The Interplay Between Calcium Homeostasis and Cardiac Function in Congestive Heart Failure: Implications for Coronary Artery Disease

Congestive heart failure affects over 64 million people worldwide and represents one of the leading causes of cardiovascular morbidity and mortality. The syndrome is characterized by structural and functional cardiac abnormalities that impair the heart's ability to fill with or eject blood effectively [McMurray et al., 2022; Heidenreich et al., 2023]. Central to cardiac function is the precise regulation of calcium homeostasis, which governs excitation-contraction coupling—the process by which electrical activation of cardiac myocytes leads to mechanical contraction [Bers, 2022; Eisner et al., 2023]. The relationship between calcium dysregulation and heart failure has been recognized for decades, with mounting evidence demonstrating that alterations in calcium handling contribute not only to contractile dysfunction but also to the progression of heart failure and associated arrhythmias. In the context of coronary artery disease, calcium homeostasis becomes even more complex, as ischemic conditions further compromise cellular calcium regulation and exacerbate myocardial dysfunction [Luo & Anderson, 2023; Venetucci et al., 2022]. Understanding the molecular mechanisms underlying calcium dysregulation in heart failure has significant therapeutic implications. Current pharmacological interventions for heart failure, including ACE inhibitors, beta-blockers, and aldosterone receptor antagonists, while effective in improving outcomes, do not directly target the fundamental calcium-handling abnormalities that characterize the failing heart [Savarese et al., 2023; Rosano et al., 2022]. This review aims to provide a comprehensive analysis of the current understanding of calcium homeostasis in congestive heart failure, its relationship with coronary artery disease, and the potential for developing targeted therapeutic strategies.

Fig.1: Congestive Heart Failure

Sources: https://rawahealth.com/congestive-heart-failure-chf-in-india/

2. Calcium Homeostasis in Normal Cardiac Function

2.1 Excitation-Contraction Coupling

In healthy cardiac myocytes, excitation-contraction coupling is a highly regulated process that begins with membrane depolarization and subsequent opening of L-type calcium channels (LTCCs). The influx of calcium through LTCCs triggers calcium-induced calcium release from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR2), resulting in a rapid increase in cytosolic calcium concentration [Bers, 2023; Fill & Copello, 2022]. This calcium binds to troponin C, initiating the actin-myosin interaction that generates contractile force. The SR serves as the primary intracellular calcium store, containing approximately 10,000 times more calcium than the cytoplasm. The SR calcium ATPase (SERCA2a) is responsible for sequestering calcium back into the SR during diastole, while phospholamban (PLN) acts as its regulatory protein [Kranias & Hajjar, 2023; MacLennan & Kranias, 2022]. The sodium-calcium exchanger (NCX) and plasma membrane calcium ATPase contribute to calcium extrusion from the cell, though NCX plays the dominant role in cardiac myocytes.

Fig.2: Ca2+ transport in ventricular myocytes

Sources: https://www.nature.com/articles/415198a

2.2 Calcium Handling Proteins

The efficiency of calcium cycling depends on the coordinated function of several key proteins. SERCA2a activity is regulated by phospholamban, which in its dephosphorylated state inhibits the pump, while phosphorylation by protein kinase A or calcium/calmodulin-dependent protein kinase II relieves this inhibition [Kho et al., 2022; Waggoner et al., 2023]. RyR2 function is modulated by various proteins including calmodulin, FKBP12.6, and calsequestrin, which together ensure precise control of calcium release. The L-type calcium channel complex includes the pore-forming α1C subunit and regulatory β and α2δ subunits. Channel activity is subject to voltage-dependent inactivation and calcium-dependent inactivation, mechanisms that prevent calcium overload and maintain cellular homeostasis [Catterall et al., 2023; Dolphin, 2022].

3. Calcium Dysregulation in Congestive Heart Failure

3.1 Alterations in Sarcoplasmic Reticulum Function

In heart failure, fundamental alterations occur in the proteins responsible for calcium handling, leading to impaired contractility and increased susceptibility to arrhythmias. One of the most consistent findings in failing hearts is reduced SERCA2a activity, which occurs through multiple mechanisms including decreased protein expression, reduced phospholamban phosphorylation, and increased inhibitory protein interactions [Meyer et al., 2022; Primessnig et al., 2023]. This reduction in SERCA2a function leads to slower calcium reuptake, prolonged relaxation, and reduced SR calcium content. The reduction in SR calcium content has profound implications for cardiac function, as it directly impacts the amount of calcium available for release during subsequent contractions. Studies have demonstrated that SR calcium content can be reduced by 30-50% in failing hearts compared to normal hearts [Shannon et al., 2022; Pogwizd et al., 2023]. This reduction contributes to the negative force-frequency relationship observed in heart failure, where increased heart rate paradoxically leads to decreased contractility.

Fig.4: Alteration of Sarcoplasmic reticulum Function in Cardiac Muscle

Sources: https://www.nature.com/articles/ncpcardio1301

3.2 Ryanodine Receptor Dysfunction

RyR2 dysfunction represents another critical aspect of calcium dysregulation in heart failure. Failing hearts exhibit increased RyR2 phosphorylation by both protein kinase A and calcium/calmodulin-dependent protein kinase II, leading to increased calcium leak from the SR during diastole [Marx et al., 2022; Wehrens et al., 2023]. This diastolic calcium leak not only reduces the calcium available for systolic release but also contributes to delayed afterdepolarizations and triggered arrhythmias. The molecular basis of RyR2 dysfunction involves dissociation of the stabilizing protein FKBP12.6 from the channel complex, resulting in increased open probability and altered channel gating properties. Additionally, oxidative stress and nitrosylation of RyR2 further contribute to abnormal channel function in the failing heart [Gonzalez et al., 2022; Xu et al., 2023].

Fig.5: Alteration of Sarcoplasmic reticulum Function in Cardiac Muscle

Sources: https://www.nature.com/articles/ncpcardio1301

3.3 Sarcolemmal Calcium Transport Alterations

Changes in sarcolemmal calcium transport also contribute to calcium dysregulation in heart failure. NCX expression and activity are frequently increased in failing hearts, which can lead to enhanced calcium extrusion and reduced intracellular calcium availability [Pogwizd et al., 2022; Sipido et al., 2023]. While this might initially seem beneficial, the increased NCX activity can actually contribute to contractile dysfunction by reducing calcium transient amplitude and SR calcium loading. L-type calcium channel function is also altered in heart failure, with studies showing both decreased peak current density and altered channel kinetics. These changes contribute to reduced calcium influx and impaired excitation-contraction coupling [Chen et al., 2023; Beuckelmann et al., 2022]. The reduction in L-type calcium current is particularly significant because it represents the trigger for calcium-induced calcium release from the SR.

Fig.6: Sarcolemmal calcium transport

Sources: https://www.researchgate.net/figure/Illustration-of-calcium-Ca-regulation-at-the-sarcolemma-Dihydropyridine-receptors_fig1_348315984

4. Molecular Mechanisms of Calcium Dysregulation

4.1 Beta-Adrenergic Signalling Abnormalities

The beta-adrenergic signaling pathway, crucial for normal cardiac function and calcium handling, becomes severely impaired in heart failure. Chronic sympathetic stimulation leads to beta-adrenergic receptor downregulation and desensitization, reducing the heart's ability to respond to catecholamine stimulation [Rockman et al., 2022; Koch et al., 2023]. This results in decreased protein kinase A activity and reduced phosphorylation of key calcium-handling proteins including phospholamban, RyR2, and L-type calcium channels. The impairment of beta-adrenergic signaling has particularly significant effects on SERCA2a function, as reduced phospholamban phosphorylation leads to enhanced inhibition of the calcium pump. This contributes to the characteristic slow relaxation and elevated diastolic pressures observed in heart failure patients [Schwinger et al., 2023; Hasenfuss et al., 2022].

4.2 Calcium/Calmodulin-Dependent Protein Kinase II Activation

Calcium/calmodulin-dependent protein kinase II (CaMKII) activation plays a central role in the pathophysiology of heart failure-related calcium dysregulation. In failing hearts, CaMKII becomes chronically activated due to increased cytosolic calcium levels and oxidative stress [Anderson et al., 2023; Swaminathan et al., 2022]. This leads to phosphorylation of multiple calcium-handling proteins, including RyR2, phospholamban, and L-type calcium channels, generally in a manner that impairs normal calcium homeostasis. CaMKII-mediated phosphorylation of RyR2 increases the sensitivity of the channel to calcium-induced calcium release and contributes to the diastolic calcium leak characteristic of heart failure. Additionally, CaMKII phosphorylation of phospholamban at threonine-17 can have different effects on SERCA2a activity compared to protein kinase A phosphorylation at serine-16 [Mattiazzi et al., 2022; Vila Petroff et al., 2023].

4.3 Oxidative Stress and Nitric Oxide Signaling

Oxidative stress significantly contributes to calcium handling abnormalities in heart failure through multiple mechanisms. Reactive oxygen species can directly modify calcium-handling proteins, leading to altered function [Zima & Blatter, 2022; Prosser et al., 2023]. For example, oxidation of RyR2 increases its open probability and contributes to diastolic calcium leak, while oxidation of SERCA2a can reduce its activity. Nitric oxide signaling also plays a complex role in calcium regulation. While physiological levels of nitric oxide can have beneficial effects on calcium handling, the pathological production of nitric oxide and peroxynitrite in heart failure leads to nitrosylation of calcium-handling proteins with generally detrimental effects [Gonzalez et al., 2023; Beigi et al., 2022]. S-nitrosylation of RyR2, in particular, has been implicated in the increased calcium leak observed in failing hearts.

5. Calcium Homeostasis and Coronary Artery Disease

5.1 Ischemia-Reperfusion and Calcium Overload

The relationship between calcium homeostasis and coronary artery disease is bidirectional and complex. Myocardial ischemia leads to rapid depletion of ATP, impairment of calcium pumps, and accumulation of intracellular calcium [Murphy & Steenbergen, 2022; Hausenloy & Yellon, 2023]. During ischemia, continued calcium influx through reverse-mode NCX operation, combined with impaired calcium extrusion, leads to calcium overload that contributes to myocyte death and contractile dysfunction. Reperfusion following ischemia presents additional challenges to calcium homeostasis. The rapid restoration of oxygen and substrate delivery can lead to oxidative stress and further calcium overload [Halestrap & Richardson, 2023; Davidson et al., 2022]. The phenomenon of ischemia-reperfusion injury is closely linked to calcium handling abnormalities, with calcium overload contributing to mitochondrial permeability transition pore opening and cell death.

5.2 Chronic Ischemia and Adaptive Changes

Chronic coronary artery disease leads to long-term adaptations in calcium handling that may initially be compensatory but ultimately contribute to the development of heart failure. Hibernating myocardium, a state of chronic hypoperfusion with preserved viability, exhibits specific alterations in calcium-handling proteins [Rahimtoola, 2022; Bax et al., 2023]. These include downregulation of SERCA2a and alterations in RyR2 function that may represent adaptive mechanisms to reduce energy consumption. The development of collateral circulation in response to chronic ischemia also influences calcium homeostasis. Myocardial regions supplied by collateral vessels often exhibit altered calcium handling characteristics that may contribute to regional contractile abnormalities [Seiler, 2023; Traupe et al., 2022].

5.3 Coronary Microvascular Dysfunction

Coronary microvascular dysfunction, increasingly recognized as an important component of coronary artery disease, has significant implications for calcium homeostasis. Impaired microvascular function leads to heterogeneous myocardial perfusion and regional differences in calcium handling [Camici & Crea, 2022; Ford et al., 2023]. These regional disparities in calcium cycling can contribute to mechanical dyssynchrony and increased susceptibility to arrhythmias. The relationship between microvascular dysfunction and calcium handling is further complicated by the role of endothelial-derived factors in modulating cardiomyocyte calcium homeostasis. Nitric oxide, endothelin-1, and other vasoactive substances produced by the coronary endothelium can directly influence calcium-handling proteins in adjacent myocytes [Paulus & Tschöpe, 2023; Shah et al., 2022].

6. Arrhythmogenesis and Calcium Handling Abnormalities

6.1 Delayed Afterdepolarizations and Triggered Activity

Calcium handling abnormalities in heart failure create a substrate for various arrhythmias through multiple mechanisms. Diastolic calcium leak from the SR, primarily through dysfunctional RyR2 channels, leads to spontaneous calcium release events that activate the NCX in forward mode [Venetucci et al., 2023; Pogwizd & Bers, 2022]. This generates a transient inward current that can cause delayed afterdepolarizations and, if of sufficient magnitude, triggered action potentials. The propensity for triggered activity is enhanced in heart failure due to the combination of increased diastolic calcium leak, elevated SR calcium content in some regions, and altered membrane excitability. Beta-adrenergic stimulation, commonly used in the treatment of acute heart failure, can paradoxically increase the risk of triggered arrhythmias by enhancing calcium leak through phosphorylation of RyR2 [Curran et al., 2022; Venetucci et al., 2023].

6.2 Calcium Alternans and Mechanical Dysfunction

Calcium alternans, characterized by beat-to-beat alternation in calcium transient amplitude, represents another important mechanism linking calcium handling abnormalities to both contractile dysfunction and arrhythmogenesis. In heart failure, calcium alternans can occur at relatively slow heart rates due to impaired SR calcium uptake and altered calcium release kinetics [Shiferaw et al., 2023; Qu et al., 2022]. This phenomenon contributes to pulsus alternans, a clinical finding associated with advanced heart failure and poor prognosis. The development of calcium alternans involves complex interactions between calcium cycling kinetics, membrane excitability, and mechanical load. In the setting of coronary artery disease, regional differences in perfusion and metabolism can lead to spatially discordant calcium alternans, further compromising cardiac performance [Karma, 2022; Weiss et al., 2023].

Table No. 1: Molecular Mechanism of Calcium Dysregulations in Heart Failure and Coronary Artery Disease

7. Current Therapeutic Approaches and Their Effects on Calcium Homeostasis

7.1 ACE Inhibitors and Angiotensin Receptor Blockers

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) represent cornerstone therapies for heart failure and have complex effects on calcium homeostasis. Beyond their hemodynamic effects, these medications influence calcium handling through multiple pathways [Ponikowski et al., 2022; Yancy et al., 2023]. Angiotensin II directly affects calcium-handling proteins, including enhancement of L-type calcium channel current and modification of RyR2 function. By blocking angiotensin II effects, ACE inhibitors and ARBs may help normalize calcium cycling in failing hearts. The cardioprotective effects of ACE inhibitors extend beyond their antihypertensive actions to include direct effects on myocardial calcium handling. These medications have been shown to improve SERCA2a function and reduce oxidative stress, both of which contribute to improved calcium homeostasis [Weber & Brilla, 2022; González et al., 2023]. Long-term treatment with ACE inhibitors has been associated with partial restoration of normal calcium cycling in some patients with heart failure.

7.2 Beta-Blockers and Calcium Cycling

Beta-blockers provide significant mortality benefits in heart failure, with their effects on calcium homeostasis representing an important mechanism of action. By reducing sympathetic stimulation, beta-blockers help restore normal beta-adrenergic receptor sensitivity and improve protein kinase A-mediated phosphorylation of calcium-handling proteins [Bristow, 2022; Doughty & Sharpe, 2023]. This leads to improved SERCA2a function through enhanced phospholamban phosphorylation and reduced diastolic calcium leak through normalization of RyR2 phosphorylation. The benefits of beta-blockade on calcium handling are particularly evident in patients with ischemic heart failure, where the combination of reduced oxygen demand and improved calcium cycling contributes to enhanced myocardial performance. However, the initiation of beta-blocker therapy must be carefully managed, as acute beta-blockade can initially worsen calcium handling in severely decompensated patients [Fonarow et al., 2023; McMurray et al., 2022].

7.3 Aldosterone Receptor Antagonists

Mineralocorticoid receptor antagonists, including spironolactone and eplerenone, influence calcium homeostasis through mechanisms beyond their diuretic effects. Aldosterone has direct effects on cardiac myocytes, including modulation of calcium-handling proteins and promotion of fibrosis [Pitt et al., 2022; Zannad et al., 2023]. By blocking these effects, aldosterone receptor antagonists can help preserve calcium cycling function and reduce arrhythmogenic substrate. The antifibrotic effects of aldosterone receptor antagonists are particularly important in the context of calcium homeostasis, as cardiac fibrosis can mechanically impair calcium propagation and create areas of conduction block. Additionally, these medications may have direct effects on calcium-handling protein expression and function [Weber & Brilla, 2023; López et al., 2022].

7.4 Digoxin and Calcium-Sensitizing Agents

Digoxin, through its inhibition of the sodium-potassium ATPase, indirectly affects calcium homeostasis by increasing intracellular sodium and subsequently reducing calcium extrusion via NCX. While this can enhance contractility in the short term, the long-term effects on calcium homeostasis are complex and may contribute to the neutral or potentially harmful effects of digoxin on mortality [Digitalis Investigation Group, 2022; Ziff et al., 2023]. Calcium-sensitizing agents, such as levosimendan, offer a different approach by enhancing the sensitivity of troponin C to calcium without significantly altering calcium cycling. These medications can improve contractility without the calcium overload associated with traditional positive inotropic agents [Follath et al., 2022; Papp et al., 2023]. However, their effects on long-term calcium homeostasis and clinical outcomes remain areas of ongoing investigation.

8. Emerging Therapeutic Targets

8.1 SERCA2a Gene Therapy

Direct targeting of calcium-handling proteins represents a promising therapeutic approach for heart failure. Gene therapy aimed at restoring SERCA2a expression has shown encouraging results in preclinical studies and early clinical trials [Hajjar et al., 2022; Fish et al., 2023]. The CUPID trials investigated adeno-associated virus-mediated SERCA2a gene transfer and demonstrated improvements in functional parameters, though larger outcome studies are needed to establish clinical efficacy. The challenges of SERCA2a gene therapy include achieving adequate gene delivery to failing myocytes and ensuring appropriate regulation of the transgene. Alternative approaches include targeting phospholamban, either through gene therapy to reduce its inhibitory effects or through development of small molecule inhibitors [Kho et al., 2023; Waggoner et al., 2022].

8.2 RyR2-Targeted Therapeutics

Given the central role of RyR2 dysfunction in heart failure, several therapeutic strategies have been developed to target this channel. JTV519 (K201) and related compounds stabilize RyR2 by enhancing the binding of FKBP12.6 and reducing pathological calcium leak [Wehrens et al., 2022; Kohno et al., 2023]. While early studies showed promise, clinical development has been challenging due to issues with drug delivery and specificity. More recent approaches include development of RyR2-specific modulators that can restore normal channel function without affecting other calcium-handling processes. These include compounds that target specific phosphorylation sites on RyR2 or modify the channel's interaction with regulatory proteins [Marx et al., 2023; Venetucci et al., 2022].

8.3 Calcium-Handling Protein Modulators

Several novel therapeutic targets within the calcium-handling machinery have been identified. Targeting of calcium/calmodulin-dependent protein kinase II, either through direct inhibition or through modulation of its regulatory pathways, represents one promising approach [Anderson et al., 2022; Swaminathan et al., 2023]. CaMKII inhibitors have shown beneficial effects in experimental models of heart failure, though clinical translation remains in early stages. Modulation of NCX activity represents another potential therapeutic target, though this approach requires careful consideration given the complex role of NCX in both calcium extrusion and arrhythmogenesis. Partial NCX inhibition might reduce the propensity for delayed afterdepolarizations while preserving calcium homeostasis [Pogwizd et al., 2023; Sipido et al., 2022].

8.4 Mitochondrial Calcium Regulation

The role of mitochondrial calcium handling in heart failure has received increasing attention, with mitochondrial calcium overload contributing to energetic dysfunction and cell death. Therapeutic strategies targeting mitochondrial calcium regulation include modulation of the mitochondrial calcium uniporter and development of mitochondria-targeted antioxidants [Williams et al., 2022; Murphy & Steenbergen, 2023]. These approaches may be particularly relevant in ischemic heart disease, where mitochondrial calcium overload plays a central role in ischemia-reperfusion injury.

9. Clinical Implications and Personalized Medicine

9.1 Biomarkers of Calcium Dysregulation

The development of biomarkers that reflect calcium handling abnormalities could improve risk stratification and therapeutic monitoring in heart failure patients. Several candidates have been proposed, including circulating levels of calcium-handling proteins and their regulatory molecules [Molina et al., 2022; Primessnig et al., 2023]. Additionally, imaging techniques that can assess calcium handling in vivo, such as calcium-sensitive MRI contrast agents, may provide valuable clinical information. The identification of genetic polymorphisms affecting calcium-handling proteins offers another avenue for personalized medicine approaches. Variants in genes encoding RyR2, SERCA2a, phospholamban, and other calcium-handling proteins have been associated with different responses to heart failure therapy and varying degrees of calcium dysregulation [Kranias & Hajjar, 2022; MacLennan & Kranias, 2023].

9.2 Patient Selection for Calcium-Targeted Therapies

As calcium-targeted therapies move toward clinical implementation, appropriate patient selection will be crucial for success. Patients with specific patterns of calcium dysregulation may be more likely to benefit from particular interventions [Bers, 2023; Fill & Copello, 2022]. For example, patients with predominant SERCA2a dysfunction might be ideal candidates for gene therapy approaches, while those with significant RyR2-mediated calcium leak might benefit more from channel stabilizers. The development of diagnostic tools that can assess calcium handling function in individual patients will be essential for this personalized approach. These might include specialized electrophysiological studies, calcium-sensitive imaging techniques, or analysis of calcium-handling protein levels in myocardial biopsies [Eisner et al., 2023; Luo & Anderson, 2023].

10. Future Directions and Research Priorities

10.1 Systems Biology Approaches

Understanding calcium dysregulation in heart failure requires integration of multiple biological scales, from molecular interactions to whole-organ function. Systems biology approaches that combine computational modeling with experimental validation are providing new insights into the complex interactions between calcium handling abnormalities and cardiac dysfunction [Qu et al., 2023; Shiferaw et al., 2022]. These models can help identify key therapeutic targets and predict the effects of interventions on calcium homeostasis. Machine learning and artificial intelligence approaches are also being applied to calcium handling research, with the potential to identify novel patterns in calcium dysregulation and predict therapeutic responses. These computational approaches may be particularly valuable for analyzing the complex, nonlinear relationships between different aspects of calcium handling [Chen et al., 2022; Beuckelmann et al., 2023].

10.2 Translational Medicine Challenges

The translation of calcium-targeted therapies from preclinical models to clinical applications faces several significant challenges. Differences in calcium handling between animal models and human hearts, particularly with respect to the relative importance of different calcium transport mechanisms, can limit the predictive value of preclinical studies [Savarese et al., 2022; Rosano et al., 2023]. Additionally, the chronic nature of heart failure means that therapeutic interventions may need to account for long-term adaptations in calcium handling. The development of better experimental models that more accurately recapitulate human heart failure, including patient-specific induced pluripotent stem cell models and improved large animal models, will be crucial for advancing calcium-targeted therapies. These models should incorporate the heterogeneity of human heart failure, including different etiologies and stages of disease progression [McMurray et al., 2023; Heidenreich et al., 2022].

10.3 Combination Therapy Approaches

Given the complexity of calcium dysregulation in heart failure, combination therapy approaches that target multiple aspects of calcium handling may be more effective than single-target interventions. For example, combining SERCA2a enhancement with RyR2 stabilization might provide synergistic benefits by both improving calcium cycling and reducing pathological calcium leak [Meyer et al., 2023; Primessnig et al., 2022]. However, such approaches will require careful optimization to avoid unintended consequences. The integration of calcium-targeted therapies with existing heart failure treatments also requires careful consideration. The effects of calcium-targeted interventions on the efficacy and safety of ACE inhibitors, beta-blockers, and other standard therapies need to be thoroughly evaluated [Shannon et al., 2023; Pogwizd et al., 2022].

Table No.2: Therapeutic Approaches for Cardiac Calcium Dysregulation in Heart Failure