Managing Heart Failure with Preserved Ejection Fraction (HFpEF)

Gustavo Restrepo Molina MD FSIAC, FACC, FESCPresidente Electo Sociedad Interamericana de Cardiología

Clínica Medellín. Medellín, Colombia

•  HFpEF is common (>50% of all HF), growing in prevalence!

•  Comorbidities are common and drive outcomes!

•  Associated with high morbidity and mortality!

•  5-year survival is only 35% after HF hospitalization!

•  The diagnosis is often not straightforward!

Heart Failure with Preserved Ejection Fraction (HFpEF)

Treatment of patients with HFpEF

•  No therapy has been approved specifically for HFpEF!

•  Preliminary results from many phase II trials followed by unsuccessful phase III studies!

•  Unability to identify homogeneous subsets of patients!

•  Consider therapies that facilitate reverse remodeling by directly targeting the heart itself!

Gheorghiade M. Developing new treatments for heart failure. Circulation Heart Failure 2016;9:e002727

Patients at Risk of Developing HFpEF

Older ageHypertension

Atherosclerotic heart diseaseDiabetes mellitus

ObesityMetabolic syndrome

Prior use of cardiotoxic drugsPrevious myocardial infarction

Unstable anginaLeft ventricular hypertrophy

Valvular heart diseasePatients with known structural heart disease

Chronic obstructive pulmonary diseaseAnemia

Renal dysfunctionSleep disordered breathing

Heterogeneity of Heart Failure with Preserved Ejection Fraction (HFpEF)

Heart Failurewith

Preserved EF

Lung DiseaseCOPD

Iron deficiencyand Anemia

Renal DysfunctionVolume overload

Aging &Deconditioning

Obesity &Sarcopneia

HTNDiabetes

ROS production

Ventricular dysfunctionDiastolic dysfunctionSystolic dysfunction

Atrial dysfunctionAtrial fibrillation

Autonomic dysfunctionChronotropic incompetence

Vascular dysfunctionVascular stiffeningVentriculo-arterial

uncoupling

Pulmonary hypertensionInadequate BP response

to exercise

ValvularDynamic mitral

regurgitation

Cardiac Structural Phenotypes in HFpEF !

Role of biomarkers as a clinical bridge-tool between HFpEF cardiacstructural phenotypes and potential treatment strategies

Myocardial Hypertrophy!

Interstitial Fibrosis!

Myocardial!Inflammation and Oxidative

Stress!

Coronary Disease!

Renin!Aldosterone!

Angiotensin II!

Galectin-3!sSt-2!

!

Interleukins!CRP!TNF∝

Matrix turnover biomarkers

ACE-I!ARBs!ARNi!

MRA!!

Weight loss!Metformin!

AGE crosslink breakers!Statins!

Troponin!!

T!

Ranolazine!ARNi!

Ivabradine!Calcium antagonists!

Beta-blockers!D´Elia E. European Journal of Heart Failure 2015;17:1231

European Heart Journal Advance access published May 20, 2016

Borlaug B. Redfield MM. Are systolic and diastolic heart failure overlapping or distinct phenotypes within the heart failure spectrum? Circulation 2011;123:2006-2014

European Heart Journal Advance access published May 20, 2016

Potential approach for matching key HFpEF phenotypes toselect therapeutic interventions (I)

HF symptoms, EF ≥ 50%+ primary Comorbidity(es)

HTN Fluid retentionElevated

filling pressure

DiabetesObesity

Metabolic syndrome

ARB/ACEIMRAARNi

Autonomicmodulation

ARNiGlycemic control

MetforminWeight loss

Bariatric surgeryDiet

PKG stimulationAGE crosslink

breakers?

Senni M. New strategies for HFpEF: the importance of targeted therapies for heart failure phenotypes. Eur Heart J 2014;35:2797

Potential approach for matching key HFpEF phenotypes toselect therapeutic interventions (II)

HF symptoms, EF ≥ 50%+ primary Comorbidity(es)

Pulmonaryhypertensionor right heart involvement

Ischemiacoronary

heart disease

Renaldisease

PD5 InhibitorOrally active

soluble guanylate cyclase

stimulator

Na channel blockersNitrates

Beta blockersCalcium

antagonistsIvabradine

Sodium restrictionACEI or ARB

Senni M. New strategies for HFpEF: the importance of targeted therapies for heart failure phenotypes. Eur Heart J 2014;35:2797

Role of the nitric oxide-cyclic guanosine monophosphate protein kinase pathway in the cardiomyocyte.

Cardiomyocyte signalling pathways involved in regulating cardiac titin stiffness

Kruger M. Linke WA. Titin- based mechanical signalling in normal and failing myocardium. Journal of Molecular and Celular Cardiology 2009; 46(4):490-498 Senni M. New strategies for HFpEF: the importance of targeted therapies for heart failure phenotypes. Eur Heart J 2014; 35: 2797

Select planned or ongoing studies in HFpEFTrial acronym! Target intervention!FAIR-HPEF!

(not yet recruiting)!Iron deficiency: ferric carboxymaltose (iv. iron)!

Mito-HPEF!(not yet recruiting)!

Energy deficit: bendavia (mithocondrial enhancer)!

EDIFY! Heart rate: ivabradine (sinus node inhibition)!

Ex-DHF! Deconditioning: endurance/resistance training!

OPTIM-EX! Deconditioning: high intensity interval training!

SOCRATES-!Preserved!

cGMP deficiency: vericiguat (soluble guanilate !cyclase stimulation)!

PARAGON-HF! cGMP deficiency: LCZ 696 (neprilysin inhibition)!

Treatment of HFpEF !Summary points!

The macroscopic and microscopic structural abnormalities of the heart should!be the focus of HF research and drug development!

Lack of therapies for HFpEF continues to be a huge unmet need!

Testing novel therapeutic hypothesis to extend healthy life among HF patients!must continue!