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Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action

Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action
Authors:
Michael M Givertz, MD
Wilson S Colucci, MD
Section Editor:
Marc A Pfeffer, MD, PhD
Deputy Editor:
Todd F Dardas, MD, MS
Literature review current through: Jan 2024.
This topic last updated: Sep 01, 2022.

INTRODUCTION — Evidence-based pharmacologic therapy for heart failure with reduced ejection fraction (HFrEF; commonly defined as heart failure with left ventricular ejection fraction [LVEF] ≤40 percent) involves combination therapy with drugs proven to improve clinical outcomes in randomized trials.

As discussed separately, initial long-term therapy for HFrEF generally includes diuretic therapy to treat volume overload along with a renin-angiotensin system inhibitor (angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin converting enzyme [ACE] inhibitor, or angiotensin receptor blocker [ARB]) plus a beta blocker. For patients unable to take a renin-angiotensin system inhibitor due to an intolerance, the combination of hydralazine plus an oral nitrate is an alternative. The following secondary long-term agents are added to initial therapy for selected patients who meet specific criteria for each agent: a mineralocorticoid receptor antagonist (MRA), sodium-glucose cotransporter 2 (SGLT2) inhibitor, ivabradine, vericiguat, hydralazine plus nitrate, and digoxin. The clinical use of these agents and evidence supporting their use are discussed separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

This topic will review the proposed mechanisms of action for initial and secondary pharmacologic agents for HFrEF. The proposed mechanisms are not mutually exclusive or considered definitive. They are based on mechanistic human as well as animal studies which generated supportive insights into the more robust clinical outcome data from major randomized controlled trials. However, clinical decisions regarding the use of these agents for the treatment of HFrEF should be based on the clinical outcome trials rather than the presumed supportive mechanisms.

The pathophysiology of HFrEF and an overview of the management of HFrEF are discussed separately. (See "Pathophysiology of heart failure: Neurohumoral adaptations" and "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

RENIN-ANGIOTENSIN SYSTEM INHIBITORS — Blockade of the renin-angiotensin system by an angiotensin receptor-neprilysin inhibitor (ARNI), or angiotensin-converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) is a key component of treating patients with HFrEF [1-3]. Each of these agents attenuates adverse cardiac remodeling [4-7]. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.)

ACE inhibitors — The mechanism by which ACE inhibitors act in HF is incompletely understood. The observation that other pure vasodilators (ie, those that are not neurohumoral modulators) do not improve survival (or do so to a lesser degree than ACE inhibitors) or may actually worsen cardiac function and/or clinical outcomes has led to the conclusion that ACE inhibitors work primarily by a mechanism other than simply decreasing preload and afterload, or that detrimental effects due to excessive vasoconstriction per se (eg, renin-angiotensin aldosterone system or sympathetic activation) are countered by other actions of ACE inhibitors.

The following are possible mechanisms for ACE inhibitor effects in patients with HF:

●Inhibition of the adverse effects of circulating angiotensin and/or aldosterone on target organs such as heart, blood vessels, and kidney.

●Modulation of the tissue renin-angiotensin systems in the heart, vasculature, and other organs [6,7] (see "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Renin-angiotensin system'). In the heart this system may contribute to pathological myocardial remodeling leading to deleterious effects on ventricular structure and function.

●Reduction in central sympathetic outflow and enhancement of sympathoinhibitory responses to baroreceptor stimulation [8,9].

●Improvements in arterial tone and/or compliance leading to decreased LV afterload [10], thereby contributing to improved systolic function and/or decreased hypertrophy and diastolic dysfunction.

●Elevation in the concentration of kinins, most importantly bradykinin, by inhibiting the kininase activity of ACE [11].

●Improvement in endothelial function leading to improved vascular function [12].

●Favorable effects on atherosclerosis as suggested by reduction in risk of myocardial infarction in randomized trials [13,14].

●Alterations in protein composition of skeletal muscle [15], which may contribute to improvement in exercise capacity [16,17].

●Beneficial effects on insulin sensitivity and glycemic control [18,19].

●Attenuation of atrial remodeling and reduced incidence of atrial fibrillation [20]. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation", section on 'Possible mechanisms'.)

●Antiinflammatory effects through inhibition of renin-angiotensin system signaling [21].

Angiotensin II receptor blockers — Angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors reduce the stimulation of angiotensin II (AT) receptors via different mechanisms (figure 1). ACE inhibitors block the formation of angiotensin II, thereby decreasing the amount of angiotensin available to both AT type 1 (AT1) and AT type 2 (AT2) receptors. ARBs selectively block the binding of angiotensin II to the AT1 receptor, but do not affect the AT2 receptor [22]. The importance of this is uncertain, since the AT1 receptor seems to dominate, and clinical trials generally show equivalent benefits of ACE inhibitors and ARBs in patients with HFrEF. To attain clinical benefits comparable to those observed with an ACE inhibitor, it is important to select an appropriate ARB dose [23]. (See "Differences between angiotensin-converting enzyme inhibitors and receptor blockers" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Sacubitril-valsartan, ACE inhibitor, or ARB' and "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Renin-angiotensin system'.)

Another difference is that ACE inhibitors, but not ARBs, reduce kinin degradation, since ACE is also a kininase (figure 1). The accumulation of kinins may mediate some of the benefits as well as the adverse effects of ACE inhibitors. One important clinical consequence resulting from the lack of kinin accumulation is that the ARBs do not induce cough, a complication that occurs in 3 to 20 percent of patients treated with ACE inhibitors, and do not increase the risk of angioedema. The approach to using one of these agents for the treatment of HFrEF is discussed separately. (See "ACE inhibitor-induced angioedema".)

Angiotensin receptor-neprilysin inhibitor (ARNI) — The drug combination sacubitril-valsartan (a neprilysin inhibitor plus an ARB) is known as an angiotensin receptor-neprilysin inhibitor (ARNI). This drug combination was developed to block harmful effects of renin-angiotensin-aldosterone system (RAAS) activation while also raising levels of potentially beneficial endogenous vasoactive peptides, particularly natriuretic peptides that are degraded by neprilysin. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.)

Detrimental neurohormonal activation involving the RAAS and sympathetic nervous system is a key target for HF therapy. Augmentation of beneficial counter-regulatory systems such as natriuretic peptides is an additional strategy to treat HF. Inhibition of neprilysin (a neutral endopeptidase) raises levels of several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin, and may thus have beneficial effects in patients with HF.

Two pharmacologic strategies have been undertaken to inhibit both neprilysin and the RAAS system; while the first (omapatrilat) was complicated by an unacceptable adverse effect, the latter (sacubitril-valsartan) successfully improved outcomes in patients with HFrEF compared with ACE inhibitor:

●Omapatrilat was a compound that inhibited neprilysin, angiotensin converting enzyme (ACE), and aminopeptidase P. The commercial development of this compound was halted due to an unacceptably high rate of angioedema, attributed to an increase in bradykinin levels, which occurred since neprilysin, ACE, and aminopeptidase P each degrade bradykinin [24]. This is an important outcome to remember for it emphasizes the need to avoid concomitant neprilysin inhibition and ACE inhibition when treating patients with HF.

●The strategy that ultimately proved successful in improving outcomes in HFrEF was to combine a neprilysin inhibitor with an angiotensin receptor blocker (ARB) to create an angiotensin receptor-neprilysin inhibitor (ARNI).

It has been hypothesized that the elevated angiotensin II levels resulting from neprilysin inhibition are blocked by the ARB, preventing elevated angiotensin II levels from exerting detrimental effects (figure 2). In PARADIGM-HF, the rate of angioedema with ARNI was nominally but not significantly elevated compared with ACE inhibitor [25]. In PIONEER-HF, rates of angioedema in patients with acute HF were similarly low and not significantly different between the sacubitril-valsartan (0.2 percent) and enalapril (1.4 percent) groups [26].

The mechanism responsible for the incremental benefit of neprilysin inhibition versus ARB alone is not clear. Ecadotril, a pure neprilysin inhibitor, was found not to be beneficial in HF patients [27], presumably because the benefit of raising levels of favorable neurohormones (the natriuretic peptides) was offset by elevated levels of angiotensin II, which has deleterious effects in HF. Likewise, the administration of nesiritide (B-type natriuretic peptide) did not improve clinical outcomes in the setting of acute HF in the ASCEND-HF trial [28].

Possible mechanisms for greater clinical benefit with ARNI compared with ACE inhibitor may be greater blood pressure lowering [25,26] or reduced requirement for diuretic [29].

Clinical studies suggest that ARNI may reverse adverse remodeling in patients with HFrEF [4,30], possibly through direct antifibrotic effects [31-34]. A short-term (12-week) randomized trial (EVALUATE-HF) in 464 patients with HFrEF found that changes in aortic characteristic impedance and ejection fraction were similar with sacubitril-valsartan and enalapril despite significant reductions in LV volumes with ARNI [4]. Small studies suggest direct benefits of ARNI on left atrial remodeling [35,36], and a meta-analysis of observational studies showed improved right ventricular performance and reduced pulmonary hypertension [37].

Emerging preclinical and clinical data suggests that ARNI therapy may have beneficial effects on renal function and glucose control in diabetes mellitus.

●In a rat model of diabetic nephropathy, compared with ARB alone, ARNI was more effective in reducing proteinuria and renal tubular injury independent of changes in blood pressure and glycemia [38].

●In a secondary analysis from PARADIGM-HF, patients treated with sacubitril-valsartan compared with enalapril had slower decline in estimated glomerular filtration rate, and the magnitude of the benefit was greater in patients with diabetes, independent of changes in hemoglobin A1c [39].

●In patients with type 2 diabetes and HFrEF enrolled in PARADIGM-HF, hemoglobin A1c levels decreased by 0.16 percent over the first year in the enalapril group compared with 0.26 percent in the sacubitril-valsartan group. Likewise, new use of insulin was 29 percent lower in patients receiving sacubitril-valsartan (7 percent versus 10 percent for enalapril; HR 0.71, 95% CI 0·56-0·90) [40].

The beneficial effects of ARNI on diabetic kidney disease may result from decreases in oxidative stress and inflammation [41].

BETA BLOCKERS — The mechanism of benefit from beta blocker therapy in patients with HFrEF is likely related to reducing detrimental effects of catecholamine stimulation including elevated heart rate, increased myocardial energy demands, adverse remodeling due to cardiac myocyte hypertrophy and death, interstitial fibrosis, impaired beta-adrenergic signaling, arrhythmia promotion, and stimulation of other detrimental systems such as the renin-angiotensin-aldosterone axis [42,43]. The sympathetic nervous system is activated in patients with asymptomatic LV dysfunction, and further activated in patients with symptoms [44]. An elevated plasma norepinephrine concentration is a marker for poor survival in patients with HFrEF [45]. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Neurohumoral activation and heart rate' and "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Neurohumoral adaptations' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)

Beta blocker therapy may have the following effects in patients with HF:

●Reduction of detrimental direct effects of catecholamines on myocardium – Long-term exposure to catecholamines is directly detrimental to the myocardium in both animals and humans [46-48]. The effect of catecholamines on the heart and the likelihood of developing HF may be amplified by gene polymorphisms in adrenergic receptors that enhance cardiac sympathetic activity [49].

•Restoration of beta receptor responsiveness – Chronic stimulation of beta receptors reduces the responsiveness to beta adrenergic agonists due to downregulation and desensitization of the beta receptor and its coupled signaling pathways [44,50-52]. Beta blockade upregulates myocardial beta-1-receptor density in patients with HF [50], helping to restore the inotropic and chronotropic responsiveness of the myocardium, thereby improving contractile function. The effect of beta-blockers on exercise capacity in HFrEF, however, is modest [53].

•Heart rate lowering – Beta blocker therapy benefits may be mediated in part by heart rate lowering. Heart rate reduction is a potential therapeutic target in patients with HFrEF since an elevated heart rate is associated with worse cardiovascular outcomes. While the relative contributions of increased heart rate versus the underlying neurohumoral abnormalities are difficult to determine, the beneficial effects of ivabradine, an agent that acts solely by decreasing heart rate, suggests that an elevated heart rate, per se, contributes to adverse outcomes in patients with HFrEF. Possible detrimental effects of elevated heart rate include heart rate-related increases in myocardial energy demands and decreases in myocardial perfusion [54]. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Neurohumoral activation and heart rate'.)

•Improving the balance of myocardial supply and demand – In ischemic cardiomyopathy, beta blockers may improve function in regions of hibernating myocardium by reducing myocardial oxygen consumption and increasing diastolic perfusion [55]. (See "Clinical syndromes of stunned or hibernating myocardium".)

●Ventricular remodeling and performance - Beta blockade acutely depresses cardiac function due to decreases in both stroke volume and heart rate. In contrast, beta blockade improves cardiac structure and function when given chronically to patients with HF. Beta blockers have a beneficial effect on LV remodeling and can decrease LV end-systolic and end-diastolic volume [56-58] and improve systolic function over a period of three to six months (eg, mean LVEF change with carvedilol 4.2 percent, 95% CI 2-6.4 percent [59]) [57,60-67]. The improvement in LV geometry can diminish wall stress and functional mitral regurgitation [68,69]. (See "Chronic secondary mitral regurgitation: General management and prognosis", section on 'Heart failure management' and "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Remodeling'.)

Improvements have been best demonstrated with metoprolol and bisoprolol, which are beta-1 selective agents [57,64], and carvedilol, a nonselective beta blocker that also blocks the alpha-1 receptor [65-67]. The improvement in LVEF (figure 3) and the reduction in symptoms observed with carvedilol occurred in patients with mild (class II) and more severe disease (class III and IV); dose-dependence was more prominent in patients with nonischemic cardiomyopathy (figure 4) [70]. Improvement in contractile function with beta blocker therapy occurs in regions of dysfunctional but viable myocardium, but not in regions of extensive scarring [71,72].

●Reduction of vasoconstrictor levels – Beta blockers reduce the circulating level of vasoconstrictors, including norepinephrine [60,73], renin [61,74], and endothelin [75]. Vasoconstriction induced by these hormones increases afterload, thereby promoting the rate of progression of cardiac dysfunction.

●Effects on myocardial gene expression

•Functional improvement with beta blockers is associated with normalization in the expression of a number of myocardial genes [76]. The changes that occur would be expected to enhance contractility and reduce pathologic hypertrophy, but it is not clear if they were responsible for or a result of the clinical improvement.

•Beta blockade may reduce myocardial gene expression of some of the inflammatory cytokines that occurs during the development of HF [77-79]. (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Other factors'.)

●Antiarrhythmic effects

•In addition to possible hemodynamic benefits, beta blockers also decrease the frequency of ventricular premature beats and the incidence of sudden cardiac death, especially after a myocardial infarction. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF", section on 'Guideline-directed medical therapy' and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy" and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy", section on 'Heart failure therapy'.)

•There is evidence that beta blockers may also reduce the likelihood of the development of atrial fibrillation in patients with HFrEF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Beta blockers'.)

MINERALOCORTICOID RECEPTOR ANTAGONISTS — In addition to the diuretic and blood pressure lowering effects of MRA therapy, two major, not mutually exclusive mechanisms may contribute to the benefits associated with such therapy in patients with HFrEF: maintenance of a higher serum potassium concentration via reduced urinary potassium loss, and blockade of the deleterious effects of aldosterone on the heart and possibly other targets such as kidney and blood vessels. To the degree that the tissue-level effects are important, a similar benefit would not be expected with other potassium-sparing diuretics (such as amiloride).

Raising serum potassium — Mineralocorticoid receptor antagonism may preserve serum potassium concentration and thus counter the risk of hypokalemia and associated arrhythmic risk caused by non-potassium-sparing diuretics. Support for this mechanism comes from observation of increased arrhythmic mortality in patients with HF treated with non-potassium-sparing diuretics alone in a retrospective analysis of data from the SOLVD trial [80]. In comparison, there was no association between arrhythmic death and use of a potassium-sparing diuretic, either alone or in combination with a non-potassium-sparing agent.

MRA therapy reduced the risk of hypokalemia in patients with HFrEF in clinical trials (eg, in the EPHESUS trial, serum potassium <3.5 meq/L occurred in 8.4 percent with eplerenone versus 13.1 percent with placebo) [81,82].

However, it seems unlikely that maintenance of serum potassium concentration is the main mechanism for MRA benefit in HF. In the RALES trial, similar significant mortality benefits were seen in patients with median potassium levels ≥4.2 and <4.2 mmol/L [83]. Similarly, there was no differential effect of baseline serum potassium level on beneficial outcomes in EPHESUS [81].

Blocking aldosterone effect on the heart — The rationale for the importance of blocking the effects of aldosterone on the heart comes in part from two observations: The heart contains mineralocorticoid receptors and aldosterone is produced locally in the diseased heart in proportion to the severity of HF [84]. The latter effect is mediated by the induction of aldosterone synthase (CYP11B2) by angiotensin II in the failing ventricle [85].

Locally produced aldosterone may create a vicious cycle by stimulating angiotensin converting enzymes in the local renin-angiotensin system, an effect blocked by mineralocorticoid receptor antagonism [86]. Direct effects of aldosterone on the heart may include promoting the development of cardiac hypertrophy and fibrosis [87,88], proarrhythmia [89], and, with chronic pressure overload, promoting the transition from hypertrophy to HF [90].

Activatable mineralocorticoid receptors are also present in coronary artery and aortic vascular smooth muscle cells [91]. These receptors can be activated by aldosterone as well as by angiotensin II; thus, inhibition of this system may contribute to the beneficial effects of angiotensin inhibition in patients with HF. Activation of these receptors may contribute to the increased incidence of stroke and coronary events in patients with primary aldosteronism compared with matched patients with primary (essential) hypertension [92].

Support for a pathogenetic role for aldosterone in humans with HF comes from the following observations in RALES [93]. Patients with higher serum concentrations of markers of collagen synthesis (procollagen type I carboxy-terminal peptide, procollagen type I amino-terminal peptide, and procollagen type III amino-terminal peptide) had higher rates of death and hospitalization.

Spironolactone, but not placebo, reduced the serum concentrations of these markers, and the survival benefit of spironolactone was primarily seen in patients with higher baseline procollagen concentrations. The reduction in procollagen type III amino-terminal peptide also correlated with an improvement in LV remodeling and a reduction in the serum concentrations of atrial and B-type natriuretic peptide, which are markers of myocardial remodeling, disease severity, and prognosis [94].

A pilot trial of spironolactone in patients with idiopathic dilated cardiomyopathy and mild symptoms (NYHA class I or II) also provided support for a pathogenetic role of aldosterone on the heart [95]. Benefit from spironolactone (improved LV diastolic function and regression of myocardial fibrosis) was only seen in patients with increased myocardial collagen accumulation at baseline.

Beneficial effects of eplerenone, a selective mineralocorticoid receptor antagonist, have also been reported from the EPHESUS and EMPHASIS studies [81,82] including:

●Reduced levels of aminoterminal propeptide type 1 and type III procollagen [96]

●Decreased incidence of new onset atrial fibrillation or flutter (2.7 percent with eplerenone vs. 4.5 percent in the placebo group) [97] although this has not been consistently found [98]. Pre-clinical studies demonstrate salutary effects of eplerenone on atrial fibrosis and dilation [99] that may explain these clinical benefits.

In an animal model of ischemic cardiomyopathy, treatment with either eplerenone or spironolactone down-regulated tissue markers of inflammation (sST2) and fibrosis (galectin-3/transforming growth factor-β) [100]. Notably, however, a randomized controlled trial of eplerenone in 226 patients with mild-moderate HFrEF showed no benefit of mineralocorticoid receptor antagonism on LV volumes or ejection fraction despite a reduction in collagen turnover markers and BNP [101].

Increased levels of endothelin-1 and plasma aldosterone may decrease nitric oxide (NO) levels. In experimental models, the effects of ET-1 and aldosterone on NO synthesis are mediated by PPAR-gamma coactivator (PGC)-1 alpha, endothelin-B receptors, and mineralocorticoid receptors [102]:

●In human pulmonary artery endothelial cells, MRA therapy decreased aldosterone-mediated reactive oxygen species generation and restored ET(B)-dependent NO production.

●In two animal models of pulmonary arterial hypertension, spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics.

Effect of concurrent ACE inhibitors — Mineralocorticoid receptor antagonism is beneficial in HFrEF patients treated with ACE inhibitors as demonstrated by the RALES, EPHESUS, and EMPHASIS-HF trials [81-83]. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.)

One might postulate that mineralocorticoid receptor antagonism would be less beneficial in patients treated with ACE inhibitors, given the effects of ACE inhibitors on reducing angiotensin II and on raising serum potassium. Angiotensin II is the major physiologic stimulus to aldosterone secretion; as a result, reducing angiotensin II production with an ACE inhibitor should lower plasma aldosterone levels.

One proposed explanation for the beneficial effect of MRA in patients with HF treated with an ACE inhibitor is that many of these patients have plasma aldosterone concentrations above the upper limit of normal (11 of 34 in one report), often with virtually complete inhibition of vascular angiotensin converting enzyme [103]. The stimulus to aldosterone secretion in such patients could be mediated by tissue renin-angiotensin systems not inhibited by the ACE inhibitor, angiotensin II generation via pathways not requiring angiotensin converting enzyme, or other stimuli such as a high serum potassium concentration [104], which is not uncommon in patients with advanced HF. However, it has not been established that baseline aldosterone levels are predictive of MRA benefit.

SODIUM-GLUCOSE CO-TRANSPORTER 2 INHIBITORS — A number of mechanisms have been proposed for the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in preventing HF hospitalizations in patients with type 2 diabetes mellitus (DM) and improving outcomes in patients with HFrEF with or without DM [105-113]. SGLT2 inhibitors promote osmotic diuresis and natriuresis in patients with and without diabetes, and thus may reduce preload [114-116]. SGLT2 inhibitors may also have vascular effects (including improving endothelial function) that promote vasodilation and thus may also reduce afterload [117-120]. It has also been postulated that SGLT2 inhibitors may improve myocardial metabolism and thus improve cardiac efficiency [121,122]. Another hypothesis is that SGLT2 inhibitors may inhibit the sodium-hydrogen exchanger 1 isoform in the myocardium and thus may reduce cytoplasmic sodium and calcium levels, while increasing mitochondrial calcium levels [123-125]. SGLT2 inhibition has also been postulated to reduce cardiac fibrosis [126,127] and to alter adipokines and cytokine production [128,129]. In addition, beneficial effects of SGLT2 inhibitors on renal function may contribute to improved outcomes in patients with HF [130]. SGLT2 inhibitors have also been shown to reduce the risk of atrial arrhythmias by mechanisms that may include reductions in atrial dilation, inflammation, oxidative stress, and sympathetic overdrive [131]. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus" and "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)

In a secondary analysis of the EMPA-TROPISM study, empagliflozin was associated with significant reductions in epicardial adipose tissue, subcutaneous adipose tissue, interstitial myocardial fibrosis, aortic stiffness, and inflammatory biomarkers [132].

There are no data showing that the beneficial actions of SGLT2 inhibitors in patients with HFrEF are related to glucose lowering.

HYDRALAZINE PLUS NITRATE — A hemodynamic rationale for the combined use of hydralazine and nitrate therapy is to reduce cardiac preload and afterload by achieving both venous and arterial vasodilation. Hydralazine is an arterial vasodilator, and nitrates are predominantly venodilators. These vasodilatory effects can reduce LV afterload and intracardiac filling pressures, and thereby may decrease pathologic cardiac remodeling. (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Remodeling'.)

It has also been hypothesized that the combination of hydralazine with nitrates enhances nitric oxide bioavailability since nitrates serve as nitric oxide donors and hydralazine is an antioxidant that reduces consumption of nitric oxide [133-135]. It has been postulated that this protective mechanism can be recruited even in the presence of neurohormonal blockade (eg, use of angiotensin converting enzyme inhibitors).

IVABRADINE — Ivabradine is a selective inhibitor of the sinoatrial pacemaker modulating "f-current" (If) [54]. Ivabradine slows the sinus rate by prolonging the slow depolarization phase. Because of the very selective role of the f-current in the heart, it is likely that the mechanism of clinical benefit from ivabradine in patients with HFrEF [136] is related to heart rate reduction. This concept is supported by the association between clinical benefit and heart rate change.

Heart rate as a therapeutic target — Heart rate reduction is a potential therapeutic target in patients with HFrEF since an elevated heart rate is associated with worse cardiovascular outcomes. An elevated heart rate reflects, in part, activation of the sympathetic nervous system and withdrawal of parasympathetic activity, which are components of the neurohumoral response to HF [44]. An elevated plasma norepinephrine concentration is a marker for poor survival in these patients [45]. It has been unclear whether heart rate is a determinant of prognosis, or simply a marker for increased sympathetic tone. While the relative contributions of increased heart rate versus the underlying neurohumoral abnormalities are difficult to determine, the beneficial effects of ivabradine, an agent that acts solely by decreasing heart rate (discussed below), suggests that an elevated heart rate, per se, contributes to adverse outcomes in patients with HFrEF. Possible detrimental effects of elevated heart rate include heart rate-related increases in myocardial energy demands and decreases in myocardial perfusion [54]. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Neurohumoral activation and heart rate'.)

Various heart rate lowering drugs have differing effects — While some heart rate lowering drugs are beneficial in patients with HFrEF, various types of heart rate lowering drugs have differing mechanisms of action, as well as differing effects on outcomes in patients with HFrEF.

Beta blockers and ivabradine both decrease heart rate and improve clinical outcomes in patients with HFrEF, but they have different mechanisms of action as discussed above. In patients with HFrEF with resting heart rate of 70 bpm or greater despite maximum tolerated beta blocker dose up to target (or who have a contraindication to beta blocker use), there is clinical benefit from ivabradine. For both drugs, there is evidence that clinical benefit is related to heart rate lowering, although beta blockers likely have other beneficial effects. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)

Digoxin has anti-sympathetic and pro-parasympathetic actions that may reduce the heart rate in patients with HFrEF who are in sinus rhythm [54], although there is no evidence that a change in heart rate contributes to its clinical benefit. In patients with HFrEF, digoxin reduces the risk of hospitalization for HF. As digoxin exerts multiple effects on cardiovascular function and neurohumoral activity, it is unclear whether the modest decrease in heart rate contributes to the overall clinical effects of the drug. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Optional therapies'.)

Non-dihydropyridine calcium channel blockers (eg, diltiazem and verapamil) have negative inotropic effects and reduce heart rate in patients in sinus rhythm or atrial fibrillation but are not beneficial in patients with HFrEF. Since calcium channel blockers provide no direct clinical benefit in patients with HFrEF, these agents are generally avoided in this clinical setting. (See "Calcium channel blockers in heart failure with reduced ejection fraction".)

VERICIGUAT — Vericiguat is an oral soluble guanylate cyclase stimulator with associated vasodilatory effects. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Vericiguat'.)

●Vericiguat enhances the cyclic guanosine monophosphate (cGMP) pathway by directly stimulating soluble guanylate cyclase through a binding site independent of nitric oxide (NO), and it sensitizes soluble guanylate cyclase to endogenous NO by stabilizing NO binding to the binding site [137,138].

●In addition to direct myocardial and pulmonary vasodilator effects, vericiguat causes a significant decrease in aortic wave reflection parameters even at doses that do not reduce blood pressure in dogs with hypertension [139].

●In animal and in vitro studies, GMP exerts myocardial antiremodeling effects by inhibiting cardiac myocyte hypertrophy and apoptosis, as well as fibroblast-mediated fibrosis [140], but the role of this mechanism in patients with HF has not been tested.

DIGOXIN — Digoxin acts by inhibiting the Na-K-ATPase pump, thus reducing the transport of sodium from the intracellular space in myocytes [141] as well as noncardiac cells to the extracellular space [142]. This mechanism contributes to digoxin’s hemodynamic, neurohumoral, and electrophysiologic effects [143].

Digoxin dosing, cautions, and monitoring are discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Optional therapies'.)

Hemodynamic effects — In myocytes, increased intracellular sodium (resulting from Na-K-ATPase inhibition by digoxin) reduces sodium-calcium exchange (which normally causes calcium extrusion from the cell), leading to a rise in the intracellular calcium concentration. This results in increased myocyte contractile performance (increased shortening velocity) and improved overall LV systolic function [141,144].

Several small trials have examined the short-term hemodynamic efficacy of digoxin in patients with HFrEF using invasive monitoring [145-147]. These studies showed that the administration of 1 mg of intravenous digoxin resulted in acute increases in cardiac output and LV stroke work index, and decreases in mean pulmonary capillary wedge pressure, pulmonary artery diastolic pressure, and right atrial pressure, either at rest or with exercise.

Digoxin has variable effects on systemic vascular resistance: digoxin may reduce systemic vascular resistance in patients with severe HF [145,148], but digoxin may have no effect on systemic vascular resistance or even increase it in patients with less hemodynamic impairment [145,147].

Neurohumoral effects — In patients with HF, digoxin also inhibits sympathetic outflow and augments parasympathetic tone. Digoxin may decrease sympathetic tone by multiple mechanisms, including direct autonomic effects, as well as by normalizing impaired baroreflex responsiveness (improving carotid sinus baroreceptor sensitivity), and increasing cardiac output [149-151]. At excess levels, digoxin may augment sympathetic tone.

HF is characterized by activation of neurohumoral systems, resulting in progressive increases in the plasma concentrations of norepinephrine, renin, arginine vasopressin, atrial natriuretic peptide, and endothelin. The degree of neurohumoral activation generally varies directly with the severity of the HF and inversely with patient survival [45,152,153].

Reductions in the plasma norepinephrine concentration have been demonstrated after the administration of intravenous digoxin [146,147] and with chronic therapy [154-156]. In one report, plasma norepinephrine levels decreased (from a mean of 552 to 390 ng/mL) and parasympathetic activity increased in 26 patients receiving oral digoxin for the first time [155].

Similar results were noted in the Dutch Ibopamine Multicenter Trial [156]. In this study, 161 patients were randomly assigned to ibopamine, digoxin, or placebo. Patients randomly assigned to digoxin therapy had a significant reduction in plasma norepinephrine and renin activity after six months compared with an increase with placebo.

Electrophysiologic effects — As discussed separately, digoxin increases vagal tone (via hypersensitization of carotid sinus baroreceptors, central stimulation, increased vagal output, and possible potentiation of the effect of acetylcholine on the sinoatrial [SA] node) and reduces sympathetic tone, thus slowing the firing of the SA node and prolonging conduction at the atrioventricular (AV) node. As noted above, in the myocardium digoxin inhibits the ATPase-dependent sodium-potassium pump, thus increasing intracellular sodium; this in turn reduces the activity of sodium-calcium exchange, resulting in an increase in intracellular calcium. Elevated intracellular calcium facilitates the development of arrhythmias. (See "Cardiac arrhythmias due to digoxin toxicity", section on 'Mechanisms of cardiac toxicity'.)

Supratherapeutic digoxin levels (or therapeutic levels, particularly in the setting of comorbid conditions such as hypokalemia, hypomagnesemia, hypercalcemia, or myocardial ischemia) can cause sinus bradycardia (or acceleration of sinus rate), SA nodal block, AV block, and atrial, junctional, and ventricular arrhythmias. These adverse effects may be enhanced in women compared to men with HFrEF [157] (See "Cardiac arrhythmias due to digoxin toxicity", section on 'Digoxin-induced arrhythmias'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults".)

SUMMARY

●Renin-angiotensin system inhibitors – Each of the renin-angiotensin system antagonists (angiotensin-converting enzyme [ACE] inhibitor, single agent angiotensin II receptor blocker [ARB], and angiotensin receptor-neprilysin inhibitor [ARNI]) blocks harmful effects of renin-angiotensin-aldosterone system activation and attenuates adverse cardiac and vascular remodeling. Neprilysin inhibition contributes to the clinical effects of ARNI by inhibiting the levels of natriuretic peptides and/or other peptides that are degraded by neprilysin. ACE inhibitor and ARNI (but not single agent ARB) also raise levels of kinins which may have beneficial hemodynamic effects but also increase the risk of angioedema. (See 'Renin-angiotensin system inhibitors' above.)

●Beta blockers – The mechanism of benefit from beta blocker therapy in patients with heart failure with reduced ejection fraction (HFrEF) is likely related to reducing detrimental effects of catecholamine stimulation including elevated heart rate, increased myocardial energy demands, adverse remodeling due to cardiac myocyte hypertrophy and death, interstitial fibrosis, impaired beta-adrenergic signaling, arrhythmia promotion, and stimulation of other detrimental systems such as the renin-angiotensin-aldosterone axis. (See 'Beta blockers' above.)

●Mineralocorticoid receptor antagonists – Mineralocorticoid receptor antagonist (MRA) therapy has diuretic and blood pressure lowering effects, raises serum potassium concentration via reduced urinary potassium loss, and blocks deleterious effects of aldosterone on the heart (including hypertrophy and fibrosis) and possibly other target organs such as kidney and blood vessels. MRA therapy may also have antiinflammatory and antioxidant properties. (See 'Mineralocorticoid receptor antagonists' above.)

●Sodium-glucose co-transporter 2 inhibitors – A number of mechanisms have been proposed for the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors in preventing HF hospitalizations in patients with type 2 diabetes mellitus (DM) and improving outcomes in patients with HFrEF with or without DM. SGLT2 inhibitors promote osmotic diuresis and natriuresis, may promote vasodilation, improve myocardial metabolism, inhibit sodium-hydrogen exchange in myocardium, reduce cardiac fibrosis, and alter adipokine and cytokine production, as well as attenuate progression of renal dysfunction. (See 'Sodium-glucose co-transporter 2 inhibitors' above.)

●Hydralazine plus nitrate – The combined use of hydralazine and nitrates reduces cardiac afterload and preload, and may also enhance nitric oxide bioavailability. (See 'Hydralazine plus nitrate' above.)

●Ivabradine – The mechanism of benefit from ivabradine in patients with HFrEF is likely slowing of the sinus rate. (See 'Ivabradine' above.)

●Vericiguat – Vericiguat enhances the cyclic guanosine monophosphate (cGMP) pathway by directly stimulating soluble guanylate cyclase through a binding site independent of nitric oxide (NO), and it sensitizes soluble guanylate cyclase to endogenous NO by stabilizing NO binding to the binding site. (See 'Vericiguat' above.)

●Digoxin – Digoxin acts by inhibiting the Na-K-ATPase pump, thus reducing the transport of sodium from the intracellular space in myocytes as well as noncardiac cells to the extracellular space. This mechanism contributes to digoxin’s hemodynamic, neurohumoral, and electrophysiologic effects. (See 'Digoxin' above.)

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  121. Lopaschuk GD, Verma S. Empagliflozin's Fuel Hypothesis: Not so Soon. Cell Metab 2016; 24:200.
  122. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care 2016; 39:1108.
  123. Packer M, Anker SD, Butler J, et al. Effects of Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Patients With Heart Failure: Proposal of a Novel Mechanism of Action. JAMA Cardiol 2017; 2:1025.
  124. Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia 2018; 61:722.
  125. Baartscheer A, Schumacher CA, Wüst RC, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 2017; 60:568.
  126. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med 2017; 104:298.
  127. Januzzi JL Jr, Butler J, Jarolim P, et al. Effects of Canagliflozin on Cardiovascular Biomarkers in Older Adults With Type 2 Diabetes. J Am Coll Cardiol 2017; 70:704.
  128. Packer M. Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis. Diabetes Obes Metab 2018; 20:1361.
  129. Zhang N, Feng B, Ma X, et al. Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction. Cardiovasc Diabetol 2019; 18:107.
  130. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019; 380:2295.
  131. Zelniker TA, Bonaca MP, Furtado RHM, et al. Effect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus: Insights From the DECLARE-TIMI 58 Trial. Circulation 2020; 141:1227.
  132. Requena-Ibáñez JA, Santos-Gallego CG, Rodriguez-Cordero A, et al. Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study. JACC Heart Fail 2021; 9:578.
  133. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351:2049.
  134. Taylor AL, Ziesche S, Yancy CW, et al. Early and sustained benefit on event-free survival and heart failure hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across subgroups in the African-American Heart Failure Trial. Circulation 2007; 115:1747.
  135. Cole RT, Kalogeropoulos AP, Georgiopoulou VV, et al. Hydralazine and isosorbide dinitrate in heart failure: historical perspective, mechanisms, and future directions. Circulation 2011; 123:2414.
  136. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010; 376:875.
  137. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011; 123:2263.
  138. Triposkiadis F, Xanthopoulos A, Skoularigis J, Starling RC. Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure. Heart Fail Rev 2022; 27:1991.
  139. Boden K, Sandner P, Roessig L, et al. Vericiguat Improves Aortic Wave Reflection Parameters in a New Preclinical Model of Hypertension. Circ Heart Fail 2022; 15:e008735.
  140. Calderone A, Thaik CM, Takahashi N, et al. Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest 1998; 101:812.
  141. Smith TW. Digitalis. Mechanisms of action and clinical use. N Engl J Med 1988; 318:358.
  142. Gheorghiade M, Ferguson D. Digoxin. A neurohormonal modulator in heart failure? Circulation 1991; 84:2181.
  143. Ambrosy AP, Butler J, Ahmed A, et al. The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions. J Am Coll Cardiol 2014; 63:1823.
  144. McMahon WS, Holzgrefe HH, Walker JD, et al. Cellular basis for improved left ventricular pump function after digoxin therapy in experimental left ventricular failure. J Am Coll Cardiol 1996; 28:495.
  145. Gheorghiade M, St Clair J, St Clair C, Beller GA. Hemodynamic effects of intravenous digoxin in patients with severe heart failure initially treated with diuretics and vasodilators. J Am Coll Cardiol 1987; 9:849.
  146. Gheorghiade M, Hall V, Lakier JB, Goldstein S. Comparative hemodynamic and neurohormonal effects of intravenous captopril and digoxin and their combinations in patients with severe heart failure. J Am Coll Cardiol 1989; 13:134.
  147. Ribner HS, Plucinski DA, Hsieh AM, et al. Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: a hemodynamic-hormonal study. Am J Cardiol 1985; 56:896.
  148. Arnold SB, Byrd RC, Meister W, et al. Long-term digitalis therapy improves left ventricular function in heart failure. N Engl J Med 1980; 303:1443.
  149. Ferguson DW, Abboud FM, Mark AL. Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction. Circulation 1984; 69:451.
  150. Schobel HP, Oren RM, Roach PJ, et al. Contrasting effects of digitalis and dobutamine on baroreflex sympathetic control in normal humans. Circulation 1991; 84:1118.
  151. Ferguson DW, Berg WJ, Sanders JS, et al. Sympathoinhibitory responses to digitalis glycosides in heart failure patients. Direct evidence from sympathetic neural recordings. Circulation 1989; 80:65.
  152. Cohn JN, Johnson GR, Shabetai R, et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 1993; 87:VI5.
  153. Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 1986; 73:257.
  154. Alicandri C, Fariello R, Boni E, et al. Captopril versus digoxin in mild-moderate chronic heart failure: a crossover study. J Cardiovasc Pharmacol 1987; 9 Suppl 2:S61.
  155. Krum H, Bigger JT Jr, Goldsmith RL, Packer M. Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure. J Am Coll Cardiol 1995; 25:289.
  156. van Veldhuisen DJ, Man in 't Veld AJ, Dunselman PH, et al. Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT). J Am Coll Cardiol 1993; 22:1564.
  157. Bots SH, Groepenhoff F, Eikendal ALM, et al. Adverse Drug Reactions to Guideline-Recommended Heart Failure Drugs in Women: A Systematic Review of the Literature. JACC Heart Fail 2019; 7:258.
Topic 122165 Version 15.0

References

1 : 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.

2 : 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.

3 : 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management 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.

4 : Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

5 : Myocardial recovery and the failing heart: myth, magic, or molecular target?

6 : Neurohormonal activation in heart failure with reduced ejection fraction.

7 : Intracrine angiotensin II functions originate from noncanonical pathways in the human heart.

8 : Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure.

9 : Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure.

10 : Radial, carotid and aortic distensibility in congestive heart failure: effects of high-dose angiotensin-converting enzyme inhibitor or low-dose association with angiotensin type 1 receptor blockade.

11 : Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure.

12 : Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure : role of nitric oxide, prostanoids, oxidant stress, and bradykinin.

13 : Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.

14 : Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).

15 : Improved exercise tolerance after losartan and enalapril in heart failure: correlation with changes in skeletal muscle myosin heavy chain composition.

16 : A meta-analysis of the effect of angiotensin-converting enzyme inhibitors on functional capacity in patients with symptomatic left ventricular systolic dysfunction.

17 : Skeletal muscle changes in patients with chronic heart failure before and after treatment with enalapril.

18 : Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials.

19 : Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure.

20 : Angiotensin II and angiotensin 1-7: which is their role in atrial fibrillation?

21 : The potential therapeutic use of renin-angiotensin system inhibitors in the treatment of inflammatory diseases.

22 : Angiotensin receptor blockers: Focus on cardiac and renal injury.

23 : Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

24 : Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema.

25 : Angiotensin-neprilysin inhibition versus enalapril in heart failure.

26 : Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure.

27 : Lack of efficacy of neutral endopeptidase inhibitor ecadotril in heart failure. The International Ecadotril Multi-centre Dose-ranging Study Investigators.

28 : Effect of nesiritide in patients with acute decompensated heart failure.

29 : Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial.

30 : Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction.

31 : Sacubitril/Valsartan Decreases Cardiac Fibrosis in Left Ventricle Pressure Overload by Restoring PKG Signaling in Cardiac Fibroblasts.

32 : Effect of SAcubitril/Valsartan on left vEntricular ejection fraction and on the potential indication for Implantable Cardioverter Defibrillator in primary prevention: the SAVE-ICD study.

33 : The benefits of sacubitril-valsartan in patients with acute myocardial infarction: a systematic review and meta-analysis.

34 : Reverse Cardiac Remodeling and Outcome After Initiation of Sacubitril/Valsartan.

35 : Effect of angiotensin receptor neprilysin inhibitors on left atrial remodeling and prognosis in heart failure.

36 : Sacubitril/valsartan attenuates atrial structural remodelling in atrial fibrillation patients.

37 : Effect of Sacubitril/Valsartan on the Right Ventricular Function and Pulmonary Hypertension in Patients With Heart Failure With Reduced Ejection Fraction: A Systematic Review and Meta-Analysis of Observational Studies.

38 : The combination of a neprilysin inhibitor (sacubitril) and angiotensin-II receptor blocker (valsartan) attenuates glomerular and tubular injury in the Zucker Obese rat.

39 : Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial.

40 : Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.

41 : Sacubitril/valsartan treatment has differential effects in modulating diabetic kidney disease in db/db mice and KKAy mice compared with valsartan treatment.

42 : beta-adrenergic receptor blockade in chronic heart failure.

43 : The Evolution ofβ-Blockers in Coronary Artery Disease and Heart Failure (Part 1/5).

44 : Achieving a Maximally Toleratedβ-Blocker Dose in Heart Failure Patients: Is There Room for Improvement?

45 : Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.

46 : Apoptosis: basic mechanisms and implications for cardiovascular disease.

47 : New Insights in Cardiacβ-Adrenergic Signaling During Heart Failure and Aging.

48 : Mechanisms of physiological and pathological cardiac hypertrophy.

49 : Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure.

50 : Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart.

51 : Reduced beta 1 receptor messenger RNA abundance in the failing human heart.

52 : Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts.

53 : Effects of bisoprolol fumarate on left ventricular size, function, and exercise capacity in patients with heart failure: analysis with magnetic resonance myocardial tagging.

54 : Heart rate: a prognostic factor and therapeutic target in chronic heart failure. The distinct roles of drugs with heart rate-lowering properties.

55 : Myocardial viability as a determinant of the ejection fraction response to carvedilol in patients with heart failure (CHRISTMAS trial): randomised controlled trial.

56 : Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group.

57 : Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure.

58 : Effects of carvedilol on left ventricular remodelling in chronic stable heart failure: a cardiovascular magnetic resonance study.

59 : Benefits ofβblockers in patients with heart failure and reduced ejection fraction: network meta-analysis.

60 : Long-term beta-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo.

61 : Effects of metoprolol CR in patients with ischemic and dilated cardiomyopathy : the randomized evaluation of strategies for left ventricular dysfunction pilot study.

62 : Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy.

63 : Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure. Improvements in hemodynamic, contractile, and diastolic performance with bucindolol.

64 : A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees.

65 : Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise.

66 : Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group.

67 : Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Australia/New Zealand Heart Failure Research Collaborative Group.

68 : Effects of carvedilol on left ventricular mass, chamber geometry, and mitral regurgitation in chronic heart failure.

69 : Beta-blockade therapy in chronic heart failure: diastolic function and mitral regurgitation improvement by carvedilol.

70 : Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators.

71 : Gadolinium cardiovascular magnetic resonance predicts reversible myocardial dysfunction and remodeling in patients with heart failure undergoing beta-blocker therapy.

72 : Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with beta-blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST).

73 : Early reduction of neurohumoral factors plays a key role in mediating the efficacy of beta-blocker therapy for congestive heart failure.

74 : Effects of bucindolol on neurohormonal activation in congestive heart failure.

75 : Changes in plasma endothelin-1 levels reflect clinical response to beta-blockade in chronic heart failure.

76 : Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.

77 : Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression.

78 : Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy.

79 : beta-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling.

80 : Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction.

81 : Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.

82 : Eplerenone in patients with systolic heart failure and mild symptoms.

83 : The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.

84 : Aldosterone production is activated in failing ventricle in humans.

85 : Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis.

86 : Aldosterone induces angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes.

87 : Induction of cardiac fibrosis by aldosterone.

88 : Aldosterone and cardiac fibrosis: in vitro studies.

89 : Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias.

90 : Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload.

91 : Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells.

92 : Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism.

93 : Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators.

94 : Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure.

95 : Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study.

96 : Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study.

97 : Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study.

98 : Mineralocorticoid Receptor Antagonism in Patients With Atrial Fibrillation: Findings From the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) Registry.

99 : Eplerenone Reduces Atrial Fibrillation Burden Without Preventing Atrial Electrical Remodeling.

100 : Mineralocorticoid receptor antagonists modulate galectin-3 and interleukin-33/ST2 signaling in left ventricular systolic dysfunction after acute myocardial infarction.

101 : Randomized, double-blind, multicenter, placebo-controlled study evaluating the effect of aldosterone antagonism with eplerenone on ventricular remodeling in patients with mild-to-moderate heart failure and left ventricular systolic dysfunction.

102 : Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension.

103 : Elevated plasma aldosterone levels despite complete inhibition of the vascular angiotensin-converting enzyme in chronic heart failure.

104 : Multiplicative interaction between angiotensin II and K concentration in stimulation of aldosterone.

105 : Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials.

106 : Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion.

107 : Cardiac and Renal Effects of Sodium-Glucose Co-Transporter 2 Inhibitors in Diabetes: JACC State-of-the-Art Review.

108 : Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America: This statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update.

109 : Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.

110 : Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.

111 : Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes.

112 : Mechanisms and Models in Heart Failure: A Translational Approach.

113 : Sodium glucose cotransporter 2 inhibitors: mechanisms of action in heart failure.

114 : Empagliflozin and Kinetics of Renal Glucose Transport in Healthy Individuals and Individuals With Type 2 Diabetes.

115 : Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes.

116 : Empagliflozin (BI 10773), a Potent and Selective SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects.

117 : Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.

118 : The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels.

119 : Effects of the Selective Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin on Vascular Function and Central Hemodynamics in Patients With Type 2 Diabetes Mellitus.

120 : Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study.

121 : Empagliflozin's Fuel Hypothesis: Not so Soon.

122 : CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis.

123 : Effects of Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Patients With Heart Failure: Proposal of a Novel Mechanism of Action.

124 : Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.

125 : Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits.

126 : Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts.

127 : Effects of Canagliflozin on Cardiovascular Biomarkers in Older Adults With Type 2 Diabetes.

128 : Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis.

129 : Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction.

130 : Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.

131 : Effect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus: Insights From the DECLARE-TIMI 58 Trial.

132 : Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study.

133 : Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.

134 : Early and sustained benefit on event-free survival and heart failure hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across subgroups in the African-American Heart Failure Trial.

135 : Hydralazine and isosorbide dinitrate in heart failure: historical perspective, mechanisms, and future directions.

136 : Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.

137 : Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease.

138 : Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure.

139 : Vericiguat Improves Aortic Wave Reflection Parameters in a New Preclinical Model of Hypertension.

140 : Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts.

141 : Digitalis. Mechanisms of action and clinical use.

142 : Digoxin. A neurohormonal modulator in heart failure?

143 : The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions.

144 : Cellular basis for improved left ventricular pump function after digoxin therapy in experimental left ventricular failure.

145 : Hemodynamic effects of intravenous digoxin in patients with severe heart failure initially treated with diuretics and vasodilators.

146 : Comparative hemodynamic and neurohormonal effects of intravenous captopril and digoxin and their combinations in patients with severe heart failure.

147 : Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: a hemodynamic-hormonal study.

148 : Long-term digitalis therapy improves left ventricular function in heart failure.

149 : Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction.

150 : Contrasting effects of digitalis and dobutamine on baroreflex sympathetic control in normal humans.

151 : Sympathoinhibitory responses to digitalis glycosides in heart failure patients. Direct evidence from sympathetic neural recordings.

152 : Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. The V-HeFT VA Cooperative Studies Group.

153 : Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure.

154 : Captopril versus digoxin in mild-moderate chronic heart failure: a crossover study.

155 : Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure.

156 : Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT).

157 : Adverse Drug Reactions to Guideline-Recommended Heart Failure Drugs in Women: A Systematic Review of the Literature.

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