Targeting mitochondrial dysfunction in the treatment of heart failure

ABSTRACT

Introduction: Heart failure (HF) has reached epidemic proportions worldwide. Despite the availability of drugs that reduce mortality and afford good symptom relief, HF continues to exact a considerable clinical and economic burden. Current HF therapies elicit benefit by reducing cardiac workload by lowering heart rate and loading conditions, thereby reducing myocardial energy demands.

Areas covered: Recent recognition that the failing heart is ‘energy deprived’ and its primary energy source, the mitochondria, is dysfunctional, has focused attention on mitochondria as a worthy therapeutic target. In HF, mitochondrial dysfunction leads to reduced adenosine triphosphate (ATP) synthesis and excessive formation of damaging reactive oxygen species (ROS), a combination the failing heart can ill afford.

Expert commentary: Correcting mitochondrial dysfunction can help forge a new therapeutic approach based on readily available energy that can meet increasing cardiac demands. This paradigm shift, once implemented successfully, is likely to elicit better overall cardiac function, better quality of life, and improved survival for patients with HF.

KEYWORDS:

• Heart failure
• myocyte
• mitochondria
• cardiovascular therapy
• left ventricular function

1. Introduction

Cardiovascular disease is the leading cause of death in the United States for men and women [1], of which congestive heart failure (HF) is a major component. Current estimates indicate that approximately 6.0 million people in the United States suffer from HF, accounting for nearly one out of every nine deaths [2]. An analysis of the prognosis of patients with HF shows that 50% of patients with HF die within 5 years of their first diagnosis [3]. The burden of HF continues to grow and is a leading cause of health-care expenditures, hospitalizations, and mortality in the United States and worldwide. HF imposes a significant economic burden on the health-care system, with costs estimated at $32 billion each year in the United States alone [4]. With an aging population, the burden is more likely to increase, with projections that there will be >8 million people with HF by 2030 [5]. With the implementation of evidence-based treatment paradigms, the number of deaths from HF has essentially remained unchanged over recent decades: 287,000 in 1995 and 284,000 in 2013 [5].

Currently, most treatments for HF ameliorate symptoms, improve survival, and reverse remodeling of the failing left ventricle, but do not directly target the underlying pathology in the failing myocardium. Current therapies achieve their benefits primarily by targeting the periphery to block the adverse effects of enhanced activation of compensatory neurohumoral systems, specifically the sympathetic nervous system and renin–angiotensin–aldosterone system [6,7]. This blockade is effective in reducing systemic vascular resistance and heart rate, and, in doing so, it reduces workload on the failing heart and reduces myocardial oxygen consumption. The achieved reduction in myocardial energy demands falls in line with the limited energy supply of the failing heart, thereby achieving a ‘rebalancing’ between energy supply and demand, albeit at a lower plane. This transient energy equilibrium leads to improved survival but does little to improve the quality of life of the affected patient. Reducing cardiac demands for energy by reducing cardiac workload, therefore, is the foundation of current HF therapy [8]. Although this approach has been effective in improving survival of patients with HF, continuing to lower heart rate and systemic vascular resistance cannot be expected to further improve survival, as these modalities themselves begin to adversely impact the survival and well-being of patients with HF by raising the specter of bradycardia and hypotension. To achieve better outcomes in patients with HF, a new paradigm is needed ─ one that seeks to enhance the energy supply of the failing heart to meet the desired energy demands. This paradigm shift can be achieved by targeting the mitochondria and alleviating mitochondrial dysfunction in HF. This new thinking, based on a sound biologic foundation, can chart a promising new direction for drug discovery for treating HF, as well as several other diseases associated with mitochondrial dysfunction. The aim of this review is to describe the role of mitochondria in the healthy and failing heart, suggest mitochondrial pathophysiologic targets for intervention, and discuss studies of agents that target mitochondrial dysfunction for the treatment of HF.

2. Mitochondrial function in the healthy heart

Mitochondria are present and perform a vital function in every cell in the body (except in red blood cells) by generating life-supporting energy through the production of adenosine triphosphate (ATP) commensurate with the energy needs of constituent cells of an individual organ. As such, the density of mitochondria within constituent cells of a particular organ is dependent on the energy requirements of that organ. The importance of optimal mitochondrial function for the proper function of essential cell populations, such as neurons, intestinal epithelial cells, and cardiomyocytes, is underscored by life-threatening pathologies that arise from human mitochondrial diseases driven by mitochondrial DNA (mtDNA) and nuclear DNA mutations [9,10].

The normal heart produces the majority (95%) of the required levels of ATP through the process of oxidative phosphorylation within the electron transport chain (ETC) embedded within the mitochondria. In cardiomyocytes, as well as in other cells that require high levels of energy, nearly one-third of the cell’s volume is occupied by mitochondria, which is needed to sustain an energy-requirement level of approximately 30 kg of ATP/day [11,12]. The production of ATP is achieved through the coordination of electron transport and enzyme complexes (CI, CII, CIII, CIV, and CV) located on the inner membrane of the mitochondria (Figure 1) [13,14]. The energy released from the electron transfer is used to generate a proton gradient needed for the synthesis of ATP. All components of the complexes are encoded by nuclear and mtDNA, with the exception of CII, which is only encoded by nuclear DNA. Accumulating evidence suggests that the mitochondrial respiratory complex is composed of supercomplexes or respirasomes consisting of CI, CIII, and CIV [12,15,16]. These supercomplexes are thought to be key for efficient ATP generation and optimal control of the generation of reactive oxygen species (ROS); the latter is a normal by-product of the energy production process.

Figure 1. Depiction of mitochondrial inner membrane and electron transport chain consisting of complexes I through V. ROS are generated at complexes I and III. Excessive ROS production can lead to mitochondrial and cardiomyocyte dysfunction by inhibiting the TCA cycle enzymes and ATP synthase, and by damaging mtDNA. Adapted with permission from Okonko DO, et al., Nat Rev Cardiol 2015 [14]. CK: creatine kinase; CoQ₁₀: coenzyme Q₁₀; Cyt C: cytochrome c; mtDNA: mitochondrial DNA; Pi: inorganic phosphate; ROS: reactive oxygen species; TCA: tricarboxylic acid.

In addition to the enzymes (ETC complexes) required for oxidative phosphorylation, mitochondria contain many other active enzymes and phospholipids that control mitochondrial dynamics. Among the important phospholipids in mitochondria is cardiolipin, which is located in the inner mitochondrial membrane and functions as a cofactor for mitochondrial transport proteins, including stabilization of supercomplexes (CI, CIII, CIV, and CV) and retention of cytochrome c to the inner mitochondrial membrane (Figure 1) [14,17–22]. Cytochrome c is not only a key electron carrier for electron transport, but it is also instrumental in triggering cellular apoptosis (programmed cell death) when released from mitochondria into the cellular cytoplasm. Peroxidation of cardiolipin and its release into the cytoplasm can also trigger apoptosis [17,21]. Cardiolipin is important for mitochondrial health. Diseases that arise from genetic mutations adversely impact the ability of cardiolipin to perform key functional processes. Barth syndrome, for example, is a disease that arises from genetic mutations of a key enzyme responsible for formation and remodeling of cardiolipin and is clinically manifested as cardiomyopathy, skeletal myopathy, neutropenia, and growth retardation [22].

3. Mitochondrial abnormalities in the failing heart

It has long been recognized that abnormalities of mitochondria in constituent cardiomyocytes of the failing heart exist in patients with HF and animals with experimentally induced HF [13,23,24]. The dysregulation of mitochondria in HF spans a wide range that includes structural, dynamic, as well as functional abnormalities. Structural abnormalities are characterized by reduced organelle size, hyperplasia, or fragmentation, and often loss of electron-dense matrix, and disruption of the inner and outer membranes (Figure 2) [13,23,24]. Matrix depletion, myelinization, and mitochondrial membrane disruption were observed in 27% of mitochondria in dogs with HF compared with only 3% in normal controls (Figure 2) [13]. The amount of mitochondrial injury also correlated with increased plasma norepinephrine, suggesting a role for sympathoadrenergic hyperactivity in mitochondrial dysfunction in the failing heart [13]. Mitochondria of the failing heart also manifest dynamic abnormalities characterized by abnormal mitochondrial biogenesis along with dysregulation of fission and fusion proteins. Mitochondrial biogenesis or turnover is regulated largely by the transcriptional factor peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) and PGC-1β [25,26]. In the failing heart, PGC-1α is significantly downregulated with markedly diminished phosphorylation (Figure 3) [27], a dysregulation indicative of abnormal biogenesis [27].

Figure 2. Transmission electron micrographs of LV mitochondria in normal dogs and dogs with HF. Top left: normal showing predominantly normal, large mitochondria with tightly packed cristae and electron dense matrix, with insert depicting various structural components of mitochondria. Top right: coronary microembolization-induced HF showing mild abnormalities of mitochondria in the form of clearance of electron dense matrix. Bottom left: coronary microembolization-induced HF showing moderate abnormalities of mitochondria in the form of reduced organelle size and marked disorganization of cristae. Bottom right: coronary microembolization-induced HF showing severe mitochondrial injury with inner and outer membrane disruption and myelinization. Adapted with permission from Sabbah HN, et al. J Mol Cell Cardiol 1992 [13]. HF: heart failure; ID: intercalated disc; LV: left ventricular; M: mitochondrium.

Figure 3. Mean (± SEM) protein levels of PGC-1α (top) and phosphorylated PGC-1α (bottom) in LV myocardium of normal dogs and those with HF. Adapted from Gupta RC, et al. J Am Coll Cardiol 2013 [27]. HF: heart failure; LV: left ventricular; PGC-1α; peroxisome proliferator-activated receptor coactivator-1α; SEM: standard error of the mean.

Mitochondria are also dynamic organelles that change shape by undergoing fusion to generate elongated interconnected mitochondrial networks and fission to produce discrete fragmented mitochondria. Both processes are regulated by specific mitochondrial fusion and fission proteins. These processes ensure that mtDNA integrity is maintained by eliminating mitochondria with damaged DNA and promoting functional mtDNA content. There is a growing awareness of the role for microRNA in modulating mitochondrial function and biogenesis during the development of HF [28]. Aberrations in fission and fusion proteins through mutation or dysregulation have been associated with many cardiovascular abnormalities, including HF [29–31]: fission suppression accelerates mitophagy and cell necrosis and fusion inhibition suppresses mitophagy and increases toxic, ROS-producing mitochondria. Studies in our laboratories showed reduced levels of fusion-regulating proteins and increased levels of fission-regulating proteins in myocardium of patients with advanced HF, as well as in myocardium of dogs with microembolization-induced HF (Figure 4) [32,33].

Figure 4. Dysregulation of mitochondria fission and fusion proteins in LV myocardium of dogs with chronic HF. Bar graphs (mean ± SEM) show significant reduction in Mfn-2 and dominant OPA-1 mitochondrial fusion protein levels (top) and significant increases in Fis1 and Drp1 mitochondrial fission protein levels (bottom) in LV myocardium of dogs with chronic HF compared to normal dogs. Adapted from Sabbah HN, et al. Circulation 2014 [33]. Drp1: dynamin-related protein-1; Fis1: fission-1; HF: heart failure; LV: left ventricular; Mfn-2: mitofusion-2, NL: normal; OPA-1: optic atrophy-1; SEM: standard error of the mean.

In addition to the structural and dynamic abnormalities or, perhaps, as partially a result of them, mitochondria of the failing heart manifest marker ‘functional’ abnormalities highlighted by excessive production of ROS with reduced production of ATP [23,24,34]. Studies in our laboratories have shown mitochondrial abnormalities in a failing heart consisting of collapse of the membrane potential; opening of the permeability transition pore (PTP); reduced activity of CI and CIV; reduced level of the 18:2 species of cardiolipin, a key structural lipid of the inner mitochondrial membrane and an integral foundation upon which the mitochondrial ETC resides; and, importantly, reduced maximal rate of ATP synthesis and ATP/ADP ratio (Figure 5) [23,24,35–37]. These structural, dynamic, and functional abnormalities coupled with excessive ROS production are undoubtedly instrumental in mediating progressive cellular injury and dysfunction that culminate in progressive worsening of the HF state.

Figure 5. Reduction in mitochondrial membrane potential in LV myocardium of dogs with chronic HF. Bar graphs (mean ± SEM) show significant reduction in mitochondrial membrane potential (top left), significant increase in cytochrome c in cardiomyocyte cytosolic fraction (top right), significant reduction in the maximum rate of ATP synthesis by mitochondria in cardiomyocytes (bottom left), and significant reduction in 18:2 cardiolipin (bottom right) in LV myocardium of dogs with chronic HF compared with normal dogs. Adapted with permission from Sharov VG, et al. J Mol Cell Cardiol 2007 [36] and Sharov VG, et al. Heart Fail Rev 2005 [35]. HF: heart failure; LV: left ventricular, NL; normal, SEM: standard error of the mean.

4. Mitochondria-induced cell injury and cell death

As eluded to earlier, once abnormalities of mitochondria develop, two key adverse consequences emerge ─ namely excessive production of ROS and reduced production of ATP, both of which can have a major adverse impact on cell function and cell survival. An elevated level of ROS, beyond that which is produced by normally functioning mitochondria, can cause loss of cristae; thereby creating morphologic changes in mitochondria that lead to mtDNA damage, cellular DNA damage, and ultimately destruction of the cell itself through the induction of apoptosis [13,14,38,39]. When mitochondria are functioning normally, the production of ROS is at a minimum [38,39]. Indeed, a physiological level of ROS is produced and required for normal mitochondrial function and for the repair and remodeling of damaged mitochondria. When mitochondria are dysfunctional, however, an overproduction and accumulation of ROS ensue, leading to cellular injury (Figure 1) [14]. When electrons do not flow properly through the ETC for optimal oxidative phosphorylation to produce ATP, an excess production of toxic amounts of ROS leads to oxidative damage to cardiolipin and cristae structures, and to the release of cytochrome c into the cytoplasm that sets the stage for activation of the apoptosis machinery that can culminate in the cell’s death [13,14]. The release of cytochrome c from mitochondria is partially facilitated through abnormal opening of the PTP. The overall damage to mitochondria from excess ROS production results in limited production of ATP. Although the amount of ATP produced is sufficient to sustain cell survival and limited cellular functions, it is not enough to support the H⁺ pump function during times of high oxidative energy requirements, which is particularly true for the high-energy requirements of the contractile machinery of cardiomyocytes [38,39].

5. Role of mitochondrial dysfunction in energy deprivation of the failing heart

As described earlier, abnormalities of mitochondria exist in constituent cardiomyocytes of the failing heart and can lead to excessive production of ROS and to a reduction in the rate of ATP synthesis, which is the energy currency of living cells and the lifeline of cardiomyocytes [40]. Excessive formation of ROS by abnormal mitochondria results in cardiomyocyte injury and death, whereas reduced rates of ATP synthesis contribute to cardiomyocyte dysfunction, with both ultimately contributing to progressive worsening of left ventricular (LV) function that characterizes HF. Considerable evidence exists to support the existence of excessive ROS production and reduced ATP synthesis in the heart of patients with HF with reduced ejection fraction (EF) [40].

Myocardial contraction and relaxation are strongly dependent on ATP generated by mitochondria located within cardiomyocytes. Nearly 70% of all ATP generated by mitochondria is used in the processes of cardiomyocyte contraction and relaxation [40]. In addition to maintaining energy homeostasis, normally functioning mitochondria and the ATP it generates are important in the regulation of a host of cellular functions ranging from receptor signaling and enzymatic activities to cellular apoptosis. Mitochondrial complex V codes for ATP synthase, which converts ADP to ATP [38,39]. ATP synthase catalyzes the final coupling step of oxidative phosphorylation to supply energy in the form of ATP. Alterations or dysfunction of ATP synthase activity crucially impact mitochondrial ability to generate ATP and subsequently overall cardiac performance. In bacteria and higher organisms, energy is generated through mitochondrial respiratory complexes, whereby ATP synthase is organized into supercomplexes in a close association with cardiolipin. These cardiolipin supercomplexes are crucial for the efficient activity of ATP synthase and ADP–ATP translocase, a process that allows ATP and ADP to move within the inner mitochondrial membrane. Disruption of this process results in ATP deprivation and culminates in cardiomyocyte dysfunction [17–22].

Early studies have investigated the role of apoptosis versus necrosis in the development of HF (for review, see [41]). Cardiomyocytes, like neurons, do not regenerate, so their loss has long-term consequences for normal cardiac function. Accumulated evidence from animal and human studies shows that pathophysiologic events can trigger apoptosis of cardiomyocytes and that apoptosis is mediated through mitochondria. The key pathophysiologic conditions giving rise to apoptosis in HF are high levels of angiotensin II, excess levels of norepinephrine, and limited oxygenation of cardiomyocytes, which are also indicators of the progression of HF [41]. Evidence that these pathophysiologic conditions are directly involved with cardiomyocyte apoptosis was demonstrated by attenuation of cardiomyocyte apoptosis after long-term treatment of the same dogs with the angiotensin-converting enzyme inhibitor enalapril [42].

Mitochondrial respiratory activity has been evaluated in dogs with induced HF and in tissue from explanted failed human hearts [23,24]. Respiratory rate after the addition of ADP (state 3 respiration) was measured in the subendocardial and subepicardial LV free wall, interventricular septum, and right ventricular free wall. In both dog and human hearts, there was a failed response to the addition of ADP in all regions, indicating a reduction in mitochondrial respiration and, hence, a reduction in oxidative phosphorylation in mitochondria [23,24].

6. Expert commentary

Novel therapies for treating HF are currently being investigated; they directly or indirectly target the mitochondria, with the object of correcting or modifying existing mitochondrial abnormalities. The rationale for these new experimental therapeutics is based on the reasonable assumption that normalizing mitochondrial function in HF will improve ATP availability and reduce ROS production, thereby leading to improved global LV function and overall HF state [21]. There is a considerable array of such potential novel therapies that have undergone in vitro investigation but have not progressed to preclinical and/or clinical development (for reviews, see [21,43]). Hereafter, focus is given to those therapeutic agents that have entered preclinical and/or clinical development.

Opening or activation of the mitochondria permeability transition pore (mPTP) is a key event leading to programmed cell death through the release of cytochrome c into the systolic compartment. The event is also associated with an increase in ROS production and suppression of oxidative phosphorylation [44]. The exact physiologic function of the mPTP is uncertain, but it has been preserved in many species and may provide a protective mechanism by triggering apoptosis of irreversibly damaged cells. It has been speculated that inhibition of the mPTP by cyclosporine A can potentially alleviate mitochondrial dysfunction in patients with HF [32]. In a porcine model of coronary occlusion and reperfusion, cyclosporine A improved microvascular damage and appeared to preserve LV function [45]. Studies of cardiomyocytes isolated from LV myocardium of dogs with chronic HF, treated in vitro with cyclosporine A improved mitochondrial membrane potential, preserved expression of cytochrome c oxidase (CIV), improved mitochondrial cytochrome c oxidase-dependent respiration, and tended to enhance the maximum rate of ATP synthesis compared with untreated cardiomyocytes [32,35]. Further studies will be required to investigate the potential benefits of cyclosporine A, if any, in patients with HF.

Drugs that target the adenosine-signaling pathway have recently received attention as modalities that indirectly target mitochondrial dysfunction in HF. Adenosine signaling has long been recognized to have considerable cardioprotective effects, primarily through activation of the adenosine-1 receptor (A1R) subtype [46]. Activation of A1R reduces adenylyl cyclase levels, which in turn reduce sympathetic overdrive and also results in the release of atrial natriuretic peptide. Both of these effects have been shown to be cardioprotective [46–48]. A1R agonists also affect mitochondrial function through inhibition of mPTP opening [49]. Effectors downstream of the A1R including protein kinase C, K_ATP channels, and mitogen-activated protein kinase also have cardioprotective effects that can be modulated through A1R activation [50,51].

Full A1R agonists cannot be used for the treatment of HF because of undesirable side effects that include bradycardia, atrioventricular blocks, vasoconstriction, negative inotropy and dromotropy, sedation, and antidiuretic effects [52]. A solution to this problem arose with the finding of partial A1R agonists, such as capadenoson (CAP; BAY 68-4986), that have high affinity and selectivity for A1R, with a minimal effect on heart rate [53,54]. In dogs with chronic HF, treatment of 3 months with CAP resulted in significantly decreased volume fraction of interstitial fibrosis and normalization of sarcoplasmic reticulum calcium ATPase-2a activity [46]. In the same study, long-term therapy with CAP improved myocardial protein levels of mitochondria uncoupling proteins 2 and 3 (UCP-2 and UCP-3; regulators of membrane potential and ATP synthesis) and normalized levels of mitochondrial citrate synthase (Figure 6) [46]. In addition, treatment with CAP normalized cardiac protein levels of the glucose transporters, GLUT-1 and GLUT-4, as well as levels of muscle carnitine palmitoyl transferase-1, indicators of a return, albeit in part, to a near-normal cardiac metabolic state [46]. These improvements were associated with improved LV function and remodeling, as well as with significant reduction of plasma norepinephrine and n-terminal pro-brain natriuretic peptide. Partial A1R agonists are safer and more effective than CAP and are currently undergoing clinical trials in patients with HF.

Figure 6. LV myocardium protein levels of various metabolic proteins in dogs with chronic HF treated with (CAP) or without (CON) capadenoson compared to normal dogs (NL). Bar graphs (mean ± SEM) show changes in UCP-2 (top left), UCP-3 (top middle), CS (top right), GLUT-1 (bottom left), GLUT-4 (bottom middle), and mCPT-1 (bottom right). Adapted with permission from Sabbah HN, et al. Circ Heart Fail 2013 [46]. CAP: HF treated with capadenoson; CS: mitochondrial citrate synthase; CON: untreated HF; GLUT: glucose transporter; LV: left ventricular, mCPT-1; muscle carnitine palmitoyl transferase-1; NL: normal; SEM: standard error of the mean; UCP: mitochondrial uncoupling protein. *p < 0.05 vs NL; **p < 0.05 vs. CON.

The search for novel compounds that can ‘directly’ target mitochondria uncovered a family of small peptides able to penetrate lipid bilayers and access the inner mitochondrial membrane. An example of such a peptide is elamipretide (previously referred to as Bendavia, MTP-131, SS-31). Elamipretide is a water-soluble tetrapeptide that is able to access the inner mitochondrial membrane and associate with the key phospholipid, cardiolipin [55,56]. As discussed earlier, cardiolipin is thought to stabilize ETC supercomplexes and mitochondrial cristae, which are essential for optimal mitochondrial function. In a modeling study of the mechanism of action of elamipretide, the peptide’s association with cardiolipin was proposed to stabilize cytochrome c conformation in a form that promoted efficient electron transport in mitochondria and, therefore, improved oxidative phosphorylation [55].

In dogs with coronary microembolization-induced chronic HF, long-term treatment (3 months) with daily subcutaneous injections of elamipretide normalized cardiac mitochondrial function as evidenced by normalization of mitochondrial membrane potential, mPTP activation, CI and CIV activity, maximum rate of ATP synthesis, and ATP/ADP ratio. These improvements were accompanied by a significant reduction of n-terminal pro-brain natriuretic peptide, tumor necrosis factor-α, interleukin-6, and C-reactive protein [37]. In LV tissue obtained from these dogs, long-term therapy with elamipretide normalized the regulation of mitochondrial fission and fusion proteins in LV myocardium [33]. After 3 months of therapy with elamipretide, protein levels of dominant optic atrophy-1, mitofusion-2, fission-1, and dynamin-related protein-1 were at near-normal levels. The observed improvements in the dynamics and function of mitochondria in dogs with HF treated with elamipretide were associated with marked improvement in global LV systolic function and prevention of progressive LV remodeling, evidenced by significant increases in left-ventricular ejection fraction and LV fractional area of shortening, and by a decrease in LV volumes compared with untreated control dogs (Figure 7) [37]. A phase 1/2 study of elamipretide in patients with HF with reduced EF was recently conducted to evaluate the safety and efficacy of elamipretide in human subjects [57]. Two phase 2 clinical trials are currently underway that examine the effects of elamipretide in patients with HF with reduced or preserved EF.

Figure 7. Effect of elamipretide treatment in dogs with HF. Change (Δ, treatment effect) between pretreatment and 12 weeks post-treatment for left ventricular EDV, ESV, EF, and FAS (left) and plasma nt-pro BNP (right) in untreated HF control dogs (HF-CON) and HF dogs treated with elamipretide (HF+ELA). All bar graphs are depicted as mean ± SEM. Adapted with permission from Sabbah HN, et al. Circ Heart Fail 2016 [37]. EDF: end-diastolic volume; EF: ejection fraction; ESV: end-systolic volume; FAS: fractional area of shortening; HF: heart failure; nt-pro BNP: n-terminal pro-brain natriuretic peptide; SEM: standard error of the mean.

7. Five-year view

HF exacts substantial clinical burden and economic costs worldwide. The disease is particularly prevalent in the elderly; in this population, the incidence and associated costs (currently at $32 billion annually in the United States alone) are projected to double over the next 20 years. Despite these enormous costs, mortality from HF remains high, with death from HF within 5 years of the first diagnosis as the norm despite current optimal medical therapy. Commonly prescribed HF medications, while beneficial in promoting some symptom relief, do not fully address the underlying causes of progressive LV dysfunction, a characteristic feature of the HF state. Most standard-of-care pharmacologic approaches for HF act by reducing workload on the failing heart and, in doing so, reduce myocardial oxygen consumption and, therefore, rebalance energy supply and energy demands, albeit to a lower level. Although these therapies that include beta-blockers and angiotensin-converting enzyme inhibitors have delivered dividends over the last recent decades by improving survival in patients with HF, death and poor quality of life continue to plague this ever-increasing patient population. The search for more effective therapy for this patient population must be focused on improving the intrinsic function of the viable but dysfunctional myocardium.

Chemical energy in the form of ATP is essential for the survival and function of the central cardiac unit, ‘the cardiomyocyte.’ Cardiomyocyte contraction and relaxation along with most of the intermediate steps that facilitate these processes are heavily dependent on ATP generated by the mitochondria. Therefore, failure of this organelle to deliver the needed ATP is certain to cause failure of the cardiomyocyte to perform its obligatory function. There is ample evidence that in HF, the mitochondria are failing to deliver the needed energy and may, in fact, be self-destructing through excessive production of ROS. Reducing cardiac workload by reducing heart rate and afterload and, therefore, reducing demands for ATP, paid dividends in recent decades by improving survival of the patient with HF. Continuing to rely on this hemodynamic approach, however, to achieve further benefits in HF is not tenable in that further slowing of the heart rate and further lowering of blood pressure will in itself increase the risk for life-threatening complications. Therefore, a paradigm shift is necessary to continue to improve survival and quality of life in the patient with HF. The shift can be put in place by improving the energy supply side of the equation, that is, by improving mitochondrial function, so that this energy-producing organelle can meet its obligatory role by providing the needed energy (ATP) on demand. Fortunately, the HF community is well positioned to address this shift with availability of experimental drugs, such as elamipretide, that can help explore the potential of this new therapeutic approach in HF.

Key issues

• Mitochondria are the primary source of energy for the myocardium.

• Dysfunctional mitochondria cause excessive production of oxygen radicals that can damage the cardiomyocyte.

• Reversing mitochondrial damage will be a key factor in finding therapies that can improve or reverse HF.

• Overproduction of ROS leads to cytochrome c release, opening to the mPTP, and myocyte apoptosis.

• Cardiolipin is a key inner mitochondrial membrane phospholipid that stabilizes respiratory supercomplexes and maintains cristae structure.

• New therapies for HF are being developed that directly target mitochondrial dysfunction.

Declaration of interest

HN Sabbah has received research grants from Stealth BioTherapeutics, Inc., Bayer AG, Novartis Corporation, and Merck and Company and is a consultant to Stealth BioTherapeutics and Bayer AG. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by Stealth BioTherapeutics.