Future Scope and Challenges For Congestive Heart Failure Moving Towards Development of Pharmacotherapy

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For personal use only. This Just-IN manuscript is the accepted manuscript prior to copy editing and page composition. It may differ from the final official version of record. Canadian Journal of Physiology and Pharmacology (Author?s Accepted Manuscript)
Future scope and challenges for congestive
heart failure: Moving towards development of pharmacotherapy
Naranjan S. Dhalla1*, Sukhwinder K. Bhullar1, Anureet K. Shah2

Can. J. Physiol. Pharmacol. Downloaded from cdnsciencepub.com by Peking University on 07/03/22
1Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre and
Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of
Manitoba, Winnipeg, Canada.
2School of Kinesiology, Nutrition and Food Science, California State University, Los Angeles,
CA 900032, USA.
*Corresponding Author: Naranjan S. Dhalla, PhD, MD (Hon)

Institute of Cardiovascular Sciences,
St. Boniface Hospital Albrechtsen Research Centre,
Winnipeg Manitoba, Canada R2H 2A6
Telephone: 204-235-3417; Email: nsdhalla@sbrc.ca
© The Author(s) or their Institution(s)

For personal use only. This Just-IN manuscript is the accepted manuscript prior to copy editing and page composition. It may differ from the final official version of record. Canadian Journal of Physiology and Pharmacology (Author?s Accepted Manuscript) Page 2 of 47
Abstract: Heart failure is invariably associated with cardiac hypertrophy and impaired cardiac
performance. Although several drugs have been developed to delay the progression of heart failure,
none of the existing interventions have shown beneficial effects in reducing morbidity and
mortality. In order to determine specific targets for future drug development, we have discussed
different mechanisms involving both cardiomyocytes and non-myocyte (extracellular matrix)

alterations for the transition of cardiac hypertrophy to heart failure as well as for the progression
of heart failure. We have emphasized the role of oxidative stress, inflammatory cytokines,
metabolic alterations and Ca2+-handling defects in adverse cardiac remodeling and heart
dysfunction in hypertrophied myocardium. Alterations in the regulatory process due to several
protein kinases as well as participation of mitochondrial Ca2+-overload, activation of proteases and
phospholipases and changes in gene expression for subcellular remodeling have also been
described for the occurrence of cardiac dysfunction. Association of cardiac arrhythmia with heart
failure has been explained as a consequence of catecholamine oxidation products. Since these
multifactorial defects in extracellular matrix and cardiomyocytes are evident in the failing heart, it
is a challenge for experimental cardiologists to develop appropriate combination drug therapy for
improving cardiac function in heart failure.
Key words: cardiac remodeling, hemodynamic overload, cardiac extracellular matrix, subcellular
remodeling, pharmacotherapy of heart failure.
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Introduction
In subjects with heart failure, the heart is incapable of pumping sufficient blood to meet
the adequate needs of the body. Not only is the heart involved in this devastating disease, different
other organs including brain, lungs, kidney, liver, blood vessels and skeletal muscles are also
affected during the development and progression of heart failure (Dhalla et al. 1993; Cohn et al.
1997; Levy et al. 2002; Mudd and Kass 2008). Several pathological etiologies such as
atherosclerosis, hypertension, diabetes, obesity, aging, stressful situations and valvular defects as
well as genetic- and drug- induced cardiomyopathies have been shown to result in heart failure
(Jessup and Brozena 2003; Parmley 1989; McMurray and Stewart 2000). It is noteworthy that
ischemic heart disease (myocardial infarction) is the major cause of heart failure and patients have
been shown to exhibit clinical signs such as accumulation of body fluids, fatigue and exercise
intolerance. The life-time risk of developing heart failure is one in five and the long-time survival
is poor as about 30% patients die within one year and about 50% die within five years of its
diagnosis (Lloyd-Jones et al. 2002; Benjamin et al. 2019; Lippi and Sanchis-Gomar 2020). The
world-wide prevalence of heart failure due to all cardiovascular diseases has been estimated to be
about 64.4 million; 42.3% ischemic heart disease. 37% chronic pulmonary disease, 4.3% mitral
valve disease, 3.7% aortic valve disease, 3.0% rheumatic heart disease, 2.6% myocarditis and 1.4%
endocarditis. Chronic heart failure is considered to be affecting about six million people currently
and is responsible for about 700,000 deaths annually in the United States; it is costing about 50
billion to the American economy per year (Levy et al. 2002; McMurray and Stewart 2000; Lloyd-
Jones et al. 2002; Benjamin et al. 2019; Lippi and Sanchis-Gomar 2020; Cohn et al. 2000). Due to
aging population as well as increasing prevalence of diabetes, obesity and diverse types of
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infections, there is a growing concern that heart failure is becoming of epidemic proportion
throughout the world.
In spite of the complexities due to multiple risk factors involved in the pathophysiology of
heart failure, it is clear that the occurrence of cardiac dysfunction is the hallmark of this
cardiovascular disease. Earlier the development of heart failure was considered to be due to
increased preload or afterload but later it has been classified to be due to left ventricle (LV) systolic
dysfunction, LV diastolic dysfunction or both (Gaasch 1994; Zile et al. 2013). Recently, heart
failure is considered to be of two types namely heart failure with reduced ejection fraction (HFrEF)
and heart failure with preserved ejection fraction (HFpEF) (Zile et al. 2013; Owan et al. 2006;
Borlaugh and Paulus 2011). It may be noted that HFrEF is seen in about 56% patients and is mainly
associated with systolic dysfunction whereas HFpEF is observed in about 43% patient and is
associated with diastolic dysfunction (Zile et al. 2011; Ho et al. 2013; Zile et al. 2004). It is also
pointed out that HFpEF, in contrast to HFrEF, is associated with increased LV passive stiffness
due to collagen deposition in the extracellular matrix as well as increased intrinsic cardiomyocyte
stiffness due to shift in the isoforms of some myofibrillar components (Zile et al. 2004;
Westermann et al. 2008; Borbely et al. 2005). Furthermore, unlike the patients with HFrEF,
subjects with HFpEF are mostly resistant to several drugs which are currently available for the
treatment of heart failure (Packer 2019; Napoli et al. 2021; Upadhya et al. 2018). Some of the
sodium glucose cotransporter 2 (SGLT2) inhibitors (empagliflozin, sotagliflozin and
dapagliflozin) as well as blockers of the renin-angiotensin-aldosterone systems (RAAS) including
sacubitril-valsartan and aldosterone receptor antagonists (spironolactone) have shown some
potentials for the treatment of HFpEF patients (Kjeldsen et al. 2020; Anker et al. 2021; Bhatt et al.
2021; Nassif et al. 2021; Pitt et al. 2014; de Denus et al. 2017; Vaduganathan et al. 2020). Although
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these agents were found to reduce hospitalization time and improve the quality of life, the risk of
mortality was not affected for the HFpEF patients. Thus, there is an excellent opportunity for
cardiovascular investigators to develop appropriate experimental models of HFpEF and identify
exact molecular, cellular and metabolic targets for improving the pharmacotherapy of this
devastating disease. Since the pathophysiology and treatment of HFpEF patients require a detailed
discussion, it is not our intention to deal with this subject and accordingly, most of comments in
this article are limited to HFrEF.
A wide variety of drugs including inotropic agents, diuretics, β-adrenoceptor and α-
adrenoceptor blockers, as well as renin-angiotensin antagonists are now available for the treatment
of heart failure; however, none of these agents have been found to reduce the morbidity or
mortality in patients suffering from this ailment (Birkeland et al. 2007; Guo et al. 2005; Babick et
al. 2012a; Rehsia and Dhalla 2010a; Babick et al. 2012b; Rehsia and Dhalla 2010b; Gronda et al.
2019; Napoli et al. 2020). Most of these cardiac drugs have been developed either to reduce the
impact of risk factors and elevated levels of circulating vasoactive hormones for the occurrence of
heart failure or for improving cardiomyocyte function of the failing heart. Furthermore, it may be
noted that heart failure is invariably associated with cardiac hypertrophy, which not only involves
increased protein synthesis in cardiomyocytes but there also occurs proliferation of different types
of cells in the myocardial extracellular matrix (Dhalla et al. 2006; Weber 1989; Briest et al. 2003;
Zak 1973; Weber and Brilla 1991; Weber et al. 1987). Some of these cells (non-myocytes) present
in the myocardial interstitium include cardiac fibroblasts, macrophages, endothelial cells, smooth
muscle cells, mast cells and nerve terminals; these represent one-third of cell population in the
heart. Thus drug-design for developing future therapy of heart failure should also consider to
control changes in the myocardial interstitium, which release growth factors, inflammatory
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cytokines, different endogenous hormones as well as proteolytic and cytotoxic enzymes.
Nonetheless, it has become evident that cardiac hypertrophy at initial stages, irrespective of the
pathological stimulus for heart failure, is an adaptive process which exhibits either an increase or
no change in heart function. However, at a later stage, there occurs the transition of cardiac
hypertrophy to heart failure as a consequence of increased ventricular wall stress and the elevated
levels of vasoactive hormones for a prolonged period (Wikman-Coffelt et al. 1979; Dhalla et al.
1987; Molkentin and Dorn 2001; Heineke and Molkentin 2006). Thereafter, a set of complex
mechanisms come into play in the hypertrophied myocardium and these result in progression of
cardiac remodeling, myocardial dysfunction, metabolic alterations, Ca2+-handling abnormalities,
electrophysiological defects and heart failure (Xie et al. 2013; Lyon et al. 2015; Dhalla et al. 2019).
It should be emphasized that it is mainly the occurrence of marked arrhythmias and not the cardiac
pump failure which results in sudden cardiac death at the late stages of heart failure (Dhalla et al.
2010; Mialet-Perez et al. 2018; Goyal et al. 2016; Carson et al. 2013). A schematic representation
of different stages such as development of cardiac hypertrophy, transition of cardiac hypertrophy
to heart failure, progression of heart failure and sudden cardiac death following a
pathophysiological stimulus for the occurrence of heart failure is shown in Figure 1. Accordingly,
for the purpose of identifying appropriate viable targets and move towards the development of
drug therapy, this review is intended to discuss various pathophysiological events associated with
cardiac hypertrophy and heart failure at different stages of their development.
Development of Cardiac Hypertrophy
It is now well known that cardiac hypertrophy is not only associated with heart failure but
also precedes it following diverse pathological stimuli. There occurs growth of cardiomyocytes as
well as proliferation of different cell types in the myocardial interstitium for the occurrence of
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cardiac hypertrophy, which is mainly of two forms and is dependent upon the type of
hemodynamic overload. Pressure overload due to hypertension is associated with concentric
hypertrophy in which the ventricular wall is thickened whereas volume overload due to valvular
defects results in the development of eccentric hypertrophy in which the ventricular wall become
dilated. On the other hand, hypertrophy of the viable ventricle following loss of myocardium due
to myocardial infarction is of mixed type. Extensive information regarding the development of
cardiac hypertrophy due to various risk factors of heart failure involving different hormones,
growth factors, hemodynamic overload, increased ventricular wall stress and changes in redox
status has been reviewed by several investigators (Dhalla et al. 1987; Molkentin and Dorn 2001;
Shimizu and Minamino 2016; Maillet et al. 2013; Bernardo et al. 2010; Nakamura and Sadoshima
2018; Sethi et al. 2007; Oldfield et al. 2020; Shah et al. 2021). However, it is noteworthy that the
exact sequence of vasoactive hormone release from the peripheral and central sources due to the
activation of sympathetic nervous system (catecholamines), hypothalamic-pituitary-adrenal axis
(vasopressin) and renin-angiotensin system (angiotensin II) is not clear. These alterations in
hemodynamic overload and elevated levels of circulating hormones are inter-related and are
considered to be affecting each other under diverse stressful situations. Furthermore, both these
changes increase the left ventricular wall stress, which then results in inducing alterations in
myocardial interstitium to release various growth factors and different hormones in the circulation.
It should be mentioned that growth factors are released from fibroblasts and different cytokines
are released from macrophages whereas endothelin is released from endothelial cells, 5-
hydroxytryptamine is released from mast cells, angiotensin II is released due to the activation of
local (tissue) renin-angiotensin system and norepinephrine is released from the adrenergic nerve
terminals. All these hormones and growth factors from the myocardial interstitium as well as those
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released from peripheral and central neuroendocrine system are involved in the development of
cardiac hypertrophy; however, their exact contribution in the growth of myocardium is poorly
understood. A schematic representation of various events participating in the genesis of cardiac
hypertrophy is given in Figure 2.
Whenever the heart is subjected to stressful situations associated with insufficient blood
supply, there occurs a release of different vasoactive hormones to produce constriction of blood
vessels as well as to induce myocardial growth. It is pointed out that cardiac hypertrophy is of
adaptive nature (physiological hypertrophy) as it improves the ability of heart to pump adequate
amount of blood. The cellular and molecular events associated with myocardial hypertrophic
process involve the interaction of a wide variety of cardiac membrane receptors with their
respective hormones, activation of different protein kinases such as protein kinase A, protein
kinase C and mitogen activated protein kinases to generate signal transduction systems for the
synthesis of myocardial proteins (Molkentin and Dorn 2001; Heineke and Molkentin 2006;
Shimizu and Minamino 2016; Maillet et al. 2013; Nakamura and Sadoshima 2018; Sethi et al.
2007). It is noteworthy that these vasoactive hormones not only exert positive inotropic effect on
heart but also promote the formation of oxyradicals, which are rapidly removed by the presence of
a sufficient amount of antioxidants in the myocardium (Kirshenbaum and Singal 1992; Singal et
al. 1991; Gupta and Singal 1989). Nonetheless, differential increase in the generation and removal
of oxyradicals under this situation can be seen to alter the redox status of the myocardium, which
is consider to serve as a signal for the increased synthesis of proteins. It is emphasized that the
process of adaptive cardiac hypertrophy is associated with the development of capillaries and small
blood vessels (angiogenesis) in the myocardium for adequate supply of oxygen and substrates as
well as for promoting the accumulation of collagenous protein in the extracellular matrix and
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glycocalyx for providing ventricular stiffness. It is also pointed out that the activities of Ca2+-
cycling proteins in both sarcolemma and sarcoplasmic reticular are increased whereas
mitochondrial and myofibrillar functions are normal. Such alterations in subcellular activities are
consistent with observations that cardiac function of the hypertrophied myocardium is either
increased or unchanged at the adaptive phase of cardiac hypertrophy.

Transition of Cardiac Hypertrophy to Heart Failure
Exposure of adapted hypertrophied heart to high levels of vasoactive hormones and/or
abnormal hemodynamic overload for a prolonged period results in the development of cardiac
dysfunction (pathological cardiac hypertrophy). Although several investigators have dealt with the
issue of transition of physiological hypertrophy to pathological hypertrophy (Weber et al. 1987;
Wikman-Coffelt et al. 1979; Xie et al. 2013; Shimizu and Minamino 2016; Bernardo et al. 2010;
Nakamura and Sadoshima 2018; Oldfield et al. 2020), the cellular and molecular mechanism for
this pre-failure stage are not fully understood. Furthermore, no specific biomarker has been
designated to reflect this change except depression in the contractile function of the hypertrophied
myocardium become evident. It has been shown that the occurrence of oxidative stress as a
consequence of exhaustion of antioxidant mechanisms in the hypertrophied myocardium may play
a critical role in the genesis of cardiac dysfunction (Shah et al. 2021; Singal et al. 1991; Dhalla et
al. 2000; Dhalla et al. 1996). Since capillary density is decreased and there occurs coronary
constriction in the hypertrophied heart, these changes may lead to hypoperfusion, functional
hypoxia and subsequent oxidative stress (Dhalla et al. 1987; Shimizu and Minamino 2016;
Nakamura and Sadoshima 2018; Oldfield et al. 2020). It has also been claimed that degradation of
collagenous proteins and glycocalyx and extracellular matrix due to the release of metallomatrix
proteases from fibroblasts may results in the transition of adaptive cardiac hypertrophy to
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maladaptive hypertrophy (Weber and Brilla 1991; Janicki et al. 2004; Spinale 2007). These
alterations for the occurrence of heart failure in the adapted hypertrophied heart are shown in
Figure 3. Although some natriuretic peptides (ANP and BNP) are used as markers of heart failure
(Yu et al. 1996; Clerico et al. 1998), their validity during the transition of cardiac hypertrophy to
heart failure has not been established. Accordingly, it is suggested that some specific markers for
the identification of this pre-failure stage be determined. There are some investigators who are of
the view that cardiac hypertrophy is a risk factor for the development of heart failure and perhaps
they refer this event to the late stage associated with insufficiency of oxygen supply in this
condition. Nonetheless, appropriate antioxidants in combination with some angiogenic agents and
protease inhibitors may prove useful in delaying this pre-failure stage.
Progression of Heart Failure
Over the past six and a half decades, extensive work has been carried out to understand the
pathogenesis of heart failure (Dhalla et al. 1993; Mudd and Kass 2008; Cohn et al. 2000; Dhalla
et al. 2006; Machackova et al. 2006; Dhalla et al. 2012), however, the exact mechanisms for its
development and progression still remain to be poorly understood. In fact, several concepts
including hemodynamic overload, defects in energy production and utilization, neurohumoral
hypothesis, cardiac remodeling and modification of subcellular organelles have been developed
from time to time for explaining cardiac dysfunction in heart failure. However, it is becoming
apparent that all these concepts are inter-related and influence each other during the development
of heart failure. The concept of hemodynamic overload is based on observations regarding the
development of pre-load and after-load, and is considered to induce ventricular wall stress under
pathological conditions associated with hypertension and valvular defects. These hemodynamic
changes and ventricular wall stress lead to the release of different neurohormones from central and
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peripheral systems as well as from myocardial interstitium, endothelium and platelets (Dhalla et
al. 2012; Vanhoutte 1989; Sanganalmath et al. 2008a; Sanganalmath et al. 2008b; Francis et al.
1984; Packer 1988; Lee and Tkacs 2008; Rouleau 1996; Swedberg et al. 1990). Particularly, the
elevated levels of circulating vasoactive hormones for a prolonged period are considered to exert
adverse actions on the hemodynamics as well as cardiomyocyte function and metabolism. It should
also be pointed out that the concept of defects in energy production and utilization for the induction
of heart failure was formulated on the basis of inability of mitochondria to generate sufficient ATP
as well as myofibrils to hydrolyze ATP adequately (Machackova et al. 2006; Olson 1959; Dhalla
et al. 1978). This view has stimulated a great deal of research work in the area of myocardial
metabolism in the heart which has identified a shift in fuel utilization and other metabolic defects
in the genesis of cardiac dysfunction and heart failure (Bing 1965; Opie 1968, 1969; Ashrafian et
al. 2007; Lopaschuk et al. 2010).
The concept of cardiac remodeling, which is based on changes in the structure, size and
shape of the heart, has been most helpful clinically for the diagnosis of heart failure (Cohn et al.
2000; Dhalla et al. 2012). Advances in biotechnology for the measurement of structural changes
in association with cardiac function by echocardiography have now permitted the assessment of
adaptive and adverse cardiac remodeling as well as progression and stage of heart failure.
However, the measurement of adverse cardiac remodeling does not provide any information
regarding the mechanisms of cardiac dysfunction during the development of heart failure (Dhalla
et al. 2019; Dhalla et al. 2012). Since cardiac performance is mainly determined by the coordinated
functions of different subcellular organelles such as sarcolemma, sarcoplasmic reticulum,
mitochondria and myofibrils, modification of subcellular organelles has been suggested to play a
critical role in the development of cardiac dysfunction and progression of heart failure (Dhalla et
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al. 2006; Machackova et al. 2006; Dhalla et al. 1978; Dhalla et al. 2009; Dhalla et al. 1998). In
fact, evidence was presented to show that subcellular remodeling may induce cardiac dysfunction
in the failing heart (Dhalla et al. 2009). It is pointed out that alterations of Ca2+-handling proteins
in both sarcolemma and sarcoplasmic reticulum are considered to produce Ca2+-handling
abnormalities in cardiomyocytes in heart failure. The occurrence of mitochondrial Ca2+-overload

due to the increased level of cytoplasmic Ca2+, can be seen to impair energy production whereas
defects in different components of myofilaments including loss of myocardial Ca2+-sensitivity
depress the myocardial contractile activity. Such alterations in subcellular organelles have been
shown to be due to changes in cardiac gene expression as well as activation of different proteases
and phospholipases in the failing heart (Nusier et al. 2020; Muller and Dhalla 2012; Muller et al.
2012; Dhalla et al. 1982; Dhalla et al. 1977). Thus the progression of cardiac dysfunction during
adverse cardiac remodeling can be seen to be due to progressive modification of subcellular
organelles in cardiomyocytes in heart failure.
The neurohumoral hypothesis of cardiac dysfunction is based on the observations that the
circulating levels of various hormones are elevated during the development of cardiac hypertrophy
and heart failure (Rehsia and Dhalla 2010b; Sanganalmath et al. 2008b; Packer 1988; Rouleau
1996; Nicholls et al. 1996; Packer 1992; Francis et al. 1990). Pathological stimulus such as
myocardial infarction has been shown to activate sympathetic nervous system, renin-angiotensin
system, hypothalamic-pituitary-adrenal axis to release catecholamines, renin-angiotensin and
vasopressin. These hormones not only affect myocardium but also induced hemodynamic overload
and increase ventricular wall stress. Exposure of the heart to the elevated levels of these vasoactive
hormones for a prolonged period also produce changes in myocardial interstitium to release growth
factors from fibroblasts, inflammatory cytokines from macrophages, serotonin from mast cells and
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endothelin from endothelium (Dhalla et al. 2012; Vanhoutte 1989; Khalil et al. 2017; Shi and
Massague 2003). These alterations in heart failure lead to the development of oxidative stress,
inflammatory processes, metabolic defects and Ca2+-handling abnormalities (Dhalla et al. 2019;
Belch et al. 1991; Diaz-Velez et al. 1996; Ghatak et al. 1996; Bartekova et al. 2018; Das et al.
2010; Chen et al. 2020; Bartekova et al. 2021). The elevated levels of inflammatory cytokine as
well as oxidative stress will cause apoptosis, necrosis and fibrosis leading to loss of
cardiomyocytes; however, it is not clear whether these adverse effects of inflammatory cytokines
are mediated directly or through oxidative stress. Nonetheless, both oxidative stress and Ca2+-
handling defects are known to induce changes in cardiac gene expression and protein kinase
function as well as activation of proteases and phospholipases. Progressive alterations in these
events can be seen to be associated with progression of subcellular abnormalities, cardiac
dysfunction and heart failure. A schematic representation of these events leading to the progression
of adverse cardiac remodeling is shown in Figure 4. It should also be mentioned that there occurs
a loss of inotropic mechanisms due to changes in membrane receptors, cation channels, protein
kinases and associated signal transduction during the progression of heart failure as a consequence
of prolonged exposure to elevated levels of circulating vasoactive hormones (Kirchhefer et al.
1999; Vatner et al. 1999; Vatner et al. 1985; Dhalla et al. 1997; Feldman 1993; Dhalla and Muller
2010; Heger et al. 2016; Schirone et al. 2017; Sygitowicz et al. 2020; Mishra and Kass 2021).
Arrhythmias and Sudden Cardiac Death in Heart Failure
The failing hearts are quite susceptible to arrhythmias as varying degrees of
electrophysiological abnormalities are commonly seen in patients during the development of heart
failure. In fact, sudden cardiac death as a consequence of massive cardiac arrhythmias and
fibrillation is a major cause of mortality in patients with heart failure (Goyal et al. 2016; Carson et
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al. 2013). Although the exact reasons for these electrophysiological defects are not clear, it is
generally held that the occurrence of arrhythmias in failing heart is due to the development of
myocardial fibrosis and Ca2+-handling abnormalities in cardiomyocytes (Dhalla et al. 2010; Dhalla
et al. 2019). While inflammatory cytokine may induce fibrosis, Ca2+-handling abnormalities are
considered to be due to prolonged stimulation of the sympathetic nervous system, activation of β-

adrenoceptors, excessive formation of cyclic AMP and defect in Ca2+-handling proteins in the
sarcoplasmic reticulum (Dhalla et al. 2010; Mialet-Perez et al. 2018). However, the activation of
β-adrenoceptors is unlikely to be involved in causing arrhythmias because these receptors are
known to be downregulated in heart failure (Vatner et al. 1999; Vatner et al. 1985; Dhalla et al.
1997). Furthermore, treatment of animals with atenolol, a specific β-adrenoceptor blocker did not
prevent different types of arrhythmias due to coronary occlusion or high doses of catecholamines
(Adameova et al. 2018; Adameova et al. 2019). On the other hand, myocardial infarction or high
doses of catecholamine induced arrhythmias were markedly attenuated by treatments of animals
with antioxidants (Sethi et al. 2000; Sethi et al. 2009). Since oxyradicals are generated during the
oxidation of catecholamines by monoamine oxidase (Mialet-Perez et al. 2018; Dhalla et al. 2010)
and activation of NADPH oxidase by angiotensin II (Li et al. 2015; Nguyen et al. 2013) in heart
failure, it is most probable that oxidative stress may cause Ca2+-handling abnormalities for
inducing arrhythmias in heart failure (Adameova et al. 2020). Furthermore, adrenochrome, an
oxidation product of catecholamine has been shown to produce massive arrhythmias and
fibrillation (Mialet-Perez et al. 2018; Beamish et al. 1981; Rouleau et al. 2003). In fact, increased
levels of adrenochrome in plasma were found to be correlated with mortality due to sudden cardiac
death in patients with heart failure (Rouleau et al. 2003). Accordingly, various pathogenic factors
such as myocardial fibrosis, Ca2+-handling defects and oxidative products of catecholamines (both
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adrenochrome and oxyradicals) may play a critical role in inducing arrhythmias and sudden cardiac
death in heart failure. These events are presented schematically in Figure 5. It is pointed out that
varying types of arrhythmias may be seen throughout the progression of heart failure; however,
sudden cardiac death is considered to be mostly associated with the end-stage of heart failure.
Pharmacotherapy of Heart Failure

A wide variety of drugs have been used for the treatment of heart failure. Particular efforts
were directed toward improving the clinical signs, impact of vasoactive hormones, hemodynamic
overload and cardiac pump dysfunction in patients with heart failure (Mudd and Kass 2008; Cohn
et al. 2000; Gaasch 1994; Dhalla et al. 2006; Rouleau 1996; Dhalla et al. 2009; Sabbah et al. 1994;
Schrier and Abraham 1999). Several diuretics and digitalis glycosides were developed to reduce
the fluid accumulation in the body and improve the hemodynamic function associated with heart
failure, respectively. Furthermore, different inotropic agents are recommended for attenuating
cardiac dysfunction. Various adrenergic receptor blocking agents (α- and β-adrenoceptor
antagonists) have been shown to exert beneficial effects on the failing heart (Rehsia and Dhalla
2010a; Babick et al. 2012b; Babick et al. 2013). In fact, different angiotensin converting enzyme
inhibitors and angiotensin II receptor antagonists are widely used for reversing the adverse cardiac
remodeling and hemodynamic overload for the treatment of heart failure (Guo et al. 2005; Babick
et al. 2012a; Dhalla et al. 2006; Dhalla et al. 2012; Ju et al. 1997; Cohn et al. 2000; Nielsen et al.
2020). Several endothelin-1 and vasopressin antagonists have also been claimed to exert beneficial
effects in heart failure (Rehsia and Dhalla 2010b). Although different antiplatelet agents, which
are serotonin (5-HT) antagonists, have been observed to improve cardiac function in animal
models of heart failure (Birkeland et al. 2007; Sanganalmath et al. 2008a; Sanganalmath et al.
2008b), detailed clinical studies with these drugs remain to be carried out. It appears that blockers
15
of different hormone-receptors have similar degrees of beneficial effects in preventing adverse
cardiac remodeling and associated abnormalities in the failing hearts. However, the benefits with
these agents are dependent upon the type and stage of heart failure, and these treatments have not
been satisfactory in reducing the morbidity or mortality due to heart failure.
Since cardiac dysfunction in heart failure is considered to be a consequence of various

mechanisms such as metabolic defects, Ca2+-handling abnormalities, oxidative stress and
myocardial inflammation, different strategies have been developed for the discovery of drugs for
its treatment. Several metabolic interventions, which promote glucose oxidation and reduce free
fatty acids utilization or inhibit the transport of free fatty acids in mitochondria, are being
considered useful for delaying the progression of heart failure (Lopaschuk et al. 2010; Lionetti et
al. 2005; Schimidt-Shweda and Holubarsch 2000; Thrainsdottir et al. 2004; Nikolaidis et al. 2004).
Inhibition of Ca2+ entry by antagonists of voltage-sensitive Ca2+-channels has been useful in
reducing hemodynamic overload in heart failure; however, a great deal of clinical work needs to
be carried out for using inhibitors of store-operated Ca2+-channels for the therapy of heart failure
(Nusier et al. 2020; Dhalla et al. 1982; Dhalla et al. 1977; Ozcelikay et al. 2014; Bhullar et al.
2019). Because subcellular defects, which are considered to determine the progression of heart
failure, are elicited by changes in cardiac gene expression as well as activation of different
proteases, it would be prudent to undertake extensive studies for the use of interventions for
preventing changes in gene expression of Ca2+-handling proteins and protease inhibitors (Dhalla
et al. 2006; Dhalla et al. 2012; Muller and Dhalla 2012; Muller et al. 2012). Likewise, the activated
signal transduction mechanisms involving different protein kinases and inflammatory cytokines
for the occurrence of fibrosis, apoptosis and necrosis appears to be good targets for drug
development for the treatment of heart failure (Dhalla and Muller 2010; Wang et al. 1999; Zhang
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et al. 2003; English and Cobb 2002; Levine et al. 1990; Fang et al. 2017; Haudek et al. 2007). In
view of the observations that oxidative stress is an excellent therapeutic target, the development
of some appropriate antioxidants in delaying the progression of heart failure is a real challenge
(Bartekova et al. 2021; Milinkovic et al. 2020; Neri et al. 2015; Ayoub et al. 2017; van der Pol et
al. 2019; Sia et al. 2002; Qin et al. 2007; Freudenberger et al. 2004). Recent clinical trials with
SGLT2 inhibitors have shown a great potential for developing these agents for the treatment of
heart failure with reduced or preserved ejection faction (Pandey et al. 2022; Hias et al. 2022; Heath
et al. 2022; DeSa and Gong 2021; Spertus et al. 2022) It is thus evident that there are multiple sites
in cardiomyocytes as well as in myocardial interstitium which can be targeted for drug
development for the treatment of heart failure.
In view of the complexities involved in pathophysiologic mechanism of congestive heart
failure, there is no disease-specific therapy to improve its prognosis. It should be emphasized that
heart failure is not only associated with cardiac dysfunction and reduction in cardiac output, but is
also invariably accompanied by peripheral vasoconstriction, cardiorenal defects as well as
excessive salt and water retention. Although both cardiac and non-cardiac mechanisms are
considered to participate in the pathogenesis of heart failure, no conclusive study has been carried
out to determine the differences underlying these sites for developing appropriate therapy. In fact,
most of the drugs available for the treatment of heart failure have been observed to affect both
myocardial and hemodynamic functions for causing improvement in cardiac performance. The
beneficial effects of various diuretics in heart failure are attributed to the removal of excessive
body fluid whereas those of different vasodilators such as nitric oxide and natriuretic peptides are
related to improvements in the cardiocirculatory system. It should be pointed out that the various
types of drugs, which have been developed over the past 6 decades for improving the quality of
17
life in heart failure patients, have also been shown to exert their actions by acting on both cardiac
and vascular systems. Although, most of these are considered safe and do not induce major health
hazards, prolonged use of all drugs for the treatment of heart failure has been reported cause
adverse effects. For example, some of the β-adrenoceptors blockers including propranolol,
atenolol, metoprolol, acebutolol and carvedilol have been reported to cause side-effects such as
fatigue, dizziness, upset stomach, nausea, diarrhea and sexual dysfunction. Another type of drugs
(Ca2+-antagonists) for the treatment of heart failure includes verapamil, diltiazem, amlodipine and
nifedipine has been shown to produce bradycardia, hypotension, conduction disturbance, acidosis,
dizziness and fatigue. Commonly used angiotensin converting enzyme inhibitors such as enalapril,
lisinopril, ramipril and benazepril have been reported to cause dry cough, fatigue, headache,
dizziness and hyperkalemia. Most recent category of drug development for heart failure is related
to angiotensin II antagonists such as losartan, candesartan, valsartan and telmisartan; these agents
have also been shown to cause side effects including hyperkalemia, dizziness and swelling of skin.
Thus it would be prudent to state that some caution should be exercised for the use of drugs for a
prolonged period for the treatment of heart failure.
Conclusions
Both hemodynamic overload and elevated levels of vasoactive hormones are known to
produce cardiac hypertrophy, which is adaptive in nature at initial stages but develops cardiac
dysfunction due to hypoperfusion at late stages. While the hemodynamic changes are produced by
pressure overload and volume overload, various peripheral, central and interstitial neuroendocrine
systems as well as activation of endothelin and platelets participate in elevating the plasma levels
of vasoactive hormones. The development of cardiac dysfunction in hypertrophied heart is
associated with an increase in ventricular wall stress as well as alterations in the functions of both
18
Page 19 of 47
myocardial interstitium and cardiomyocytes. The progression of heart failure is closely related to
progressive development of metabolic abnormalities, subcellular defects, alterations in signal
transduction and cardiac dysfunction. Abnormalities in the function of subcellular organelles are
primarily caused by changes in gene expression and activation of various proteases. The
occurrence of fibrosis, necrosis and apoptosis in the failing heart is associated with loss of
cardiomyocytes as well as genesis of arrhythmias and fibrillation. These alterations appear to be a
consequence of elevated levels of oxidative stress and Ca2+-handling abnormalities in
cardiomyocytes as well as occurrence of myocardial inflammation. Thus the development and
progression of heart failure are a complex problem as multiple sites of both cardiac and non-cardiac
origin are involved in its pathogenesis. Accordingly, there is a challenge to design an appropriate
combination drug therapy for preventing oxidative stress, myocardial inflammation, metabolic
defects and Ca2+-handling abnormalities for the treatment of heart failure.
From the foregoing discussion, it is evident that the transition of stable/adaptive cardiac
hypertrophy to heart failure is associated with the development of cardiac dysfunction due to
hypoperfusion of myocardium, degradation of interstitial collagenous proteins and exhaustion of
antioxidant systems in cardiomyocytes. Thus there is a great merit in instituting a combination
drug therapy for promoting angiogenesis, attenuating collagenous protein degradation and
enhancing the antioxidant mechanisms at the pre-failure stage of the hypertrophied heart. It is
pointed out that the progression of heart failure due to prolonged elevated levels of vasoactive
hormones is not only associated with progressive deterioration of cardiac function and changes in
signal transduction but is also seen to be due to increased hemodynamic overload, ventricular wall
stress and alterations in myocardial interstitium. The elevated plasma levels of vasoactive
hormones including vasopressin, renin-angiotensin, catecholamines, endothelin and serotonin are
19
considered to produce marked hemodynamic and myocardial changes in heart failure. In fact,
several inhibitors and receptor antagonists of the renin-angiotensin system as well as blockers of
the sympathetic nervous system are being used to partially delay or prevent the progression of
heart failure. However, extensive experimental and clinical studies are required to develop
improved antagonists of endothelin, serotonin and vasopressin and to establish their beneficial
effects on cardiovascular function in heart failure. Perhaps appropriate combination therapy with
blockers of different hormones may prove more useful in preventing the development as well as
reversing the course of heart failure.
It is noteworthy that most of the efforts for developing the treatment of heart failure have
been devoted for improving cardiovascular function by targeting cardiomyocytes and vascular
smooth muscles; however, not much attention has been paid for attenuating defects in the
myocardial interstitium. Thus extensive studies dealing with diverse interstitial defects can be seen
to yield improved therapy for heart failure. On the other hand, it is pointed out that a wide variety
of alterations in gene expression, subcellular function, protease activation and myocardial
metabolism have been identified in cardiomyocytes during the progression of heart failure.
Particularly, there occurs a loss of cardiomyocytes and arrhythmias due to the development of
fibrosis, necrosis and apoptosis in the failing hearts. Such multifactorial defects are considered to
be a consequence of various changes such as oxidative stress, myocardial inflammation and Ca2+-
handling abnormalities, which have been demonstrated to develop during the progression of heart
failure. It is thus our opinion that a combination therapy be developed for attenuating metabolic
changes, subcellular defects and signal transduction abnormalities in the failing heart for
improving the treatment of heart failure.
20
Page 21 of 47
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgements
The infrastructural support for the preparation of this article was provided by the St. Boniface
Hospital Albrechtsen Research Centre. Thanks, are also due to Ms. Andrea Opsima for typing this
manuscript.
21
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41
Legends to the Figures
Figure 1. Various stages and major events occurring during the development of cardiac
hypertrophy, heart failure and sudden cardiac death following a pathophysiological
stimulus.
Figure 2. Involvement of some vasoactive hormones from peripheral and central systems as well
as myocardial interstitium in the development of cardiac hypertrophy.
Figure 3. Role of oxidative stress due to hypoperfusion and exhaustion of antioxidant mechanisms
in cardiomyocytes as well as alterations in the extracellular matrix for the transition of
hypertrophied myocardium to heart failure.
Figure 4. Role of excessive levels of inflammatory cytokines, oxidative stress and cytosolic Ca2+
in the progression of adverse cardiac remodeling, subcellular defects and cardiac
dysfunction in heart failure. SL- sarcolemma; SR-sarcoplasmic reticulum
Figure 5. Role of elevated levels of monoamine oxidation products, Ca2+-handling abnormalities
and electrophysiological defects in inducing sudden cardiac death in severe stage of heart
failure.
42
Page 43 of 47
Pathophysiologic Stimulus
Hemodynamic Level of Vasoactive

Overload Hormones
Ventricular Wall Stress
Development of
Cardiac Hypertrophy
Transition of Hypertrophy
to Heart Failure
Progression of
Heart Failure
Advanced Stage of
Heart Failure
Sudden Cardiac
Death
Dhalla et al
Fig. 1
Pathophysiologic Stimulus
Release of Vasoactive Increase in

Hormones from Pressure Overload
Peripheral and Central or Volume Overload
Neuroendocrine
Systems
Release of Growth
Ventricular Factors and Hormones Ventricular
Wall Stress from Myocardial Wall Stress
Interstitium
Alterations of Accumulation of Alterations of

Redox Status in Collagenous Redox Status in
Cardiomyocytes Proteins in Cardiomyocytes
Extracellular Matrix
Cardiac Hypertrophy
(Adaptive Cardiac Remodeling)
Dhalla et al
Fig. 2
Page 45 of 47
Hypertrophied Heart
Hypoperfusion and Exhaustion of

Coronary Artery Antioxidant Mechanisms
Constriction in Cardiomyocytes
Release of Proteases
from Extracellular Matrix
Oxidative Stress Oxidative Stress
Degradation of
Glycocalyx
Proteins
Transition of Cardiac
Hypertrophy to Heart failure
Dhalla et al
Fig. 3
Levels of Vasoactive Hormones and

Alterations in Myocardial Interstitium for a
Prolonged Period
Level of
Development of Level of
Inflammatory
Oxidative Stress Intracellular Ca2+
Cytokines
Alterations in Cardiac
Gene Expression and
Apoptosis,
Protein Kinases; Activation of
Proteases and Phospholipases Mitochondrial
Necrosis and
Ca2+-overload
Fibrosis
SL and SR
Myofibrillar Remodeling and Depletion of
Loss of Derangements Ca2+-handling High Energy
Cardiomyocytes Defects Stores
Progression of Adverse
Cardiac Remodeling and
Cardiac Dysfunction
Dhalla et al
Fig. 4
Page 47 of 47
Development of
Heart Failure
Elevated Levels of Marked Electrophysiological

Monoamines Ca2+-handling Defects Due to
Oxidation Products Abnormalities Fibrosis
Massive Cardiac Arrhythmias
Sudden
Cardiac Death
Dhalla et al
Fig. 5

Future Scope and Challenges For Congestive Heart Failure Moving Towards Development of Pharmacotherapy

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Future scope and challenges for congestive

heart failure: Moving towards development of pharmacotherapy

Naranjan S. Dhalla1*, Sukhwinder K. Bhullar1, Anureet K. Shah2

Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of

Manitoba, Winnipeg, Canada.

*Corresponding Author: Naranjan S. Dhalla, PhD, MD (Hon)

© The Author(s) or their Institution(s)

different mechanisms involving both cardiomyocytes and non-myocyte (extracellular matrix)

dysfunction in hypertrophied myocardium. Alterations in the regulatory process due to several

protein kinases as well as participation of mitochondrial Ca2+-overload, activation of proteases and

improving cardiac function in heart failure.

remodeling, pharmacotherapy of heart failure.

throughout the world.

sodium glucose cotransporter 2 (SGLT2) inhibitors (empagliflozin, sotagliflozin and

dapagliflozin) as well as blockers of the renin-angiotensin-aldosterone systems (RAAS) including

sacubitril-valsartan and aldosterone receptor antagonists (spironolactone) have shown some

cardiovascular investigators to develop appropriate experimental models of HFpEF and identify

this article are limited to HFrEF.

A wide variety of drugs including inotropic agents, diuretics, β-adrenoceptor and α-

cytokines, different endogenous hormones as well as proteolytic and cytotoxic enzymes.

cardiac remodeling, myocardial dysfunction, metabolic alterations, Ca2+-handling abnormalities,

of different stages such as development of cardiac hypertrophy, transition of cardiac hypertrophy

cardiac hypertrophy and heart failure at different stages of their development.

Development of Cardiac Hypertrophy

hemodynamic overload. Pressure overload due to hypertension is associated with concentric

to myocardial infarction is of mixed type. Extensive information regarding the development of

activation of sympathetic nervous system (catecholamines), hypothalamic-pituitary-adrenal axis

understood. A schematic representation of various events participating in the genesis of cardiac

hypertrophy is given in Figure 2.

increased or unchanged at the adaptive phase of cardiac hypertrophy.

Transition of Cardiac Hypertrophy to Heart Failure

Exposure of adapted hypertrophied heart to high levels of vasoactive hormones and/or

issue of transition of physiological hypertrophy to pathological hypertrophy (Weber et al. 1987;

consequence of exhaustion of antioxidant mechanisms in the hypertrophied myocardium may play

protease inhibitors may prove useful in delaying this pre-failure stage.

Progression of Heart Failure

including hemodynamic overload, defects in energy production and utilization, neurohumoral

al. 2007; Lopaschuk et al. 2010).

functions of different subcellular organelles such as sarcolemma, sarcoplasmic reticulum,

in both sarcolemma and sarcoplasmic reticulum are considered to produce Ca2+-handling

abnormalities in cardiomyocytes in heart failure. The occurrence of mitochondrial Ca2+-overload

defects in different components of myofilaments including loss of myocardial Ca2+-sensitivity

adverse cardiac remodeling can be seen to be due to progressive modification of subcellular

organelles in cardiomyocytes in heart failure.

system, hypothalamic-pituitary-adrenal axis to release catecholamines, renin-angiotensin and

function as well as activation of proteases and phospholipases. Progressive alterations in these

events can be seen to be associated with progression of subcellular abnormalities, cardiac

of prolonged exposure to elevated levels of circulating vasoactive hormones (Kirchhefer et al.

Arrhythmias and Sudden Cardiac Death in Heart Failure

The failing hearts are quite susceptible to arrhythmias as varying degrees of

considered to be due to prolonged stimulation of the sympathetic nervous system, activation of β-

β-adrenoceptors is unlikely to be involved in causing arrhythmias because these receptors are

doses of catecholamine induced arrhythmias were markedly attenuated by treatments of animals

inducing arrhythmias in heart failure (Adameova et al. 2020). Furthermore, adrenochrome, an

Pharmacotherapy of Heart Failure

of different hormone-receptors have similar degrees of beneficial effects in preventing adverse

been satisfactory in reducing the morbidity or mortality due to heart failure.

Since cardiac dysfunction in heart failure is considered to be a consequence of various

mechanisms such as metabolic defects, Ca2+-handling abnormalities, oxidative stress and

Inhibition of Ca2+ entry by antagonists of voltage-sensitive Ca2+-channels has been useful in

in cardiomyocytes as well as in myocardial interstitium which can be targeted for drug

development for the treatment of heart failure.