Angiotensin AT1 receptor blockers such as losartan (see Chapters 11 and 17) appear to have similar beneficial effects. In combination with sacubitril, valsartan is now approved for HFrEF. Angiotensin receptor blockers should be considered in patients intolerant of ACE inhibitors because of incessant cough.
Aliskiren, a renin inhibitor approved for hypertension, was found to have no definitive benefit in clinical trials for heart failure.
Vasodilators are effective in acute heart failure because they provide a reduction in preload (through venodilation), or reduction in afterload (through arteriolar dilation), or both. Some evidence suggests that long-term vasodilation by hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart.
A synthetic form of the endogenous peptide brain natriuretic peptide (BNP) is approved for use in acute (not chronic) cardiac failure as nesiritide. This recombinant product increases cGMP in smooth muscle cells and reduces venous and arteriolar tone in experimental preparations. It also causes diuresis. However, large trials with this drug have failed to show an improvement in mortality or rehospitalizations. The peptide has a short half-life of about 18 minutes and is administered as a bolus intravenous dose followed by continuous infusion. Excessive hypotension is the most common adverse effect. Reports of significant renal damage and deaths have resulted in extra warnings regarding this agent, and it should be used with great caution. A newer approach to modulation of the natriuretic peptide system is inhibition of the neutral endopeptidase enzyme, neprilysin, which is responsible for the degradation of BNP and atrial natriuretic peptide (ANP), as well as angiotensin II, bradykinin, and other peptides. Sacubitril is a prodrug that is metabolized to an active neprilysin inhibitor plus an ARB. A combination of valsartan plus sacubitril  has recently been approved for use in HFrEF.
Plasma concentrations of endogenous BNP rise in most patients with heart failure and are correlated with severity. Measurement of the plasma precursor NT-proBNP is a useful diagnostic or prognostic test and has been used as a surrogate marker in clinical trials.
Related peptides include ANP and urodilatin, a similar peptide produced in the kidney. Carperitide and ularitide, respectively, are investigational synthetic analogs of these endogenous peptides and are in clinical trials (see Chapter 15). Bosentan and tezosentan, orally active competitive inhibitors of endothelin (see Chapter 17), have been shown to have some benefits in experimental animal models with heart failure, but results in human trials have been disappointing. Bosentan is approved for use in pulmonary hypertension. It has significant teratogenic and hepatotoxic effects.
Several newer agents are thought to stabilize the RyR channel and may reduce Ca2+ leak from the SR. They are currently denoted only by code numbers (eg, TRV027, JTV519, S44121). This action, if confirmed to reduce diastolic stiffness, would be especially useful in diastolic failure with preserved ejection fraction.
Most patients with chronic heart failure respond favorably to certain β blockers despite the fact that these drugs can precipitate acute decompensation of cardiac function (see Chapter 10). Studies with bisoprolol, carvedilol, metoprolol, and nebivolol showed a reduction in mortality in patients with stable severe heart failure, but this effect was not observed with another β blocker, bucindolol. A full understanding of the beneficial action of β blockade is lacking, but suggested mechanisms include attenuation of the adverse effects of high concentrations of catecholamines (including apoptosis), up-regulation of β receptors, decreased heart rate, and reduced remodeling through inhibition of the mitogenic activity of catecholamines.