Genetic Alterations in Calcium Handling Pathways in Late-Stage Heart Failure

Nadia Basha^*
*Correspondence: Nadia Basha, Department of Cardiology, University of KwaZulu-Natal, Durban 4058, South Africa, Email:

Introduction

Heart Failure (HF) is a progressive clinical syndrome characterized by the heart's inability to pump sufficient blood to meet the body's metabolic demands. One of the hallmark features of late-stage or end-stage heart failure is impaired intracellular calcium (Ca²⁺) handling within cardiomyocytes, which contributes significantly to both systolic and diastolic dysfunction. In the healthy heart, calcium cycling is tightly regulated through the coordinated action of multiple transporters, channels and signaling molecules. These include the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a), Phospholamban (PLN), ryanodine receptors (RyR2), the Na⁺/Ca²⁺ exchanger (NCX1) and other associated regulators. In advanced stages of heart failure, not only is the function of these proteins compromised, but their gene expression is also significantly altered. Such changes in the transcriptional profiles of calcium-handling genes can exacerbate contractile dysfunction, promote arrhythmias and accelerate myocardial remodeling. This discussion provides a detailed overview of the genetic alterations in calcium regulatory pathways in late-stage heart failure, focusing on how these changes contribute to disease progression and their potential as therapeutic targets [1].

Description

One of the most consistently observed genetic changes in late-stage heart failure is the downregulation of SERCA2a, a critical enzyme that pumps calcium back into the sarcoplasmic reticulum during diastole. SERCA2a's role in calcium reuptake is essential for proper myocardial relaxation and readiness for subsequent contractions. Numerous studies, including tissue analyses from failing human hearts, have demonstrated that SERCA2a mRNA levels are significantly reduced in advanced heart failure, correlating with impaired calcium reuptake and prolonged relaxation times. This reduction contributes to diastolic dysfunction and is often considered a defining molecular feature of end-stage HF [2].

Phospholamban (PLN), a key regulator of SERCA2a activity, also undergoes genetic and post-translational alterations in HF. In its unphosphorylated form, PLN inhibits SERCA2a. During heart failure, PLN expression may either be decreased or its phosphorylation status altered, depending on the stage and severity of the condition. A failure in proper PLN phosphorylation impairs SERCA2a activation, further exacerbating calcium uptake deficiencies. Some gene therapy approaches have aimed to modify PLN expression or phosphorylation to restore normal calcium cycling in failing hearts, indicating its importance in disease modulation [3].

Another vital player in calcium handling is the Ryanodine Receptor (RyR2), which facilitates the release of calcium from the sarcoplasmic reticulum during systole. Alterations in RyR2 gene expression and function are frequently observed in failing myocardium. Studies have identified not only changes in RyR2 transcript levels but also increased receptor â??leakinessâ? due to phosphorylation and oxidation. These changes can contribute to arrhythmogenic calcium waves and disrupted excitation-contraction coupling, especially in the context of advanced disease. The Na⁺/CaÃÂ?²âº exchanger (NCX1) is upregulated in many cases of heart failure as a compensatory mechanism to extrude excess intracellular calcium. However, this upregulation can be maladaptive in late-stage HF, as it may reduce calcium availability during systole and contribute to contractile dysfunction. Elevated NCX1 gene expression has been consistently reported in studies examining failing human hearts and its increased activity may disrupt the delicate balance of sodium and calcium homeostasis, influencing electrical stability and promoting arrhythmias [4].

In recent years, attention has also turned to other less-studied calcium regulators, such as Two-Pore Channels (TPCN1 and TPCN2), which modulate calcium release from endolysosomal stores. Studies in failing hearts have shown increased expression of TPCN1 and TPCN2, suggesting a role in abnormal intracellular calcium signaling beyond the sarcoplasmic reticulum. These findings point to a broader landscape of calcium dysregulation in heart failure that may include multiple organelles and signaling pathways. Altogether, the combined alterations in gene expression of these calcium-handling proteins contribute to a vicious cycle of impaired calcium homeostasis, reduced contractility and increased susceptibility to arrhythmias. These molecular changes are not merely secondary consequences of failing myocardium but are actively involved in driving disease progression. Understanding the transcriptional reprogramming of calcium regulatory genes provides valuable insights into heart failure pathophysiology and offers potential targets for gene-based or pharmacological interventions aimed at restoring calcium balance and improving cardiac function [5].

Conclusion

In conclusion, late-stage heart failure is marked by significant genetic alterations in the key components of calcium handling pathways. These changes include the downregulation of SERCA2a, dysfunction in phospholamban regulation, alterations in ryanodine receptor expression and stability and the upregulation of NCX1 and TPCN channels. Each of these genetic shifts contributes to the progressive deterioration of calcium homeostasis within cardiomyocytes, leading to impaired contractility, poor relaxation and heightened risk of arrhythmias. Rather than being isolated molecular events, these alterations reflect a broader pattern of transcriptional remodeling in the failing heart.

As our understanding of these mechanisms grows, so does the potential for targeted therapeutic strategies. Gene therapy approaches to restore SERCA2a expression, pharmacological interventions to stabilize RyR2 function and novel therapies aimed at modulating NCX1 activity are all currently under investigation. Moreover, the recognition of non-SR calcium regulators like TPCNs opens new avenues for research. By addressing the root molecular causes of calcium dysregulation, future treatments may offer more effective ways to halt or even reverse the progression of end-stage heart failure. Continued exploration into these genetic pathways will be crucial for advancing personalized and precision medicine approaches in cardiology.

Acknowledgement

None.

Conflict of Interest

None.

References

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