Can T-type calcium channels make a change of heart after myocardial infarction? Fiction or fact, and for better or for worse?

The outcome of patients with myocardial infarction has improved dramatically over the last few decades. Evidence-based therapy comprises rapid recanalization with full restitution of flow by acute percutaneous coronary intervention, local and systemic antithrombotic treatment, the use of statins, b-adrenoceptor blockers, angiotensinconverting enzyme inhibitors, and aldosterone receptor antagonists to protect the heart from subsequent adverse remodelling. The term ‘cardiac remodelling’ refers to a process involving changes in morphology and mechanical and electrical function that occur after injury such as myocardial infarction and pressure or volume overload. Remodelling allows for the maintenance of haemodynamic function but also results in cardiac hypertrophy, reactivation of a foetal gene programme, and arrhythmias, all relevant for prevention and treatment of heart failure and sudden death. Voltage-gated calcium channels play a fundamental role in nano-environmental networks of calcium-dependent effector systems, affecting mechanical and electrical function as well as gene expression of the heart. They appear to be involved in the cardiac remodelling process. Although the classical L (‘long-lasting’, ‘large’)type calcium channel is essential for cardiac contraction, its ‘little brother’, the T (‘transient’, ‘tiny’)-type calcium channel, was proposed to be involved in cardiac pathophysiology soon after its discovery. Although known to be regulated by hormones, hypoxia, and development, its pathophysiological role in the ventricular myocardium is far from being clear (Table 1). Its subunits Cav3.1, 3.2, and 3.3 are also called a1G, a1H, and a1I, respectively. T-type calcium channels respond to more negative membrane potentials (low-voltage activated). When examined with barium ions as charge carriers, they can be discriminated from L-type channels by their lower single-channel conductance (‘tiny’), more rapid inactivation (‘transient’), and slower deactivation time course. In line with a suspected minor role in excitation–contraction coupling, T-type channels have been shown to reside at the surface sarcolemma rather than in T-tubules. T-type calcium channels play a role in initiating action potentials. In the heart, they contribute to the prepotential of the sinoatrial node. Expression of T-type calcium channels depends on species, cardiac chamber, developmental stage, and pathology (Table 1). Le Quang et al. report cardiac electrical and haemodynamic function after myocardial infarction in a genetic model lacking either of the two genes coding for the cardiac T-type calcium channel subunit, Cav3.1 or Cav3.2. Their aim was to study the contribution of T-type calcium channels in cardiac remodelling after myocardial infarction. Adult Cav3.1 or Cav3.2 knockout and littermate wild-type (WT) controls were examined before and after left anterior descending coronary artery (LAD) ligation and the resulting transmural myocardial infarction by a range of elaborate in vivo and ex vivo techniques: echocardiography, telemetry Holter ECG, programmed electrical stimulation, invasive haemodynamics, and assessment of RNA expression of Cav3.1 and Cav3.2 subunits. While at baseline the only detectable differences in the T-type calcium channel subunit Cav3.1 knockout mouse were sinus bradycardia and first-degree atrioventricular block, the adaptation to myocardial infarction revealed increased arrhythmia inducibility (in 9/11 knockout animals vs. 3/10 WT, induced by an invasive electrophysiological pacing study) and decreased contractility. Mortality, occurrence of spontaneous arrhythmias during telemetric observation, atrial arrhythmias, diastolic function, and infarction size were unchanged. Knockout of the Cav3.2 gene caused neither a difference at baseline nor after myocardial infarction. In summary, the study shows an unfavourable effect of the knockout of T-type calcium channel subunit Cav3.1 (but not of Cav3.2) on remodelling after myocardial infarction. The authors conclude that T-type calcium channel blockade targeting Cav3.1 subunits may not be beneficial. This is an important contribution to the understanding of the function of T-type calcium channels after myocardial infarction. After enthusiastic reading of the paper by Le Quang et al., we still do not know the mechanism of how the lack of the T-type calcium