Cardiovascular Research (2023) 00, 1–15 SPOTLIGHT REVIEW

https://doi.org/10.1093/cvr/cvac187

Mechanisms of current therapeutic strategies

for heart failure: more questions than answers?

Downloaded from https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvac187/6941155 by guest on 26 January 2023

Muhammad Shahzeb Khan1, Izza Shahid2, Stephen J. Greene1,3, Robert J. Mentz1,3,
Adam D. DeVore1,3, and Javed Butler 4*
1
From the Division of Cardiology, Duke University School of Medicine, Durham, NC, USA; 2Division of Cardiovascular Prevention, Houston Methodist Academic Institute, Houston, TX, USA; 3Duke
Clinical Research Institute, Durham, NC, USA; and 4Baylor Scott and White Research Institute, Baylor University Medical Center, 3434 Live Oak St Ste 501, Dallas 75204, TX, USA

Received 13 May 2022; revised 19 October 2022; accepted 21 October 2022; online publish-ahead-of-print 20 December 2022

Abstract Heart failure (HF) is a complex, multifactorial and heterogeneous syndrome with substantial mortality and morbidity. Over the last
few decades, numerous attempts have been made to develop targeted therapies that may attenuate the known pathophysiological
pathways responsible for causing the progression of HF. However, therapies developed with this objective have sometimes failed to
show benefit. The pathophysiological construct of HF with numerous aetiologies suggests that interventions with broad mechan-
isms of action which simultaneously target more than one pathway maybe more effective in improving the outcomes of patients
with HF. Indeed, current therapeutics with clinical benefits in HF have targeted a wider range of intermediate phenotypes. Despite
extensive scientific breakthroughs in HF research recently, questions persist regarding the ideal therapeutic targets which may help
achieve maximum benefit. In this review, we evaluate the mechanism of action of current therapeutic strategies, the pathophysio-
logical pathways they target and highlight remaining knowledge gaps regarding the mode of action of these interventions.
-Keywords
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
HF • HFrEF • pathophysiology • interventions

The neutral or negative results of trials pertaining to interventions dir-

1. Introduction
Heart failure (HF) is a progressive and complex clinical syndrome charac-
terized by impaired health-related quality of life, recurrent hospitalizations,
and high mortality.1 HF has a multifactorial pathophysiological construct
which is responsible for its heterogeneous clinical presentation and
course.2 Over the last few decades, numerous attempts have been made
to develop targeted therapies that may attenuate the pathophysiological
pathways thought to be responsible for causing the progression of HF.3
However, therapies developed with the objective of altering a single path-
way have at times yielded little to no clinical benefit in ameliorating adverse
events in these patients.4,5
For decades, increasing contractility of the failing heart remained the
most prevalent view to improve cardiac performance.6 It was suggested
that improving cardiac contractility would translate to improvement in cardiac
output, thereby curtailing the risk of mortality in HF. However, all clinical trials
of positive inotropic drugs failed to show any mortality benefit.4,5 Following
this, cardiac glycosides also showed no substantial improvement on mortality.
The neutral or adverse effects on mortality in clinical trials of inotropic agents
led to an increased focus on vasodilators in reducing afterload as a means to
improve cardiac efficiency in HF.7 Similar to positive inotropes, initial clinical
trials such as Vasodilator Heart Failure Trial (V-HeFT I) showed that short-
term improvement in haemodynamics does not necessarily translate to
favourable long-term survival outcomes.8 After a series of trials, it was de-
duced that in some cases these agents may be doing more harm than good
by increasing the risk of developing worsening HF and mortality.9–11
ectly targeting improvement in a cardiac performance led to re-evaluation
of the pathophysiological mechanism responsible for HF. Over time, it was
hypothesized that a complex neuroendocrine compensatory response
maybe responsible as the primary pathophysiological construct with differ-
ent mechanisms implicated in the two main clinical phenotypes of HF,
namely HF with reduced ejection fraction (HFrEF) and HF with preserved
ejection fraction (HFpEF).12,13 In HF, long-term reduction of cardiac output
causes deleterious effects on multiple organ systems, with chronic activa-
tion of the renin–angiotensin–aldosterone system (RAAS) causing further
impairment of the structure and function of cardiac myocytes. The involve-
ment of multiple pathophysiologic processes and systems potentially high-
lights the reason why previous interventions with a specific mechanism of
action did not work. Indeed, drugs that seemed counter-intuitive, such as
beta blockers yielded favourable results in improving left ventricular ejec-
tion fraction (LVEF), antagonizing cardiac remodelling, and improving sur-
vival in patients with HF.14
To this end, contemporary trials have shown that interventions often
initially investigated for purposes other than HF have yielded positive
results in HF.14–16 Current foundational therapy for HF includes angio-
tensin receptor-neprilysin inhibitors, beta blockers, mineralocorticoid
receptor antagonists (MRAs) and sodium–glucose co-transporter 2
(SGLT-2) inhibitors.17 However, questions still remain regarding
the current therapeutic modalities and the exact pathophysiological
mechanisms these drugs alter to achieve clinical benefit in HF. In this re-
view, we summarize the contemporary understanding of the mechanism(s) of
action of current therapeutic strategies, the pathophysiological pathways

* Corresponding author. Tel: +214 820 2687, E-mail: butlzih@gmail.com.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
2 M.S. Khan et al.
they target and highlight the knowledge gaps which persist regarding the
mode of action of these drugs. Of note, this review utlises publicly available
data, and no new data were generated or analysed in support of this
research.
2. Mechanisms of contemporary
pharmacologic therapies in HF:
current evidence and knowledge
gaps
Traditionally, HF is divided into three distinct phenotypes based on the
LVEF. HFrEF is defined as LVEF ≤40%, while HFpEF is designated to pa-
tients showing signs and symptoms of HF with LVEF ≥50%. Patients
with LVEF between 41 and 49% are defined as having HF with mildly re-
duced ejection fraction (HFmrEF). These phenotypes, particularly HFrEF
and HFpEF have varying underlying aetiologies and pathophysiology.
Amongst patients with HFrEF, the overactivation of the neurohormonal
pathway is the most frequently implicated pathophysiological mechanism.
In contrast, HFpEF has multiple overlapping pathophysiological constructs,
such as venous congestion leading to oxidative stress, myocardial stiffness
due to impaired phosphorylation of titin, and altered adiponectin and leptin
regulation causing epicardial adipose tissue deposition in the surrounding
myocardium. Although considerable advancement in HF research has de-
lineated the underlying mechanisms associated with these phenotypes,
pathophysiological construct of HFpEF remains less well-established.
Consequently, the majority therapeutics have yielded mortality benefits
in patients with HFrEF but not HFpEF, plausibly due to the varying under-
lying mechanistic pathways.
The activation of multiple pathophysiological pathways in HF requires
pharmacotherapy targeted at inhibiting these systems to achieve opti-
mal clinical benefit. Accordingly, a variety of pharmacological therapies
have been investigated in recent years to inform evidence-based man-
agement which improves clinical outcomes and health-related quality
of life in these patients.18 Although a primary focus of HF research
includes identifying interventions that may alter pathways that are impli-
cated in the adverse progression of HF, to date, a number of interven-
tions that have yielded substantial clinical benefits, such as the novel
SGLT-2 inhibitors, are therapies which were initially devised to counter
a disease process other than HF. This raises concerns that interventions
which target multiple pathophysiological phenotypes rather than a sin-
gle pathophysiological pathway in HF patients, potentially aid in attenu-
ating adverse events in these patients. It therefore remains crucial to
identify the key pathophysiological mechanisms and pathways which
should be targeted to achieve maximal clinical benefit in these subsets
of patients.
3. Inotropic drugs
For decades, HF research was focused on understanding the decreased
contractility of the left ventricle and the pathways which may be targeted
to mitigate it. Increasing contractility of the myocardium became an em-
phasis to improve cardiac performance. Accordingly, much of the initial re-
search was centred on developing positive inotropic drugs in an effort to
increase LVEF, which was postulated to improve long-term survival.4
Although increasing the concentration of intracellular calcium or sensitivity
of sarcomere via stimulation of β1 receptors seemed intuitive, these agents
were only successful in improving short-term surrogate endpoints
like hemodynamics, without improving long-term mortality.19,20 On the
contrary, these drug trials were often terminated prematurely due to
increased risk of adverse events, such as myocardial ischaemia or ventricu-
lar arrythmia.5,19,20
Dobutamine was first evaluated in the Flolan International Randomized
Survival Trial, where it showed an increased risk of mortality compared
with placebo.21 Although only a plausible negative association between
dobutamine and increased risk of mortality could be inferred from this
non-randomized post hoc analysis, alternate methods were suggested to
increase cardiac contractility which worked downstream to the β1 recep-
tors.21 This involved a string of phosphodiesterase inhibitors (PDEs) such
as amrinone, milrinone, and enoximone which increased intracellular cal-
cium by increasing intracellular cAMP.22–24 Although these conferred a dif-
ferential mechanism of action to enhance cardiac contractility, they yielded
no clinical benefit in HF. Rather, milrinone therapy was associated with a
28% increase in all-cause mortality compared with placebo.20 Although
the majority of positive inotropes tested to date have yielded neutral or
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negative outcomes, digoxin is the only positive inotrope that has demon-
strated a reduction in HF hospitalizations.
4. Digoxin
Digoxin is a positive inotrope that exerts its effects by blocking the Na+-K+
ATPase pump, thereby progressively accumulating Na+ ions inside the sar-
coplasma.25 This increases the intracellular Ca++ concentration, resulting in
a greater quantity of Ca++ release during excitation–contraction coupling
which causes a more forceful contraction.26 In addition to positive inotrop-
ic effects, digoxin is also considered a neurohormonal modulator due to its
favourable hemodynamic effects.27 Intravenous digoxin reduces cardiac
norepinephrine, with a decline in vascular resistance in patients with
HF.27,28 Furthermore, it enhances the cardiac vagal tone and decreases
plasma renin activity.28,29 Although the exact autonomic mechanism of ac-
tion remains unknown, failure of prior inotropic therapies indicates that
the neurohormonal attenuation of digoxin plausibly translates to the clin-
ical benefit observed in reduction of HF hospitalization in large-scale clinical
trials of this intervention.
As observed in the DIG trial (Digitalis Investigation Group), amongst
8500 chronic HF patients with LVEF ≤45%, digoxin was associated with
a relative risk reduction of 13 and 28% in hospitalization rates for a cardio-
vascular reason or for worsening HF compared to placebo, respectively.30
However, no difference was observed in the reduction of all-cause mortal-
ity between the two intervention arms. On the contrary, although there
was a trend towards reduction in mortality due to worsening HF in digoxin
group, an increased risk of cardiovascular death due to other causes was
also noted in this group (P = 0.04).30 Given the increased risk of toxicity
observed in prior positive inotropic drug trials, it is plausible that the proar-
rhythmic effects of digoxin counterbalanced any benefit on mortality from
worsening HF. Concerns over digoxin toxicity coupled with better alterna-
tives have led to a decline in the utility of this medication in HF.31 Ongoing
trials such as Digitoxin to Improve Outcomes in patients with Advance
Chronic Heart Failure and DECISION (Digoxin Evaluation in Chronic
Heart Failure) are anticipated to provide further clarity regarding efficacy,
safety and optimum dosage of digoxin in patients with HFrEF.32,33
Nevertheless, given that digoxin may be used as a viable alternative
amongst patients with severe HF who are unable to tolerate high doses
of other medications, or in patients with symptomatic HFrEF despite
guideline-directed medical therapy (GDMT), the variable mode of action
of digoxin may translate to a clinical benefit observed in HF.34
5. Beta blockers
Beta blockers are negative inotropes that are used for the management of
hypertension and as a first-line therapy for the prevention of angina. Due to
their antagonistic effect on β1 receptors in the myocardium, these agents
slow the heart rate, thereby reducing the oxygen demand of the myocar-
dium which aids in reducing the duration and frequency of angina.
Consequently, these agents were initially contraindicated in HFrEF due
to the transient negative inotropic effect of beta blockade with subsequent
risk of rapid decompensation in patients with acute HF. However, since the
early 1990s, multiple landmark clinical trials have demonstrated favourable
prognostic impact of specific beta blockers in HFrEF.35–37
The pharmacologic benefit of beta blockade is exerted via its effects on
multiple pathways (Figure 1). Blocking the B-receptors limits the effect of
Mechanisms of heart failure therapies
Epi, NE
β-receptor
β-receptor blocker
blocker
β2 β1
G
Gss
ATP cAMP
Ca 2+
PKA
Ca2+
Ca2+
Ca2+
β-blockade
Considered counterintuitive however:
2 Slows HR
Energy expense
LVEF
Figure 1 Mechanism of action of beta blockers.
increased catecholamine, inhibits renin-release, alters inotropy and chron-
otropy, and exerts anti-arrhythmic and anti-ischaemic effects on the myo-
cardium.38,39 Cardio-selective beta blockers indicated for the management
of HFrEF, such as bisoprolol, carvedilol, and metoprolol succinate have all
demonstrated mortality benefits.40 By blocking β1 receptors, these agents
cause direct antagonism of the cardiotoxic effects of catecholamines and
persistent activation of the sympathetic nervous system. Although initially
activated as a compensatory mechanism, persistent activation of RAAS
perpetuates a vicious cycle that leads to increased in cardiac preload, after-
load, and induces ventricular remodelling. Blocking the B-receptors is
therefore suggested to prevent ventricular remodelling.39
Although the use of beta blockers in HF may seem counter-intuitive, this
paradox may exist, in part, due to the inverse relationship between heart
rate and cardiac contractility in HF.3,41,42 In HF patients, as heart rate increases,
LVEF decreases due to the inability of myocardium to maintain the cardiac out-
put.41 By reducing heart rate, beta blockers increase LVEF and reduce energy
expenditure, which is postulated to prevent adverse cardiac remodelling.42–45
3
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Contractility
Peripheral perfusion
Negative
inotropy
Activation of SNS
Vaso- Oxidative Salt/water Cardiac
constriction stress retention hypertrophy
While metoprolol and bisoprolol are β1 receptor-selective, carvedilol
exerts its effects by blocking β1, β2 and α1 receptors, which additionally
causes vasodilation. The 1996 U.S. Carvedilol Heart Failure Study was
the first trial to show the mortality benefit of this intervention in HF
(Table 1). Amongst 1094 HF patients with EF <35%, carvedilol was accom-
panied by a 38% reduction in the combined risk of hospitalization or death
(24.6% vs. 15.8%, P < 0.001).37 Likewise, in the COPERNICUS study, car-
vedilol reduced the risk of mortality by 34% and HF hospitalization by
40%.36 Clinical benefits in HF patients have also been seen with metoprolol
succinate and bisoprolol.47 Metoprolol was evaluated in MERIT-HF trial in
HF patients on baseline angiotensin-converting enzyme (ACE)-inhibitor
and diuretic therapy.46 This trial was terminated early due to significantly
lower mortality risk amongst patients taking metoprolol compared with
placebo (P < 0.001), with fewer deaths due to worsening HF in the meto-
prolol group.46
Although the suggested benefits of beta blockers are widely stipulated to
be due to anti-sympathomimetic effects, evidence from the MOXCON
4 M.S. Khan et al.

Table 1 Landmark clinical trials of beta blocker therapy in heart failure

Trial Year Type of Adrenergic Patients, N Inclusion Primary outcome Mortality outcome
β-blockers receptor criteria
activity
...............................................................................................................................................................................................
CIBIS-I35 1994 Bisoprolol β1-selective 641 LVEF < 40%, Mortality No significant difference between the
NYHA class two groups
III-V

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US Carvedilol37 1996 Carvedilol β1-β2-α 1094 LVEF ≤35% Mortality Significant reduction in all-cause
mortality (mortality event rate
3.2% carvedilol vs. 7.8% placebo)
MERIT HF46 1999 Metoprolol β1-selective 3991 LVEF < 40%, Mortality 34% relative risk reduction in all-cause
NYHA class mortality.
II-IV Significant decrease in sudden death
CIBIS II47 1999 Bisoprolol β1-selective 2647 LVEF < 35%, Mortality 34% relative risk reduction in all-cause
NYHA Class III– mortality
IV
COPERNICUS36 2001 Carvedilol β1-β2-α 2289 LVEF < 25% and Mortality, composite of 31% relative risk reduction in all-cause
NYHA Class III– death and mortality
IV hospitalization
SENIORS48 2005 Nebivolol β1-selective 2128 LVEF ≤35% Composite mortality, No significant difference between the
Age ≥70 years cardiovascular two groups
hospitalization

LVEF = left ventricular ejection fraction; NYHA = New York Heart Association.

trial suggests the principal mechanism may likely differ.49 Sustained-release
preparation of moxonidine (moxonidine SR), a potent central sympathetic
inhibitor failed to show any benefit in patients with HF.49 On the contrary,
an excess of early mortality in HF patients taking moxonidine SR compared
with placebo (5.5% vs. 3.4%; P = 0.012) led to early termination of the
MOXCON trial.49 The excess short-term mortality observed in this trial
raises concerns regarding generalized sympathetic inhibition in HF, thereby
suggesting a lack of long-term benefit from inhibition of the vasoconstrictor
effects of SNS stimulation. This likely suggests that although SNS stimula-
tion remains pivotal in the pathophysiology of HF, it is plausible that cardio-
selective beta blockers achieve optimal counteraction by targeting multiple
pathophysiological pathways.
6. Angiotensin-converting enzyme
inhibitors and angiotensin receptor
blockers
Angiotensin II is a potent endogenous vasoconstrictor that increases per-
ipheral resistance and sympathetic stimulation, thereby elevating blood
pressure.50 To counter this, ACEis were developed to target the
angiotensin-converting enzyme (ACE), thereby inhibiting the conversion
of Angiotensin I to its physiologically active form, Angiotensin II, while
ARBs were used to block the binding of Angiotensin II to its receptor
(Figure 2).51 Accordingly, due to their ability to cause peripheral vasodila-
tion and reduction of cardiac preload and afterload, ACEi and ARBs
were developed and marketed specifically as anti-hypertensive agents, fo-
cusing mainly on patients with renin-dependent pathophysiology.52
Initially, ACEi was hypothesized to incur benefit in patients with HF due
to vasodilation and subsequent reduction of blood pressure. However, gi-
ven that various other more potent vasodilators with a greater reduction in
blood pressure had failed to show any mortality benefit in HF, it is import-
ant to acknowledge that any benefit observed via ACEi in HF was likely due
to the multimodal mechanism of action of these drugs.50 Indeed, as re-
search progressed in HF, it was recognized that deleterious upregulation
of RAAS served as the key pathophysiological construct of HF, and pro-
moted its progression by causing fluid retention, peripheral arterial vaso-
constriction, ventricular remodelling, interstitial fibrosis, and myocardial
hypertrophy. By blocking Angiotensin II and interfering with the maladap-
tive processes of RAAS in HF, ACEi/ARBs enhance natriuresis, prevent the
release of aldosterone, lower arterial and venous pressures, decrease pre-
load and afterload, and curtail cardiac remodelling.50,52
ACEi and ARBs have shown to reduce the risk of mortality by 20–30% in
HF possibly via direct antagonism of RAAS.53–55 The Cooperative North
Scandinavian Enalapril Survival Study (CONSENSUS trial) which evaluated
enalapril in comparison with placebo demonstrated an overall mortality
risk reduction of 27% in the enalapril group (Table 2).54 This was followed
by the Studies of Left Ventricular Dysfunction trial which similarly observed
an absolute risk reduction of 5% in all-cause mortality in NYHA II
and III HFrEF patients taking enalapril as compared to placebo. Similar
results were observed in landmark ARB trials.55 Candesartan in
Heart Failure-Assessment of Reduction in Mortality and Morbidity
(CHARM-alternative) was the first trial to demonstrate mortality and HF
hospitlaization benefit in HFrEF patients treated with candesartan vs. pla-
cebo. Patients in the candesartan group observed a significantly decreased
risk of a composite cardiovascular death and HF hospitalization [0.70
(0.60–0.81)] compared with patients in the placebo group.60 This was con-
sistent with results observed in CHARM-added trial, where ARBs were
added to background therapy with ACEi and compared with a placebo.59
Although this showed a reduction in the risk of a composite cardiovascular
death and HF hospitalization, it was accompanied by increased rates of
worsening renal function and hyperkalemia, thereby serving as a caution
against concurrent administration of both ACEi and ARBs in HFrEF.
Given the favourable mortality benefit observed in these trials, it is note-
worthy to acknowledge that ACEi was utilized in addition to usual stan-
dards of care in HFrEF such as diuretics, vasodilators, digoxin, and beta
blockers. This likely suggests that multiple mechanisms may be contributing
to attenuating the progression of HF. As such, several mechanisms have
been proposed in the ACE pathway, including the existence of alternative
pathways for the conversion of Angiotensin I to Angiotensin II which still
remain a topic of interest. Although ACEis interfere with RAAS, their effect
Mechanisms of heart failure therapies 5

ACE inhibitor
ARB

Blood pressure Kidney

K+ excretion

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Renin Aldosterone
ste
Na / H2O retention

Liver Adrenal gland

A

ACE
ACE
CE

Angiotensinogen AT I ATT II
A

Vasoconstriction
ACE 2 NEP / PEP ACE 2 GFR
Urine output Blood pressure

ACE / NEP
Angiotensin (1-9) Angiotensin (1-7)

• Vasodilatation Vasodilatation
• Blood pressure
• Originally suggested
• Anti-prolife
f rative mechanisms for HF

Figure 2 Mechanism of action of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

is not directly due to levels of renin in the blood. It is plausible that the ob-
served effects may be due to the upregulation ACE2/Angiotensin 1–7 path-
way of RAAS regulation, which remains less well-established.63 It is
suggested that ACE2, an endogenous ACE inhibitor converts Ang II into
Ang-(1–7), which acts at the Mas receptor to promote vasodilation and so-
dium and water excretion, inhibit neurohormonal activation and increase
nitric oxide production.63–65 These overlapping systemic underpinnings
suggest that targeting multiple pathophysiological mechanisms is likely re-
sponsible for the favourable pharmacodynamic profile of ACEi and ARBs.
7. Angiotensin receptor-neprilysin
inhibitor
To counter the maladaptive neurohormonal changes triggered by the ac-
tivation of RAAS in HF, natriuretic peptides (NP) such as atrial NP
(ANP), brain NP (BNP) and c-type NP are secreted from the cardiac myo-
cytes in response to mechanical stress on the heart due to excessive vol-
ume.66 These NPs alleviate the maladaptive processes triggered due to HF
by binding to NP receptor type A and activating the cyclic guanosine mono-
phosphate (cGMP) cascade, thereby promoting natriuresis, vasodilation,
and inhibiting sympathetic outflow which prevents adverse cardiac remod-
elling.67,68 In an effort to restore fluid homeostasis, promote vasodilation
and improve cardiac output, it seemed intuitive to supplement NPs in these
patients. However, clinical trials investigating BNP supplements in HF pa-
tients failed to show any mortality benefit over placebo, thereby shifting
focus to neprilysin inhibitors as a viable alternative.69
Neprilysin is responsible for cleaving NP, as well as other vasodilating
mediators such as substance P and bradykinin.66,70 Accordingly, inhibition
of neprilysin via neprilysin inhibitors increases endogenous NPs, thereby
promoting vasodilation and natriuresis.71 However, in addition to increas-
ing circulating NPs, neprilysin inhibitors also elevate the concentration of
6 M.S. Khan et al.

Table 2 Landmark clinical trials of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers therapy in
heart failure

Trial Year Type of Control Patients, N Follow-up Endpoint Outcome

intervention group (month)
...............................................................................................................................................................................................
ACE inhibitors
CONSENSUS Trial 1987 Enalapril Placebo 253 6 All-cause Mortality 27% reduction
Study Group54

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SOLVD56 1991 Enalapril Placebo 2569 41.4 Mortality 16% reduction
PEP-CHF57 2006 Perindopril Placebo 850 26.2 Composite all-cause No significant difference
mortality or HHF
HHF
ARBs
Val-HeFT53 2001 Valsartan Placebo 5010 23 All-cause Mortality No significant difference
All-cause Mortality, HF 13% reduction
hospitalization, cardiac
arrest
OPTIMAAL58 2002 Losartan Captopril 5477 32.4 All-cause Mortality No significant difference
CHARM-Added59 2003 Candesartan Placebo 2548 41 All-cause Mortality No significant difference
CV death, HF hospitalization 15% reduction
CHARM-Alternative60 2003 Candesartan Placebo 2028 33.7 CV death, HF hospitalization 30% reduction
CHARM-Preserved61 2003 Candesartan Placebo 699 36.6 CV death or HHF No significant difference
I-PRESERVE62 2008 Irbesartan Placebo 4128 49.5 All-cause mortality or CV No significant difference
hospitalization

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; HF = heart failure; HHF = hospitalization for heart failure; CV = cardiovascular.

two circulating vasopressors, namely Angiotensin II and Endothelin I.66,72
Consequently, due to opposing effects of promoting vasodilation and vaso-
constriction simultaneously, this counterbalances any prognostic benefit
neprilysin inhibitors exert when given in isolation. As a result, concomitant
inhibition of neprilysin and RAAS was considered pivotal for the manage-
ment of hypertension and HF.
ARNi resulted from the combination of a neprilysin inhibitor and an anti-
hypertensive drug, sacubitril, and valsartan. While sacubitril inhibits nepri-
lysin activity, valsartan effectively counteracts activation of the RAAS,
thereby promoting the dual effect of this therapeutic intervention.73
Modulating two essential HF pathways potentially augments the therapeut-
ic benefits observed with this intervention (Figure 3). The Prospective
Comparison of ARNi with ACEi to Determine Impact on Global
Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial found
that ARNi reduced cardiovascular mortality [13.3% vs. 16.5%; HR: 0.80
(95% CI: 0.71–0.89)] and hospitalization for HF [12.8% vs. 15.6%; HR:
0.79 (95% CI: 0.71–0.89)] when compared with enalapril in patients with
chronic HFrEF (Table 3).74 These findings extend to patients with acute de-
compensated HFrEF. As observed in the PIONEER-HF (Comparison of
Sacubitril-Valsartan vs. Enalapril on Effect on NT-proBNP in Patients
Stabilized from an Acute Heart Failure Episode) trial, over a follow-up per-
iod of 8 weeks, sacubitril/valsartan resulted in a greater reduction in
NT-proBNP and HF hospitalization [8.0% vs. 13.8%; HR: 0.56 (95% CI:
0.37–0.84)] when compared with enalapril.75
Although ARNi is believed to increase NPs in circulation, conflicting evi-
dence exists regarding BNP levels following the initiation of ARNis.74,77 In
PARADIGM-HF, 19% of study participants demonstrated an increase in
BNP. This conflicts with recent pooled analysis of Effects of Sacubitril/
Valsartan vs. Enalapril on Aortic Stiffness in Patients with Mild to
Moderate HF with Reduced Ejection Fraction and PROVE-HF (Effects of
Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and
Outcomes), where initiation of ARNi led to no significant overall change
in BNP levels.77 In addition, no association was observed between ARNi
dosage and changes in BNP.77 This may be attributed to the difference
in patient characteristics and plausibly some BNP increase due to neprilysin
inhibition being counteracted by a reduction in its production due to off-
loading. In contrast, studies have shown an increase in ANP concentrations
following treatment with ARNi, thereby suggesting that measuring an
increase in ANP concentrations following initiation of ARNi may aid
in identifying a response to sacubitril/valsartan therapy.78 However,
although neprilysin inhibition contributes as the key mechanism behind
a rise in ANP concentration, recent studies suggest that multiple mech-
anistic pathways, such as indirect regulation of microRNAs following
ARNi therapy potentially lead to an increase in ANP concentrations
as well.79 Given that neprilysin is responsible for cleaving multiple pep-
tides, the net effect of neprilysin inhibition is more complex. ARNi has
been observed to increase plasma concentration levels of adrenome-
dullin (ADM) precursor fragment MR-proADM, which is a regulatory
peptide with potent vasodilating, anti-fibrotic, anti-inflammatory and
natriuretic properties, in patients with HFrEF.80 Further, as observed
in PARADIGM-HF, ARNi also exerts beneficial effects on glycemic
control by increasing circulating GLP-1 levels.81 A sub-study of this trial
also revealed the anti-fibrotic activity of ARNi, with a significant
reduction observed in aldosterone, soluble tumorigenicity suppressor,
matrix metallopeptidase 9 and procollagen type 1 amino-terminal
propeptide after 8 months of treatment with ARNi compared with en-
alapril.82 This, therefore, provides further insights towards various no-
vel mechanism of actions of ARNi which potentially contribute
towards its therapeutic effect, with questions still persisting regarding
the magnitude of therapeutic effect these NPs confer in patients with
HF.77
Further, although neprilysin inhibition enhances the activity of cGMP,
which is suggested to reduce myocardial stiffness, no clinical benefit of
ARNi in improving survival was observed in patients with HFpEF in the
PARAGON-HF trial (Prospective Comparison of ARNi with ARB Global
Outcomes in Heart Failure with Preserved Ejection Fraction). However,
Mechanisms of heart failure therapies 7

Adaptive response
Stress on the Maladaptive response
myocardium

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Secretion of NPs RAAS

Neprilysin
Breakdown NPs

ANP BNP CNP Sacubitril / Ang II

Valsartan

Vasodilation Vasoconstriction

Natriuresis Na / H2O retension

Blood pressure Blood pressure
Sympathetic tone Sympathetic tone

Hypertrophy Hypertrophy

Figure 3 Mechanism of action of angiotensin receptor-neprilysin inhibitor.

a nominal reduction in HF hospitalization supports the use of this thera-
peutic in this subset of patients.76 ARNi, therefore, sustains itself as a
GDMT in HF, with likely therapeutic advantages observed due to its con-
comitant inhibition of two key HF pathways.
8. Mineralocorticoid receptor
antagonists
Non-selective (e.g. spironolactone) and selective (e.g. eplerenone) MRAs
target the aldosterone receptor in multiple epithelial and non-epithelial
locations.83,84 Originally developed as a potent diuretic, the limited scien-
tific knowledge regarding aldosterone and its key role in human physiology
in 1950s confined the role of MRAs as K-sparing diuretics.85 Accordingly,
these agents were initially used as anti-hypertensives and diuretics for mo-
bilization of patients with advanced ascites or cirrhosis due to their ability
of blocking the aldosterone receptor, which is an endogenous steroid hor-
mone responsible for increased sodium retention and potassium excretion
in the renal distal tubule.86 As described by Funder et al., during this time
the interaction between aldosterone and mineralocorticoid receptors
(MR) was summarised as aldosterone being derived mainly by angiotensin,
aldosterone being the only physiologic ligand of MR, and elevation of blood
8 M.S. Khan et al.

Table 3 Landmark clinical trials of angiotensin receptor-neprilysin inhibitor therapy in heart failure

Trial Year Type of HF Patients, N Follow-up (months) Endpoint Outcome

...............................................................................................................................................................................................
PARADIGM-HF74 2014 HFrEF 8442 27 All-cause mortality; 0.84 (0.76-0.93)
CV death, HF hospitalization; 0.80 (0.73-0.87)
HF hospitalization 0.81 (0.71–0.89)
PIONEER-HF75 2019 HFrEF with acute decompensated HF 881 2 HF Hospitalization 0.56 (0.37–0.84)
PARAGON-HF76 2019 HFpEF 4822 35 All-cause mortality; 0.97 (0.84–1.13)

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CV death, HF hospitalization; 0.87 (0.75–1.01)
HF hospitalization 0.85 (0.72–1.00)

HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; CV = cardiovascular.

Table 4 Landmark clinical trials of mineralocorticoid receptor antagonists in heart failure

Trial Year Type of intervention Patients, N Follow-up (months) Endpoint Outcome

...............................................................................................................................................................................................
RALES90 1999 Spironolactone 1663 24 All-cause mortality; HF hospitalization 0.70 (0.60–0.82);
0.65 (0.54–0.77)
EMPHASIS-HF91 2011 Eplerenone 2737 21 All-cause mortality; 0.76 (0.61–0.94);
CV death, hospitalization 0.63 (0.54–0.74)
TOPCAT92 2014 Spironolactone 3445 39.6 All-cause mortality; HF hospitalization 0.91 (0.77–1.08);
0.83 (0.69–0.99)

HF = heart failure; CV = cardiovascular.

pressure mainly resulting via salt and water retention.85,87 After decades of
research, however, these concepts were later refuted by denoting that
angiotensin is not the key deriver of aldosterone secretion, aldosterone
constitutes one of the physiologic ligands of MR and that increase in blood
pressure in the setting of aldosterone secretion mainly occurs due to its
effects on the vasculature and central nervous system.87,88 As numerous
studies indicated multiple pathophysiological roles of this hormone, the
mechanism of action of MRAs expanded from epithelial to non-epithelial
locations.
In addition to its initial mechanism of sodium and water retention, aldos-
terone is now implicated in promoting pro-inflammatory immune cell phe-
notypes which potentially result in oxidative stress, cardiovascular
inflammation, endothelial dysfunction, and cardiac fibrosis.89 Treatment
with MRAs can therefore attenuate the aldosterone-mediated
pro-inflammatory state, which perpetuates an increase in collagen synthe-
sis and ventricular remodelling.86 Due to their ability to curtail end-organ
damage, coupled with the natriuretic effects observed, MRAs were given
in conjunction with ACEi/ARBs and beta blockers in HFrEF patients to
amplify the effects of RAAS blockade. Although the clinical relevance of po-
tential cardiac remodelling after MRAs has not been conclusively evaluated
in humans, accumulated evidence from prior trials demonstrates the mor-
tality and morbidity benefits of these agents across the spectrum of HF.
The evidence for MRA use was first evaluated in the Randomized
Aldactone Evaluation Study (RALES) trial, which was terminated early
due to early mortality benefit of spironolactone amongst 1663 HF patients
with LVEF ≤35% and NYHA Class III or IV symptoms.90 In RALES, the add-
ition of spironolactone to standard HF therapy significantly reduced all-
cause mortality (11% absolute reduction), risk of sudden death (RR:
0.71, 95% CI: 0.54–0.95, P = 0.02), and death due to HF (RR: 0.64, 95%
CI: 0.51–0.8, P < 0.001) in the spironolactone group compared with pla-
cebo (Table 4).90
More recently, MRAs have also yielded modest results in patients with
HFpEF. In the TOPCAT (Aldosterone Antagonist Therapy for Heart
Failure with Preserved Ejection Fraction) trial, although spironolactone
did not reduce primary outcome consisting of time to cardiac death, resus-
citated cardiac arrest, or hospitalization for HF as compared with
placebo [HR 0.89; (95% CI: 0.77–1.04)], a significantly lower incidence
of HF hospitalization was observed in the spironolactone group [HR
0.83; (95% CI: 0.69–0.99)].92 Although these findings raise further ques-
tions regarding the underlying mechanisms which enable the efficacy of
spironolactone across different LVEFs, various other pathways of aldos-
terone activity remain of significant interest. The most noteworthy
of these is the role of aldosterone on ACE2/Ang-(1–7)/Mas-R axis
pathway, which contributes to the pathogenesis of adverse cardiac
and vascular remodelling.93 Although conclusive evidence remains to
be observed, some studies have shown Ang-(1–7) as a negative modu-
lator of aldosterone secretion.94 Therefore, exploring how MRAs may
target this pathway and the likely clinical benefits it may exert remains
an area of interest.
9. SGLT2 inhibitors
SGLT2 inhibitors were initially developed as antihyperglycemic agents for
the management of Type 2 diabetes mellitus (T2DM). These agents
work by blocking the SGLT2 protein located in the proximal convoluted
tubule of the nephron, which is responsible for reabsorbing up to 90%
of filtered glucose. SGLT2 inhibition, therefore, results in glycosuria with-
out interfering with endogenous insulin.95 Early cardiovascular outcome
trials of SGLT2 inhibitors demonstrated a 30–35% lower risk of HF hospi-
talization amongst T2DM patients who were at high risk of cardiovascular
disease.96–99 Failure of other, more potent antihyperglycemic therapeutics
to reduce the cardiovascular risk profile of T2DM patients, therefore, sug-
gested that SGLT2 inhibitors have a cardioprotective effect independent of
their glucose-lowering capability.95
Following cardiovascular risk reduction in T2DM trials, questions arose
regarding the efficacy of SGLT2 inhibitors amongst patients with prevalent
HF who did not have T2DM. Accumulating evidence from the DAPA-HF
(Dapagliflozin and Prevention of Adverse outcomes in Heart Failure),
EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with
Chronic Heart Failure and a Reduced Ejection Fraction) and
EMPEROR-Preserved (Empagliflozin in Heart Failure with Preserved
Mechanisms of heart failure therapies
Ejection Fraction) trials have demonstrated that the clinical benefits of
SGLT2 inhibitors extend across the HF spectrum, irrespective of diabetes
status (Table 5).15,16,100 In the DAPA-HF trial, SGLT2 inhibitors reduced
the primary endpoint of worsening heart failure or cardiovascular death
[HR: 0.74 (95% CI: 0.65–0.85); P < 0.001] and cardiovascular mortality
[HR: 0.82 (95% CI: 0.69–0.98)] amongst 4744 HFrEF patients
compared with placebo.15 Similarly, amongst 3730 HFrEF patients in
EMPEROR-Reduced trial, SGLT2 inhibitors decreased composite of car-
diovascular death or hospitalization for HF, [HR 0.75 (95% CI: 0.65–0.86;
P < 0.001)], with a significant reduction in total hospitalizations for HF in
the empagliflozin group compared with placebo [HR 0.70 (95% CI: 0.58–
0.85) P < 0.001].16 This clinical benefit extends to patients with HFpEF.
As observed in the EMPEROR-Preserved trial, SGLT2 inhibitors proved
to be the first intervention to confer a clinical benefit in patients with
HFpEF.100 In this trial of 5988 patients with HFpEF, SGLT2 inhibition
with empagliflozin led to a 21% reduction in relative risk in the composite
of cardiovascular death or hospitalization for HF, which was mainly attrib-
uted to a 29% lower risk of hospitalization for HF with empagliflozin.100
Despite the benefits of SGLT2 inhibitors for HF across spectrum of EF,
the exact mechanism by which this class of therapy confers a survival ad-
vantage is not well-established. It is suggested that SGLT2 inhibitors simul-
taneously target multiple pathways and produce favourable effects on
multiple organ systems thought to be involved in HF (Figure 4).95,102,103
A major benefit of SGLT2 inhibitors is suggested to be related to the kid-
ney, where they inhibit sodium reabsorption in the proximal tubule, there-
by promoting osmotic diuresis which is also speculated as the key
mechanism of the anti-hypertensive effect observed with this interven-
tion.104 By lowering blood pressure and antagonizing fluid retention, these
agents are suggested to decrease cardiac preload and afterload, which sub-
sequently improves ventricular-arterial coupling.103 It has also been sug-
gested that SGLT2 inhibitors attenuate oxidative stress by decreasing
the underlying systemic inflammation.105 Although the exact mechanism
of this in HF remains unknown, it is postulated that these agents potentially
exert benefit in patients with HFpEF due to their ability to decrease inflam-
matory response due to increase macrophagic activity, possible reduction
of sympathetic nerve activity and inhibition of norepinephrine turn over in
brown adipose tissue and improvement in cardiac energetics by increasing
circulating ketone levels which are utilized by the failing myocardium as an
energy source, thereby improving cardiac efficiency. However, this evi-
dence is largely accumulated by animal data and is yet to be confirmed in
patients with HF.106–109
Amongst patients with HF, SGLT2 inhibitors have demonstrated reverse
cardiac remodelling in multiple randomized controlled trials and exploratory
post hoc analysis.110–112 As observed in EMPA-TROPISM (Empagliflozin in
Nondiabetic Patients with Heart Failure and Reduced Ejection Fraction), em-
pagliflozin in HFrEF patients significantly improved left ventricular volumes,
mass, systolic function and functional capacity.111 Although only established
in patients with T2DM, SGLT2 inhibitors augment iron utilization and in-
crease erythropoiesis, which is suggested as a marker of reduced metabolic
stress.113 Further, these agents also improve vascular function by attenuating
endothelial cell activation via direct vasorelaxation, which results in favour-
able haemodynamics seen with this intervention.
The multimodal mechanism of SGLT2 inhibitors, which simultaneously
targets multiple pathways further substantiates that therapies with diffuse
mechanisms of action confer the highest clinical benefit in curtailing adverse
events of this syndrome. Although SGLT2 inhibitors are now being widely
investigated in multiple disease processes, it is plausible that many mechan-
isms through which they act still remain unknown.
10. Ivabradine
Epidemiologic evidence demonstrates a strong correlation between increased
heart rate and cardiovascular mortality.114 Elevated heart rate increases myo-
cardial oxygen demand due to shortened length of each cardiac cycle, which
reduces diastolic perfusion time.115 Accordingly, ivabradine was first investi-
gated as an antianginal therapeutic due to its ability to reduce heart rate
9
without any effect on myocardial contractility, blood pressure, intracardiac
conduction or ventricular repolarization time.115,116 Ivabradine is a heart
rate lowering agent indicated in patients who are in sinus rhythm with a resting
heart rate of 70 beats per minute, which selectively inhibits the cardiac pace-
maker current channel I(f), which is responsible for regulating heart rate by
controlling the diastolic depolarization in the sinoatrial (SA) node.115,117
Blocking of this channel leads to inhibition of sodium–potassium inward cur-
rent, thereby prolonging diastolic depolarization. The slow rate of SA node fir-
ing, therefore, leads to a reduction in heart rate without any effect on other
cardiac parameters.115
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After ivabradine was reported efficacious, safe and tolerable in clinical
trials of patients with stable angina pectoris, it was investigated in patients
with systolic dysfunction due to increased evidence of a reduction in heart
rate translating to paradoxical positive inotropism in patients with
HF.116,118,119 In SHIFT trial (Systolic Heart Failure Treatment with the If
Inhibitor Ivabradine Trial), ivabradine reduced HF hospitalization (HR
0.74 [95% CI, 0.66–0.83]; P < 0.001) and HF mortality (HR 0.74 [95% CI,
0.58–0.94]; P = 0.01) compared with placebo.120 However, no clinical
benefit was observed in the reduction of cardiovascular or all-cause mor-
tality.120 Despite its direct effect on SA node, beta blockers have demon-
strated a greater average reduction in heart rate of up to 12 beats per
minute (bpm).121 This coupled with the mortality benefits observed in
beta blockers led to the recommendation of initiating ivabradine therapy
only after maximum optimal dosing of beta blocker has been achieved in
HFrEF patients with a resting heart rate of ≥70 bpm. This substantiates
that although modulating heart rate serves as one of the pathways which
may attenuate adverse HF events, the superiority of beta blockers poten-
tially exists in their ability to modify multiple mechanistic pathways.
11. Hydralazine–isosorbide dinitrate
Both hydralazine and isosorbide dinitrate (ISDN) have vasodilatory prop-
erties which help in the reduction of preload and afterload. Hydralazine
is an arterial vasodilator that reduces peripheral vascular resistance by dir-
ectly relaxing the vascular smooth muscle.122 In isolation, it has been long-
standing treatment of hypertensive crisis and hypertensive disorders in
pregnancy due to its potent vasodilation properties.123,124 Although the
exact mechanism of inducing vasodilation remains unknown, it is suggested
that this may be attributed to altering Ca2+ balance in vascular smooth
muscles or by modulating the effect of compounds released from sympa-
thetic nerve endings.122 In addition, hydralazine is suggested to have anti-
oxidant properties that help prevent NO degradation.
ISDN is a nitric oxide (NO) donor which also aids in the relaxation of
vascular smooth muscle.125 ISDM activates the enzyme soluble guanylyl cy-
clase in the vascular smooth muscle which subsequently increases cGMP,
thereby causing vasodilation and decreases vascular resistance.125 At the
therapeutic level, ISDN is used to treat angina pectoris. The combination
of hydralazine and ISDN maintains a prolonged state of vasodilation and
augments the bioavailability of NO, thereby maintaining the vascular
tone and cellular redox balance.126
The haemodynamic effects of hydralazine and ISDN were first observed
in the V-HeFT trial, where a 34% risk reduction in mortality was observed
among patients treated with both hydralazine and ISDN compared with
placebo or prazosin.8 The most pronounced effect of this intervention
was observed among 1050 Black patients with HFrEF and NYHA Class
III–IV symptoms in the A-HeFT trial (The African-American Heart
Failure Trial).127 This trial was terminated early due to significantly im-
proved survival in hydralazine-ISDN group. At the time of cessation, a high-
er rate of all-cause mortality was observed in the control group (10.2%)
compared with the hydralazine-ISDN group (6.2%), with similarly low rates
of HF hospitalization in patients taking hydralazine-ISDN (16.4% vs. 24.4%
in control participants). Survival in patients on hydralazine-ISDN therapy
was therefore increased by 43% (P = 0.02).127 These racial differences
are thought to be due to decreased bioavailability of NO in Black patients
compared with other ethnicities.128 Resultant vasoconstriction in the set-
ting of an already failing heart can further contribute to increased cardiac
10
Table 5 Landmark clinical trials of sodium–glucose co-transporter 2 inhibitors in heart failure
Trial Year Type of HF Patients, N
...............................................................................................................................................................................................
DAPA-HF15 2019 HFrEF 4744
EMPEROR-Reduced16 2020 HFrEF 3730
SOLOIST-WHF101 2021 HFrEF, HFpEF 1222
EMPEROR-Preserved100 2021 HFpEF 5988
DELIVER 2022 HFmrEF, HFpEF 6263
HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; CV =
cardiovascular.
preload. Given that the neurohormonal system and NO characterize as
two distinct pathways, conventional HF therapeutics only alter the neuro-
hormonal overdrive without any alteration of the bioavailability of NO. In
this instance, hydralazine and ISDN is often considered an important ad-
junct with optimal HF therapy in Black patients with severe HF.
12. Soluble guanylate cyclase
stimulators
The NO-soluble guanylate cyclase (sGC)-cGMP pathways have been of
particular interest in the pathophysiology of HF due to the pivotal role
of cGMP in mediating vasodilation and cardiac relaxation.129,130 In HF, de-
ficiency of cGMP due to less bioavailability of NO or sGC perpetuates oxi-
dative stress, which stimulates autophagy, apoptosis, cardiac fibrosis, and
adverse cardiac remodelling.131 To this end, several drugs aimed to modu-
late the NO-cGMP pathway via increasing the availability of NO by using
nitrates, or reducing degradation of cGMP via PDEs have been evaluated
in HF.132,133 However, the low half-life and high-first pass metabolism of
NO, and minimal inhibition of PDE in the instance of NO yielded limited
clinical applicability of these agents in HF.132,134,135 As a result, sGC ago-
nists were considered the next best therapeutic target to directly stimulate
cGMP production.
Riociguat was developed as the first sGC stimulator. Although devel-
oped for patients with pulmonary hypertension, riociguat demonstrated
favourable safety profile, improvement in quality of life, and cardiac index
in patients with HFrEF.136 However, its short half-life presented as a limi-
tation for therapeutic use in HF patients.137 Accordingly, structural opti-
mization of riociguat was done to develop a therapy tailored for HF.
This led to the development of vericiguat, which works in synergy with
NO and produces cGMP even under low NO conditions.138 This restores
the NO-sGC-cGMP pathway, which is otherwise impaired in HF, thereby
reducing oxidative stress, improving vascular tone and myocardial dysfunc-
tion, and attenuating adverse ventricular remodelling. The molecular ad-
vantages of vericiguat also translate to clinical benefits. In the recent
Vericiguat Global Study in Subjects with Heart Failure with Reduced
Ejection Fraction, vericiguat reduced the composite primary outcome of
cardiovascular death or first HF hospitalization [35.5% vs. 38.5%; HR:
0.90 (95% CI: 0.82–0.98)], which was driven by a reduction in HF hospital-
ization [16.4% vs. 17.5%; HR 0.93 (95% CI: 0.81–1.06)] amongst 5050 pa-
tients with worsening HFrEF.139 On the contrary, although current
evidence remains limited, vericiguat failed to show any benefit in
M.S. Khan et al.
Follow-up Endpoint Outcome
(months)
18.2 All-cause mortality 0.83 (0.71–0.97)
CV death, worsening HF event 0.74 (0.65–0.85)
Worsening HF event 0.70 (0.59–0.83)
16 CV death, HF hospitalization 0.75 (0.65–0.86)
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HF hospitalization 0.69 (0.59–0.81)
All-cause mortality 0.92 (0.77–1.10)
9 CV death, HF hospitalization 0.67 (0.52–0.85)
26.2 CV death, HF hospitalization 0.79 (0.69–0.90)
HF hospitalization 0.71 (0.60–0.83)
All-cause mortality 1.00 (0.87–1.15)
29.1 HF hospitalization, urgent HF visit 0.79 (0.69–0.91)
HF hospitalization 0.77 (0.67–0.89)
CV death 0.88 (0.74–1.05)
attenuating cardiac remodelling or improving health-related quality of life
in patients with HFpEF.140,141
The sGC stimulator vericiguat targets a distinct mechanism and repre-
sents a novel therapeutic option for patients with HF. Importantly, verici-
guat targets a pathway (NO-sGC-cGMP) independent of ACEi/ARBs
(RAAS) and beta blockers (sympathetic nervous stimulation), thereby
complementing the currect pharmacotherapy of HFrEF. The clinical bene-
fits of combining vericiguat with other HF drugs to target multiple patho-
physiological pathways remains unknown. Additionally, the structural
optimization of vericiguat, its in-depth interaction with sGC and mechan-
isms by which cGMP regulates downstream pathways to improve HF out-
comes still requires further research.142
13. Omecamtiv mecarbil
Omecamtiv mecarbil is a first-in-class cardiac myosin activator, which is a
novel class of positive inotropes. These agents improve myocardial func-
tion by selectively binding to cardiac myosin. This increases the number
of myosin heads that can bind to the actin filament and initiate a power
stroke at the start of systole without increasing intracellular calcium levels,
thereby augmenting cardiac contractility.143 As a selective cardiac myosin
activator, omecamtiv mecarbil has no effect on the magnitude of intracel-
lular calcium in cardiomyocytes, which were the pivotal drivers of in-
creased incidence of ventricular arrhythmias and mortality in prior
inotropes. Despite this, omecamtiv mecarbil has yielded modest benefits.
In GALACTIC-HF trial (Cardiac Myosin Activation with Omecamtiv
Mecarbil in Systolic Heart Failure), HFrEF patients in omecamtiv mecarbil
group had a relative risk reduction of 8% in a composite of HF events
and cardiovascular mortality as compared with placebo.144 However,
this novel intervention conferred no mortality benefit. It is noteworthy
to highlight that although no mortality benefit was observed in the overall
population, a possible interaction between the trial group and LVEF at
baseline was noted. These Phase III trial results are juxtaposed with data
from the Phase II The Chronic Oral Study of Myosin Activation to
Increase Contractility in Heart Failure, where favourable improvement
with omecamtiv mecarbil was noted in stroke volume, systolic ejection
time, left ventricular end-systolic and end-diastolic dimensions, and natri-
uretic peptide levels.145 Treatment benefit was also observed in post
hoc analysis of GALACTIC-HF trial, where patients with severe HF (de-
fined as NYHA symptom Class III–IV, LVEF ≤30%, HF hospitalization in
the past 6 months and evidence of severe functional impairment) on ome-
camtiv mecarbil therapy experienced clinically meaningful reduction in
Mechanisms of heart failure therapies 11

*PCT: Proximal convoluted tubule

**ATP: Adenosine tri-phosphate
*** GLUT: Glucose transporter
Urine PCT cell Blood
Na+
Na/K
ATPase Increased urinary Na+ and glucose excretion
SGLT2 K+

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GLUT2
Increased
circulating
ketones Reduced
plasma
SGLT2 volume and
inhibition Increased improved
glucagon vs endothelial
insulin ratio function Diuresis
Reduced ATP
consumption in
PCT and
relative hypoxia
in renal cortex
Reduction Reduction
Lypolysis Improved in blood in
glycemic pressure and ventricular
Reversion of afterload preload
control
erythropoietin
Reverse
cardiac
remodelling

Increase in
haematocrit

Increased haematocrit Weight loss Improved ventricular

loading conditions
Demonstrated in patients
with T2DM Mechanism Mechanism
Modest increase observed demonstrated in animal demonstrated in patients
in patients with HF data with HF

Figure 4 Mechanism of action of sodium–glucose co-transporter 2 inhibitors. (Adapted and Modified from Joshi SS, Singh T, Newby DE, Singh J. Sodium–
glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart BMJ Publishing Group Ltd and British Cardiovascular Society; 2021;
heartjnl-2020-318060).

composite of time to first HF event or cardiovascular death compared with
patients without severe HF.146 The conflicting results and modest favour-
able benefits observed with this intervention substantiates that other neu-
rohormonal mechanisms not directly targeted by omecamtiv mecarbil in
this multifactorial disease may be at play and underscores the potential
role of this therapeutic among patients for whom current treatment op-
tions are limited, or patients already receiving maximally tolerated or target
doses of other therapies.
14. Future perspectives
HF is a multifactorial syndrome with the integration of multiple systemic
pathways. The complexity of this disease process requires a multimodal
treatment with a combination of several drugs as the cornerstone for
optimal prognostic benefit in all patients. As previously mentioned, tar-
geted therapy is ideal for monogenic disease, where a single pathway
might be responsible for adverse reactions to the disease process. In
a systemic clinical syndrome like HF, multiple compensatory pathways
affect more than one organ system. Current therapeutics which have
yielded maximum benefits and reduced all-cause mortality in HF pa-
tients, such as SGLT-2 inhibitors, ARNi, beta blockers, and MRAs
have broad mechanisms of action which simultaneously target more
than one pathophysiological pathway. When taken in combination,
these drugs provide incremental benefits with a marked reduction in
mortality, recurrent hospitalization, worsening of HF, progression of
kidney disease and enhanced quality of life. Historically, HF is a constant-
ly evolving field which despite extensive research has yielded therapies
that have not shown benefit in large-scale randomized trials. Failure of
12
therapies targeting mechanisms with sound concepts suggests that tar-
geting a single mechanism of action may not yield optimal results in
multifactorial disease process. Instead, drugs that target multiple path-
ways across different organ systems, such as the heart, kidney, and
endocrine system may aid in attaining maximal clinical benefit in patients
with HF.
Stakeholders should devise a framework that maximizes the potential of
success of novel interventions. Understanding the mechanism of action of
an intervention in depth serves as the pivotal step. However, HF is a com-
plex disease with several aetiologies. By evaluating the efficacy of novel in-
terventions based on multiple intermediate phenotypes, conducting
efficacy analyses across multiple different groups and doing a detailed
evaluation of quality of life benefit these agents may enable better under-
standing for future HF drug development.
15. Conclusion
HF is a multifactorial syndrome with integrated overlapping multiple patho-
physiological pathways. This complexity requires a multimodal treatment
with a combination of several drugs as the cornerstone for optimal benefit.
Very focused and targeted therapy is ideal for monogenic disease where a
single pathway is disrupted and is responsible for the disease process. In a
systemic clinical syndrome such as HF, multiple pathways are usually in play
affecting more than one organ system, including the myocardium, kidney,
and endocrine.
Current therapeutics which have yielded maximum benefits such as
SGLT-2 inhibitors, ARNi, beta blockers, and MRAs have broad mechanisms
of action which simultaneously target more than one pathophysiological
pathway. When taken in combination, these drugs provide incremental
benefits with a marked reduction in mortality, recurrent hospitalization,
worsening of HF, progression of end-organ damage, and enhanced quality
of life. Otherwise, failure of therapies targeting specific mechanisms with
sound concept have at large not yielded optimal results in multifactorial dis-
ease process.
Conflict of interest: J.B. reports personal consulting fees from Abbott,
Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer,
Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife,
Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk,
Relypsa, Sequana Medical, and Vifor Pharma; and payment for lectures,
presentations, speakers bureaus, manuscript writing or educational events
from AstraZeneca, BI-Lilly, Janssen, and Novartis. S.J.G. has received re-
search support from the American Heart Association, Amgen,
AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer,
and Sanofi; has served on advisory boards for Amgen, AstraZeneca,
Bristol Myers Squibb, Cytokinetics, and Sanofi; and has served as a consult-
ant for Amgen, Bayer, Bristol Myers Squibb, Merck, Sanofi and Vifor. R.J.M.
has received research support and honoraria from Abbott, American
Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly,
Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Medtronic,
Merck, Novartis, Roche, Sanofi, and Vifor. A.D.D. reports research funding
through his institution from the American Heart Association, National
Heart, Lung, and Blood Institute, and Patient-Centered Outcomes
Research Institute. He has also received nonfinancial support from
Abbott Laboratories for educational activities. The remaining authors
have no conflicts of interest to declare.
Funding
None declared.
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