; and Functional Genomics and Trans-lational Biology Interdisciplinary Working Group. Circulation. 2008;117(19):2544-2565.

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Heart Metab. (2016) 71:37-39Hot Topics

Introduction

It is well established that the failing heart is an “engine out of fuel,” where limited energetic sup-ply is not able to match the heart’s mechanical

demands.1 In vivo global analysis of the myocardial energy metabolism by phosphorus nuclear magnetic resonance (31P-NMR) showed a reduced phospho-creatine (PCr)/adenosine triphosphate (ATP) ratio—an indicator of energy deprivation—in various conditions of human heart failure (HF), including aortic valve disease, hypertrophic cardiomyopathy (HCM), and ischemic dilated cardiomyopathy (DCM).1 Moreover, the decrease in PCr/ATP ratio correlates with disease severity in end-stage failing DCM patients.2 Studies in animal models of HF also provided support for a

compromised myocardial energy metabolism. These studies showed that the smaller PCr/ATP ratio is largely attributed to a more severe reduction in the pool of PCr (up to 50%) over ATP (≤25%),3-5 which is confirmed by the equilibrium reaction of creatine kinase (CK).6 CK regenerates the ATP pool at the myofilaments at the expense of PCr, preventing an accumulation of cytosolic adenosine diphosphate (ADP).7 CK isoforms are reduced by approximately 30% in HF, and experimental blockade of cardiac CK or a decrease in [PCr] associates with contractile dys-function in rats in response to inotropic stimulation.4,8 Although [ATP] may decrease by 25%, the absolute ATP levels may never run sufficiently low to impair cardiac function. For instance, studies have shown that the reduction in [ATP] is not rate limiting for

The failing heart: an engine operating on “bad fuel”

Vasco Sequeira, PhD1; Jolanda van der Velden, PhD1,2

1Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands

2ICIN-Netherlands Heart Institute, Utrecht, the Netherlands

Correspondence: Jolanda van der Velden, Department of Physiology, VU University Medical Center, Van der Boechorsts-traat 7, 1081, BT Amsterdam, the Netherlands


AbstractThe failing heart is energetically starved, where inefficient adenosine triphosphate (ATP) energy conver-sion and transfer is unable to match the high workload of the heart. Evidence emerging from the last decades of research suggests that such reductions in ATP cannot solely explain the onset of contractile dysfunction in human heart failure. Here, we propose that the “by-product” adenosine diphosphate (ADP) may be a key driver underlying impaired cardiac function, as minute elevations of intracellular ADP concentration augments the diastolic calcium (Ca2+) level and associates with slowing of myocar-dial relaxation with limited ventricular compliance due to high diastolic pressure. Drug therapies should aim to lower use of ATP-consuming systems and to improve ADP conversion to ATP. L Heart Metab. 2016;71:37-39

Keywords: ADP elevation; cardiac contractility and energetics; cardiomyocyte contractile reserve; diastolic dysfunction

38

cardiomyocyte relaxation at rest and under stressful conditions. In HF, ATP decreases maximally from 10 to 7 mM;5,9 however, as little as 0.1 mM ATP is suf-ficient for cardiac relaxation.10 Additionally, estimates of the thermodynamic limits of the sarcoplasmic reticulum calcium (Ca2+)-ATPase (SERCA) suggest that decreases in the free energy released from ATP hydrolysis (∆GATP) in HF precede any large drops in [ATP].6 This is corroborated by findings in animal models of HF, where ATP levels measured by 31P-NMR are practically unchanged, whereas substantial diastolic abnormalities are present.8,9,11 These find-ings are consistent with the notion that ATP reduction cannot explain the onset of cardiac dysfunction.

A role for ADP in cardiac dysfunction

Recent data from our group and others suggest that the “by-product” ADP may be a key driver of impaired cardiac function.8,9,11,12 Myocardial ADP levels in ani-mal models are reported in the range of 10 to 50 μM in healthy animals and in the range of 40 to 140 μM in animals with disease, and the ADP level increases further during stress or vigorous exercise.9 Selectively increasing ADP levels without altering cytosolic ATP levels increases left ventricle end-diastolic pressure and limits myocardial relaxation in rats.8,9,11 Pathologi-cal ADP elevation may drive the myocardium into a diastolic HF phenotype by increasing residual acto-myosin interactions at diastolic Ca2+ levels.8 In a re-cent study, we showed that pathological ADP levels, in concert with diastolic [Ca2+], lead to high myocardi-al stiffness and limited relaxation of the myocardium, associated with reduced ventricular compliance.8 The ADP-mediated enhancement of myofilament Ca2+ activation was associated with increased diastolic [Ca2+].8 The high diastolic Ca2+ level probably re-sults from Ca2+ buffering at the myofilaments (Ca2+ is “trapped to sticky myofilaments”) and/or decreases in the free energy released from ATP hydrolysis (∆GATP) due to an extremely high ADP level that exacerbates

diastolic Ca2+ overload by reducing ∆GATP required for SERCA activity. Worth mentioning is the recently established link between increased myofilament Ca2+ sensitivity as a proarrhythmic factor.13,14 This finding indicates that a high myofilament Ca2+ level is suffi-cient to “trap” more Ca2+ at the myofilaments, which in turn affects the electrical activity of the heart. Apart from the ADP-mediated increase in myo-filament Ca2+ sensitivity, high myofilament sensitivity to Ca2+ has been related to a reduction in troponin I phosphorylation due to desensitization and downreg-ulation of the β-adrenergic receptor pathway during disease progression. High myofilament Ca2+ sensitiv-ity12,15,16 and myocardial energy deprivation are com-monly seen in human HCM and end-stage HF1 and may be sufficient to increase diastolic Ca2+ level. In the human failing heart, high myofilament Ca2+ activa-tion coincides with high myosin-ATPase consumption at the myofilaments.16,17 As a consequence, the con-tinuous high energetic demand may elevate cytosolic ADP and Ca2+, leading to a vicious cycle. Basic studies on ADP-mediated cardiac effects may provide insight into how energy-sparing thera-pies exert a beneficial effect in human end-stage HF. For instance, the clinically approved trimetazidine18 has been shown to improve symptoms and left ven-tricle function in HF patients, and this was associ-ated with improved PCr/ATP ratio.19 Using an animal model of chronic hypoxia, Wei and coworkers20 dem-onstrated that trimetazidine prevented elevation of diastolic Ca2+ by promoting the metabolic shift from lipid to glucose oxidation. Although lipid oxidation provides highest energetic yield per molecule of sub-strate when compared with glucose, it is less efficient with regard to ATP synthesis per molecule of oxygen consumed.21 Overall, these studies indicate that drug therapies that induce a metabolic shift may improve cardiac efficiency and optimize the balance between ATP and ADP and thereby improve diastolic perfor-mance of the heart.

Conclusion

In conclusion, rather than an “engine out of fuel,” the heart may actually resemble an “engine running on bad fuel,” where ADP elevation impairs diastolic per-formance. ADP elevates myofilament Ca2+ sensitivity and stiffness and thereby compromises myocardial relaxation and reduces ventricular compliance. These

AbbreviationsADP: adenosine diphosphate; ATP: adenosine triphos-phate; Ca2+: calcium; CK: creatine kinase; HF: heart failure; PCr: phosphocreatine; 31P-NMR: phosphorous nuclear magnetic resonance; SERCA: sarcoplasmic re-ticulum Ca2+-ATPase

sequeira and van der velden Heart Metab. (2016) 71:37-39The failing heart: an engine operating on “bad fuel”

39

Heart Metab. (2016) 71:37-39 sequeira and van der velden The failing heart: an engine operating on “bad fuel”

ADP-mediated defects may be explained by the pu-tative role of ADP to “trap” more Ca2+ at the myo-filaments, but also by its potential effects on SERCA activity and on other ion pumps, due to alterations in ∆GATP requirements. Drug therapies should aim to lower use of ATP-consuming systems, in concert with improving myocardial metabolism efficiency. L

REFERENCES

1. Neubauer S. The failing heart - an engine out of fuel. N Engl J Med. 2007;356:1140-1151.

2 Neubauer S, Horn M, Pabst T, et al. Contributions of 31P-mag-netic resonance spectroscopy to the understanding of dilated heart muscle disease. Eur Heart J. 1995;16:115-118.

3. Neubauer S, Horn M, Naumann A, et al. Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction. J Clin Invest. 1995;95:1092-1100.

4. Hamman BL, Bittl JA, Jacobus WE, et al. Inhibition of the cre-atine kinase reaction decreases the contractile reserve of iso-lated rat hearts. Am J Physiol. 1995;269:H1030-H1036.

5. Pinz I, Ostroy SE, Hoyer K, et al. Calcineurin-induced energy wasting in a transgenic mouse model of heart failure. Am J Physiol Heart Circ Physiol. 2008;294:H1459-H1466.

6. Allen DG, Orchard CH. Myocardial contractile function during ischemia and hypoxia. Circ Res. 1987;60:153-168.

7. Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuat-ing energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J. 1992;281:21-40.

8. Sequeira V, Najafi A, McConnell M, et al. Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness. J Physiol. 2015;593:3899-3916.

9. Tian R, Nascimben L, Ingwall JS, Lorell BH. Failure to maintain a low ADP concentration impairs diastolic function in hypertro-phied rat hearts. Circulation. 1997;96:1313-1319.

10. Cooke R, Bialek W. Contraction of glycerinated muscle fi-

bers as a function of the ATP concentration. Biophys J. 1979;28:241-258.

11. Tian R, Christe ME, Spindler M, et al. Role of MgADP in the development of diastolic dysfunction in the intact beating rat heart. J Clin Invest. 1997;99:745-751.

12. Sequeira V, Najafi A, Wijnker PJ, et al. ADP-stimulated contrac-tion: a predictor of thin-filament activation in cardiac disease. Proc Natl Acad Sci U S A. 2015;112:E7003-E7012.

13. Schober T, Huke S, Venkataraman R, et al. Myofilament Ca sensitization increases cytosolic Ca binding affinity, alters in-tracellular Ca homeostasis, and causes pause-dependent Ca-triggered arrhythmia. Circ Res. 2012;111:170-179.

14. Baudenbacher F, Schober T, Pinto JR, et al. Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J Clin Inv. 2008;118:3893-3903.

15. Sequeira V, Wijnker PJ, Nijenkamp LL, et al. Perturbed length-dependent activation in human hypertrophic cardiomy-opathy with missense sarcomeric gene mutations. Circ Res. 2013;112:1491-1505.

16. Hamdani N, Kooij V, van Dijk S, et al. Sarcomeric dysfunction in heart failure. Cardiovasc Res. 2008;77:649-658.

17. Witjas-Paalberends ER, Güçlü A, Germans T, et al. Gene-specific increase in the energetic cost of contraction in hyper-trophic cardiomyopathy caused by thick filament mutations. Cardiovasc Res. 2014;103:248-257.

18. Ponikowski P, Voors AA, Anker SD, et al; Authors/Task Force Members. 2016 ESC Guidelines for the diagnosis and treat-ment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129-2200.

19. Fragasso G, Perseghin G, De Cobelli F, et al. Effects of meta-bolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J. 2006;27:942-948.

20. Wei J, Xu H, Shi L, Tong J, Zhang J. Trimetazidine protects car-diomyocytes against hypoxia-induced injury through amelio-rates calcium homeostasis. Chem Biol Interact. 2015;236:47-56.

21. Giuseppe MC, Massimo F, Giuseppe C, Giuseppe B. Car-diac metabolism in myocardial ischemia. Curr Pharm Des. 2008;14:2551-2562.

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Heart Metab. (2016) 71:40-41Glossary gary d. lopaschuk

ATP/ADP ratio The ratio of adenosine triphosphate (ATP) to adenos-ine diphosphate (ADP) indicates cellular status and is responsible for controlling a myriad of metabolic ac-tivities, including the balance between catabolic and anabolic processes. A high ATP/ADP ratio indicates that the cell is replete with ATP, whereas a low ATP/ADP ratio is indicative of cellular energy depletion. Importantly, the ATP/ADP ratio determines the free energy change of ATP hydrolysis.

B-type natriuretic peptide (BNP)B-type natriuretic peptide (BNP) is a 32-amino-acid vasoactive peptide secreted by the atria and ven-tricles in response to increased wall stress (cardio-myocyte stretch) due to pressure overload and/or volume expansion. BNP elicits its biological actions (eg, natriuresis, vasodilation, diuresis, inhibition of the renin-angiotensin-aldosterone system, enhanced myocardial relaxation, inhibition of fibrosis and hyper-trophy, promotion of cell survival, and inhibition of in-flammation) by activating specific natriuretic peptide receptors (natriuretic peptide receptor A [NPR-A]/guanylate cyclase A [GC-A]) that utilize cyclic gua-nosine monophosphate (cGMP) as an intracellular second messenger. Circulating BNP levels have been demonstrated to be a marker for prognosis and risk stratification in the setting of heart failure.

N-terminal pro–B-type natriuretic peptide (NT-proBNP)N-terminal pro–B-type natriuretic peptide (NT-proB-NP) is a 76-amino-acid peptide generated from cleavage of the 108-amino-acid proBNP (the storage form of BNP): cleavage of proBNP generates 76-ami-no-acid NT-proBNP and 32-amino-acid BNP. NT-proBNP is not biologically active; however, the level of circulating NT-proBNP is a marker for prognosis and risk stratification in the setting of heart failure.

DGATP

DGATP represents the free energy change of adenos-ine triphosphate (ATP) hydrolysis (ie, ATP + H2O → ADP +Pi ). DGATP drives ATP-dependent reactions. DGATP can be calculated from the cellular contents of ATP, adenosine diphosphate (ADP), and phosphate (Pi ) as: DGATP = DG˚ATP + RT ln [ADP] [Pi ] / [ATP], where G˚ATP = 30 500 J/mol, and R= 8.315 J/mol.K.

Extracellular volume (ECV)Extracellular volume (ECV) represents the volume of the extracellular fluid compartment (ie, plasma and interstitial fluid). It is generally accepted that under normal conditions, ECV (measured in liters) is 20% of body weight (measured in kilograms).

End-diastolic pressure-volume relationship (EDPVR)The end-diastolic pressure-volume relationship (ED-PVR) defines the changes in ventricular pressure and volume during passive ventricular filling and can be readily discerned from invasively measured ventricu-lar pressure-volume relationships (ie, pressure-vol-ume loops). The inverse of the slope of the EDPVR (ie, ∆V/∆P) represents ventricular compliance, which can be altered in heart failure.

Ejection fraction (EF)Ejection fraction (EF) represents the proportion of ventricular volume ejected relative to end-diastolic volume. EF can be calculated as follows: EF = (stroke volume / end-diastolic volume) . 100. Under normal conditions, EF is ≥ 60%, whereas in severe heart fail-ure, it can be ≤ 20%.

Heart failure with preserved ejection fraction (HFpEF)Heart failure with preserved ejection fraction (HFpEF) is usually defined as heart failure with an ejection fraction higher than 50% and is characterized by di-astolic dysfunction rather than systolic dysfunction. It is primarily accompanied by concentric remodel-ing and defects in left ventricular compliance. Ap-proximately 50% of all heart failure cases are classi-fied as HFpEF.

Heart failure with reduced ejection fraction (HFrEF)Heart failure with reduced ejection fraction (HFrEF) is usually defined as heart failure with an ejection frac-tion lower than 40% and is characterized by systolic dysfunction. It is primarily accompanied by eccentric remodeling and a decreased left ventricular wall thick-ness. Approximately 50% of all heart failure cases are classified as HFrEF.

Glossary Gary d. lopaschuk

Heart failure with midrange ejection fraction (HFmrEF)Heart failure with midrange ejection fraction (HFmrEF) is a new category of heart failure defined as heart fail-ure with an ejection fraction between 40% and 49%. This new class of heart failure is meant to apply to pa-tients in a “gray zone,” where the benefits of therapies on morbidity and mortality have not been conclusively proven as they have been for patients with HFrEF.

Global longitudinal strain (GLS)Global longitudinal strain (GLS) is a new technique for detecting, quantifying, and evaluating subtle distur-bances/deteriorations in left ventricular systolic func-tion via use of speckle-tracking echocardiography.

T1 mappingT1 mapping is a new noninvasive cardiac magnetic resonance imaging technique that can be performed with or without contrast and is useful in character-izing myocardial tissue properties such as increased extracellular volume in conditions such as hypertro-phic cardiomyopathy and aortic stenosis. It can also noninvasively detect myocardial fibrosis.

Nitric oxide–cyclic guanosine monophosphate (NO-cGMP) axisThe nitric oxide–cyclic guanosine monophosphate (NO-cGMP) axis refers to the signaling transduction pathway mediated by the gaseous signaling mol-ecule NO, which activates soluble guanylyl cyclase (sGC). NO induction of sGC activity leads to massive increases in the intracellular levels of the second mes-senger cGMP, which leads to activation of protein ki-nase G–mediated signaling events.

Wild-type transthyretin amyloid (WTTA)Wild-type transthyretin amyloid (WTTA) is a disease that arises from the accumulation of wild-type trans-thyretin (normal version of the protein) in the heart or tendons, and it primarily affects the elderly. Men are affected to a much greater degree than women. As wild-type transthyretin accumulates in the heart, it re-sults in increased myocardial stiffness and wall thick-ness, precipitating symptoms often including short-ness of breath and exercise intolerance.

Heart Metab. (2016) 71:40-41

EDITORIALL. H. W. Gowdak

ORIGINAL ARTICLESRefractory angina or inappropriate antianginal therapy? A. Huqi, M. Marzilli

Prevalence of refractory angina in clinical practiceL. H. W. Gowdak

Prognostic implications of persistent anginaG. Steg

Nonpharmacological approach to refractory angina T. Henry

Clinical benefits of treating angina directly at the cardiac cell level with trimetazidine I. Milinkovi ’c, A. J. Coats, G. Rosano, Y. Lopatin, P. M. Seferovi ’c

CASE REPORTThe role of optimal medical therapy in patients with refractory anginaL. H. W. Gowdak

REFRESHER CORNEREstimating ischemic burdenV. Agarwal, M. F. Di Carli

HOT TOPICSErrare humanum est, perseverare autem diabolicumA. Huqi

GLOSSARYG. D. Lopaschuk

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