Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

Abstract

Diseases of the heart, such as heart failure and cardiac arrhythmias, are a growing socio-economic burden. Calcium (Ca²⁺) dysregulation is key hallmark of the failing myocardium and has long been touted as a potential therapeutic target in the treatment of a variety of cardiovascular diseases (CVD). In the heart, Ca²⁺ is essential for maintaining normal cardiac function through the generation of the cardiac action potential and its involvement in excitation contraction coupling. As such, the proteins which regulate Ca²⁺ cycling and signaling play a vital role in maintaining Ca²⁺ homeostasis. Changes to the expression levels and function of Ca²⁺-channels, pumps and associated intracellular handling proteins contribute to altered Ca²⁺ homeostasis in CVD. The remodeling of Ca²⁺-handling proteins therefore results in impaired Ca²⁺ cycling, Ca²⁺ leak from the sarcoplasmic reticulum and reduced Ca²⁺ clearance, all of which contributes to increased intracellular Ca²⁺. Currently, approved treatments for targeting Ca²⁺ handling dysfunction in CVD are focused on Ca²⁺ channel blockers. However, whilst Ca²⁺ channel blockers have been successful in the treatment of some arrhythmic disorders, they are not universally prescribed to heart failure patients owing to their ability to depress cardiac function. Despite the progress in CVD treatments, there remains a clear need for novel therapeutic approaches which are able to reverse pathophysiology associated with heart failure and arrhythmias. Given that heart failure and cardiac arrhythmias are closely associated with altered Ca²⁺ homeostasis, this review will address the molecular changes to proteins associated with both Ca²⁺-handling and -signaling; their potential as novel therapeutic targets will be discussed in the context of pre-clinical and, where available, clinical data.

Keywords: arrhythmia; calcium; calcium dysregulation; cardiovascular disease; heart failure.

FIGURE 1

The cardiac action potential. The cardiac action potential represents the electrical activity of a cardiomyocyte during cardiac contraction and is governed by changes in outward (blue boxes) and inward (green boxes) cardiac ion currents. Generally, the cardiac action potential is divided into five Phases. (Phase 4: Resting) The resting membrane potential is stable (∼–90 mV) and maintained by outward leak of K⁺ (I_KACh, I_K1). Here the Na⁺ and Ca⁺ channels are closed. (Phase 0: Upstroke) An action potential at a neighboring cardiomyocyte initiates a rise in membrane potential. When the membrane potential reaches the threshold potential (∼70 mV), Na⁺ channels open, resulting in a rapid influx of Na⁺ and the generation on the inward Na⁺ current (I_Na). Na⁺ channels become inactivated soon after opening (Phase 1: Early repolarization). Some K⁺ channels transiently open causing an outward K⁺ current (I_to, I_Kur). This results in a period of rapid repolarization. (Phase 2: Plateau phase) L-type Ca²⁺ channels are open to create a small, constant inward Ca²⁺ current (I_CaL) which triggers excitation contraction coupling resulting in cardiomyocyte contraction. K⁺ currents remain active, although the two currents are electrically balanced and maintain a plateau. (Phase 3: Repolarization) Ca²⁺ channels become gradually inactivated and the outflow of K⁺ exceeds the Ca²⁺ inflow. K⁺ currents (I_Ks, I_Kr, I_KACh, I_K1) repolarize the cell and the resting membrane potential is restored. Note, the figure represents the typical ventricular cardiac action potential. The action potential of atrial cells and pacemaker cells (those found in the sinus node, atrioventricular node, and Purkinje fibers) differ. K⁺, potassium; Na⁺, sodium; Ca²⁺, calcium; I_KACh, muscarinic-gated K⁺ current; I_K1, inward rectifier K⁺ current; I_Na, Na⁺ current; I_to, transient outward K⁺ current; I_Kur, delayed rectifier K⁺ current; I_CaL, L-type Ca²⁺ current; I_Ks, delayed rectifier (slow) K⁺ current; I_kr, delayed rectifier (fast) K⁺ current.

FIGURE 2

Physiological Ca²⁺ cycling in cardiomyocytes. Ca²⁺ cycling in cardiomyocytes generates cardiac contraction through excitation-contraction coupling. Briefly, (1) Ca²⁺ (yellow circles and arrows) rapidly enters the cell through LTCC where it causes (2) Ca²⁺-induced Ca²⁺ release from Ca²⁺ stores in the sarcoplasmic reticulum. During these early stages of ECC, intracellular Ca²⁺ ([Ca²⁺]_i) levels rapidly increase (red line, insert) following the onset of the cardiac action potential and cardiomyocyte depolarization (and black line, insert). (3) The amplified Ca²⁺ signal then induces actin-myosin myofilament crossbridge formation, resulting in cardiac contraction. Following this action, as the cardiac action potential enters the plateau phase (black line), the inward [Ca²⁺]_i levels begin to slowly decrease (red line). (4) Ca²⁺ is either returned to internal stores through SR-located SERCA2a and mitochondrial MCU or to the extracellular space through NCX (in exchange for 3Na⁺, blue circle and arrow) and PMCA. Here, as cardiac repolarization occurs (black line) the levels of [Ca²⁺]_i return to baseline (red line) in order to return membrane polarization to baseline. Free Ca²⁺ can also drive intracellular signaling (yellow box) which can influence gene transcription. Ca²⁺ homeostasis is also maintained by the TRP channel family of proteins. Ca²⁺, calcium; Na⁺, sodium; LTCC, L-type Ca²⁺ channel; TTCC, T-type Ca²⁺ channel; NCX, sodium calcium exchanger; PMCA, plasma membrane Ca²⁺ ATPase; TRP, transient receptor potential (canonical, vallinoid-related, melastatin-related), RyR, ryanodine receptor; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; PLN, phospholamban; MCU, mitochondrial Ca²⁺ uniporter.

FIGURE 3

Therapeutically targeted Ca²⁺-handling proteins and their function in cardiomyocytes. Ca²⁺ handling proteins are extensively involved in intracellular signaling and the regulation of Ca²⁺-channels and pumps, as such their modulation presents a different avenue for therapeutic targeting. Both current and potential therapeutics are shown for cardiac hypertrophy (white box, red text) and cardiac arrhythmias (gray box, black text).

FIGURE 4

Therapeutic targeting of Ca²⁺ ion channels and pumps in cardiac hypertrophy and cardiac arrhythmia. Ca²⁺ ion channels and Ca²⁺ pumps have been the subject of pharmacological and gene therapy intervention; however, not all therapies have been translated from pre-clinical studies into human trials. Both current and potential therapeutics and their Ca²⁺ ion channel or Ca²⁺ pump target are shown for cardiac hypertrophy (white box, red text) and cardiac arrhythmias (gray box, black text), note there are some agents which have been tested in models of HF and arrhythmia. The LTCC are currently targeted by Ca²⁺ channel blockers which are prescribed to patients with CVD, as such, these are not shown on the schematic.