Altering Calcium Sensitivity in Heart Failure: A Crossroads of Disease Etiology and Therapeutic Innovation

Abstract

Heart failure (HF) presents a significant clinical challenge, with current treatments mainly easing symptoms without stopping disease progression. The targeting of calcium (Ca²⁺) regulation is emerging as a key area for innovative HF treatments that could significantly alter disease outcomes and enhance cardiac function. In this review, we aim to explore the implications of altered Ca²⁺ sensitivity, a key determinant of cardiac muscle force, in HF, including its roles during systole and diastole and its association with different HF types-HF with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). We further highlight the role of the two rate constants k_on (Ca²⁺ binding to Troponin C) and k_off (its dissociation) to fully comprehend how changes in Ca²⁺ sensitivity impact heart function. Additionally, we examine how increased Ca²⁺ sensitivity, while boosting systolic function, also presents diastolic risks, potentially leading to arrhythmias and sudden cardiac death. This suggests that strategies aimed at moderating myofilament Ca²⁺ sensitivity could revolutionize anti-arrhythmic approaches, reshaping the HF treatment landscape. In conclusion, we emphasize the need for precision in therapeutic approaches targeting Ca²⁺ sensitivity and call for comprehensive research into the complex interactions between Ca²⁺ regulation, myofilament sensitivity, and their clinical manifestations in HF.

Keywords: arrhythmias; calcium sensitivity; heart failure; rate constant; troponin C.

Figure 1

Assessment of myofilament Ca²⁺ response variability. Top: Force-pCa²⁺ relationship curves showing variations in myofilament Ca²⁺ sensitivity. The solid line represents the baseline force-Ca²⁺ relationship. Curve (A) demonstrates increased Ca²⁺ sensitivity, indicated by a leftward shift, where a given steady-state force is achieved at lower Ca²⁺ concentrations. Curve (B) demonstrates decreased Ca²⁺ sensitivity, indicated by a rightward shift, requiring higher Ca²⁺ concentrations to generate the same steady-state force. Bottom: This panel shows a biochemical representation of the Ca²⁺ binding dynamics to Troponin C (TnC). It includes the calcium association rate (k_on) and dissociation rate (k_off) from TnC, alongside a formula illustrating the relationship between the equilibrium dissociation constant (Kd), k_on, and k_off.

Figure 2

Calcium-handling in excitation–contraction (EC) coupling. Schematic overview of key Ca²⁺-handling proteins and their roles in the process of EC coupling. NCX, Na⁺/Ca²⁺ exchanger; PM, Plasma membrane; RyR, Ryanodine receptor; SERCA2a, Sarco/endoplasmic reticulum ATPase type-2a; SR, Sarcoplasmic reticulum; TT, Transverse tubule.

Figure 3

A schematic representation of cardiac troponin’s interaction with the thin filament under two conditions: absence and presence of Ca²⁺ ions (represented as white dots), emphasizing its role in modulating cardiac muscle contraction. In the thin filament OFF state (up), myosin binding sites on actin are obstructed by tropomyosin (green), preventing contraction. Upon Ca²⁺ binding to the C-terminal lobe of troponin C (C-TnC; pink), a key conformational change occurs. The switch peptide of troponin I (TnI), which includes helix H3 (H3; blue), interacts with the regulatory N-terminal lobe of TnC (N-TnC; pink). This interaction triggers the removal of the C-terminal lobe of TnI, allowing tropomyosin to shift azimuthally around the thin filament. Consequently, this shift exposes the myosin binding sites on actin, facilitating muscle contraction. The C-lobe of TnC (C-TnC; pink), which is constantly bound to divalent cations alongside the anchoring region of TnI (blue), plays a vital role in the stability and function of the thin filament complex. TnC, Troponin C; TnI, Troponin I; TnT, Troponin T.