Recent advances in management of heart failure

Rahul aroraJunior resident 3

DEFINITION OF HFDEFINITION OF HF

Heart Failure is a pathophysiological state in which the heart is unable to pump blood at a rate to commensurate with the requirements of the metabolizing tissues (systolic failure) or can do so only with elevated filling pressures (diastolic failure ). Eugene Braunwald

CLASSIFICATION OF HEART FAILURE

• DURATION: • ACUTE • CHRONIC

• PATHOPHYSIOLOGY: • SYSTOLIC • DIASTOLIC•

•EJECTION FRACTION• REDUCED• NORMAL

WHY THIS IS IMPORTANT?

Current Treatment of Acute Heart Failure

Diuretics

Reducefluidvolume

Vasodilators

DecreasePreloadAndAfterload

ionotropes

AugmentContract-ility

LasixPDE 3 Inhibitors: milrinone

Dobutamine, norepinephrine, levosimendan

LasixNtg: sl, top, ivMSO4ACEiBiPAP/CPAP

NorepinephrineEndothelinAldosteroneRAASVasopressin

Natreuretic peptideNitric oxideBradykinin

Soluble Guanylate Cyclase Activators

Cinaciguat : AHFS. organic nitrates = CinaciguatDIRECTLY activates the soluble form of guanylate cyclase in

smooth muscle cells, thus leading to the synthesis of cGMP and subsequent vasodilation

In AHFS - periods of increased oxidative stress, a significant proportion of heme-bound iron may become oxidized, potentially blunting the effects of nitric oxide donors.

cinaciguat is a heme-independent soluble guanylate cyclase activator, with more predictable vasodilator response in conditions of elevated oxidative stress.

cinaciguat improve hemodynamics in patients with AHFS. however, at high doses, it has been associated with significant hypotension but this was not associated with other major adverse events, nor did it affect mortality at 30-days postdischarge.

The effects of cinaciguat are now being investigated in the COMPOSE program that includes three phase II trials in patients admitted with AHFS

Chimeric Natriuretic Peptides Nesiritide:

◦ natriuresis, vasorelaxation, inhibition of renin and aldosterone, inhibition of fibrosis, and increased lusitropy.

◦ iv infusion of nesritide ; decrease in arterial and venous pressures, increase in cardiac output, and suppression of neurohormonal activation.

◦ FDA approved for use in ADHF (ASCEND HF Trial) with hypotension being important side effect.

Chimeric Natriuretic Peptide (CD-NP) combines the beneficial aspects of C-type natriuretic peptide (CNP) with dendroaspis NP (DNP) with absence of hypotension.◦ CNP lacks the natriuretic effects of ANP or BNP but has the benefit

of less hypotension because it is a primary venodilator, as opposed to BNP, which dilates both arteries and veins.

◦ DNP has significant natriuretic effects but also causes hypotension.

◦ CD-NP ideally combines the lack of unwanted arterial vasodilation of CNP with the positive natriuretic effects of DNP.

◦ Preliminary studies in AHFS are ongoing (ClinicalTrials.gov Identifier NCT00839007)

Ularitide

a synthetic analogue of urodilatin, a natriuretic and diuretic hormone of the family of A-type natriuretic peptides produced by tubular renal cells.

Besides the effects on sodium and water handling, ularitide induces peripheral arterial vasodilation by activating the cGMP pathway.

The effects of a short-term infusion of ularitide in patients with ADHF have been investigated in the SIRIUS (Safety and Efficacy of an Intravenous Placebo-Controlled Randomized Infusion of Ularitide in a Prospective Double-Blind Study in Patients with Symptomatic Decompensated Chronic Heart Failure) trials I and II.

Compared with placebo, ularitide improved clinical status, hemodynamics, and neurohormonal profile; however, it was associated with significant hypotension.

Direct Renin Inhibitors: aliskerin

inhibitor of the first enzymatic step in the RAAS cascade, leading to a profound suppression of this neurohormonal system.

Aliskiren, the first oral direct renin inhibitor on the market and currently approved for the treatment of hypertension, is undergoing a phase III trial (ASTRONAUT) to test whether the addition of a direct renin inhibitor to standard therapy delays time to events, including cardiovascular death or HF rehospitalization within 6 months in patients hospitalized for AHFS and ejection fraction <40%.[127] (ClinicalTrials.gov Identifier NCT00894387).

Adenosine Antagonists

The glomerular filtration rate of the kidney is adapted to changes in the sodium concentration in the early distal tubule through the mechanism termed tubuloglomerular feedback. Tubuloglomerular feedback refers to a series of events whereby changes in the Na+, Cl−, and K+ concentrations in the tubular fluid are sensed by the macula densa through the Na+-K+-2Cl− cotransporter. An increase or decrease in Na+, Cl−, and K+ uptake elicits inverse changes in glomerular filtration rate by altering the vascular tone, predominantly of the afferent arteriole. Studies indicate that adenosine (through activation of the adenosine A1 receptor) and possibly ATP mediate this mechanism, which is increased in HF. Given that adenosine levels are increased in HF patients and may contribute to the progression of renal dysfunction, adenosine A1 receptor antagonists have been developed to increase renal blood flow and to enhance diuresis without activating the tubuloglomerular feedback. Rolofylline is a highly selective adenosine A1 receptor antagonist that has been studied in patients with HF. Despite the positive trends seen in the PROTECT pilot study,[128] the phase III PROTECT II trial showed only a mild benefit on symptoms, but no effects on renal protection and other prespecified outcomes, and was associated with more central nervous system events compared with placebo (ClinicalTrials.gov Identifier: NCT00354458).[129] Given these results, it is doubtful that these agents will undergo further evaluation in AHFS

Endothelin Antagonists

Endothelin 1 ◦ most powerful endogenous vasoconstrictor◦ produced by the vascular endothelial cells. ◦ exerts its effects by

ETA

ETB, located on the vascular smooth muscle cells, resulting in significant systemic arterial vasoconstriction.

Tezosentan, a nonselective ETA-B antagonist, has been shown to improve hemodynamics in patients with AHFS.

The Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study (VERITAS) studied more than 1400 patients admitted with AHF in an international trial The addition of intravenous tezosentan to standard therapy did not improve symptoms or decrease mortality at 7 days after randomization.[132]

Cardiac Myosin Activators Cardiac myosin activators (CMA) increase, specifically, cardiac myosin ATPase,

enhancing the release of inorganic phosphate, which strengthens binding between myosin and actin, the fundamental power-stroke leading to shortening of the cardiac sarcomere.

CMAs increase the efficiency with which ATP is utilized without increasing ATP consumption by increasing the number and duration of actin-myosin crossbridges for each ATP molecule consumed. This prolongs systole but not the rate at which force is developed.

How it is different from other Unlike conventional inotropic agents that generally increase ATP consumption,

increase the velocity of contraction, and rate of force generation, but may shorten the duration of systole.

Importantly, CMAs do not possess phosphodiesterase activity, do not increase diastolic calcium concentrations and can increase cardiac performance in patients receiving beta-blockers.

Preliminary data from studies of the CMA, omecamtiv mecarbil (CK-1827452), given intravenously either to healthy volunteers or to patients with stable, mild-to-moderate HF show marked dose-dependent increases in systolic ejection time, with a reflex decline in heart rate at higher concentrations.

Concentration-dependent increases were also observed in Doppler-derived stroke volume, fractional shortening, and ejection fraction. OM was well tolerated with no serious adverse events at intended doses in this group of HF patients. OM is well absorbed from the gut and an oral formulation is being developed.

Ionotropes

Istaroxime

has dual action on the myocyte: ◦ by inhibition of the membrane-bound Na+,K+-ATPase (similar to digoxin)

and ;

◦ by enhancing the activity of the sarcoendoplasmic reticulum Ca2+-ATPase type 2a (SERCA-2a).

These distinct mechanisms respectively result in positive inotropic effects, and enhanced lusitropic effect.

Experimentally, istaroxime appears to improve both systolic and diastolic function, to reduce LV dimension in diastole, and to increase SBP. These beneficial effects were not associated with an increase in myocardial oxygen consumption.

The HORIZON-HF (A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Patients with Worsening HF and Reduced LV Systolic Function) studied 120 patients admitted with AHF and decreased ejection fraction. The addition of istaroxime to standard therapy lowered PCWP and heart rate and increased SBP. The higher infusion dose (1.5 ?g/k/min) increased cardiac index and reduced LV end-diastolic volume. There were no changes in neurohormones, renal function, or troponin I levels during the short 6-hour infusion.

This agent is being developed for patients presenting with AHFS and low cardiac output because the majority of inotropes that are often required for these patients tend to decrease blood pressure and have significant side effects.

Stresscopin member of the urocortin family, strong affinity to the corticotropin-releasing hormone receptor

2, which is highly expressed in the myocardium and in the vascular endothelium.

Urocortins exhibit potent inotropic and lusitropic effects on rat and sheep heart and activate a group of myocyte protective pathways collectively known as reperfusion injury salvage kinase (RISK).

Studies in healthy volunteers and HF patients showed that brief intravenous infusions of urocortin 2 induced pronounced dose-related increases in cardiac output, heart rate, and LV ejection fraction while decreasing systemic vascular resistance. The hemodynamic effects of stresscopin in patients admitted with AHFS is being studied now in a Phase IIa trial.

This molecule is presently being studied for its hemodynamic effects in patients admitted with AHFS (ClihicalTrials.gov NCT01120210).

Relaxin major hormone of pregnancy powerful systemic and renal vascular effects. recent dose-finding phase IIb study Pre-RELAX-AHF

assessed the dose-response effects of 48-hour infusion of relaxin versus placebo on symptom relief, other clinical outcomes, and safety in patients with AHF and normal to increased blood pressure.

Relaxin therapy was associated with improvement in dyspnea and other clinical outcomes, with an acceptable safety profile.

Relaxin is currently being evaluated in the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) phase II/III clinical trial (ClinicalTrials.gov Identifier: NCT00520806).