Based on recent findings, an increased late sodium current (I_Na,late) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is I_Na,late and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased I_Na,late in heart diseases, and also discusses how the upregulated I_Na,late can play a role in the generation of cardiac arrhythmias. The last part of the article is about I_Na,late inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials.

Transient receptor potential melastatin 4 (TRPM4) is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca²⁺ sensitive and permeable for monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions; it regulates membrane potential and Ca²⁺ homeostasis in both excitable and non-excitable cells. This part of the review discusses the currently available knowledge about the physiological and pathophysiological roles of TRPM4 in various tissues. These include the physiological functions of TRPM4 in the cells of the Langerhans islets of the pancreas, in various immune functions, in the regulation of vascular tone, in respiratory and other neuronal activities, in chemosensation, and in renal and cardiac physiology. TRPM4 contributes to pathological conditions such as overactive bladder, endothelial dysfunction, various types of malignant diseases and central nervous system conditions including stroke and injuries as well as in cardiac conditions such as arrhythmias, hypertrophy, and ischemia-reperfusion injuries. TRPM4 claims more and more attention and is likely to be the topic of research in the future.

Due to the limited availability of healthy human ventricular tissues, the most suitable animal model has to be applied for electrophysiological and pharmacological studies. This can be best identified by studying the properties of ion currents shaping the action potential in the frequently used laboratory animals, such as dogs, rabbits, guinea pigs, or rats, and comparing them to those of human cardiomyocytes. The authors of this article with the experience of three decades of electrophysiological studies, performed in mammalian and human ventricular tissues and isolated cardiomyocytes, summarize their results obtained regarding the major canine and human cardiac ion currents. Accordingly, L-type Ca²⁺ current (I_Ca), late Na⁺ current (I_Na-late), rapid and slow components of the delayed rectifier K⁺ current (I_Kr and I_Ks, respectively), inward rectifier K⁺ current (I_K1), transient outward K⁺ current (I_to1), and Na⁺/Ca²⁺ exchange current (I_NCX) were characterized and compared. Importantly, many of these measurements were performed using the action potential voltage clamp technique allowing for visualization of the actual current profiles flowing during the ventricular action potential. Densities and shapes of these ion currents, as well as the action potential configuration, were similar in human and canine ventricular cells, except for the density of I_K1 and the recovery kinetics of I_to. I_K1 displayed a largely four-fold larger density in canine than human myocytes, and I_to recovery from inactivation displayed a somewhat different time course in the two species. On the basis of these results, it is concluded that canine ventricular cells represent a reasonably good model for human myocytes for electrophysiological studies, however, it must be borne in mind that due to their stronger I_K1, the repolarization reserve is more pronounced in canine cells, and moderate differences in the frequency-dependent repolarization patterns can also be anticipated.

The cardiac late sodium current (I_Na,late) is the small sustained component of the sodium current active during the plateau phase of the action potential. Several studies demonstrated that augmentation of the current can lead to cardiac arrhythmias; therefore, I_Na,late is considered as a promising antiarrhythmic target. Fundamentally, enlarged I_Na,late increases Na⁺ influx into the cell, which, in turn, is converted to elevated intracellular Ca²⁺ concentration through the Na⁺/Ca²⁺ exchanger. The excessive Ca²⁺ load is known to be proarrhythmic. This review describes the behavior of the voltage-gated Na⁺ channels generating I_Na,late in health and disease and aims to discuss the physiology and pathophysiology of Na⁺ and Ca²⁺ homeostasis in context with the enhanced I_Na,late demonstrating also the currently accessible antiarrhythmic choices.

Transient receptor potential melastatin 4 is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca²⁺-sensitive and permeable to monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions by regulating the membrane potential and Ca²⁺ homeostasis in both excitable and non-excitable cells. This part of the review discusses the pharmacological modulation of TRPM4 by listing, comparing, and describing both endogenous and exogenous activators and inhibitors of the ion channel. Moreover, other strategies used to study TRPM4 functions are listed and described. These strategies include siRNA-mediated silencing of TRPM4, dominant-negative TRPM4 variants, and anti-TRPM4 antibodies. TRPM4 is receiving more and more attention and is likely to be the topic of research in the future.

Recent cardiotropic drug developments have focused on cardiac myofilaments. Danicamtiv, the second direct myosin activator, has achieved encouraging results in preclinical and clinical studies, thus implicating its potential applicability in the treatment of heart failure with reduced ejection fraction (HFrEF). Here, we analyzed the inotropic effects of danicamtiv in detail. To this end, changes in sarcomere length and intracellular Ca²⁺ levels were monitored in parallel, in enzymatically isolated canine cardiomyocytes, and detailed echocardiographic examinations were performed in anesthetized rats in the absence or presence of danicamtiv. The systolic and diastolic sarcomere lengths decreased; contraction and relaxation kinetics slowed down with increasing danicamtiv concentrations without changes in intracellular Ca²⁺ transients in vitro. Danicamtiv evoked remarkable increases in left ventricular ejection fraction and fractional shortening, also reflected by changes in systolic strain. Nevertheless, the systolic ejection time was significantly prolonged, the ratio of diastolic to systolic duration was reduced, and signs of diastolic dysfunction were also observed upon danicamtiv treatment in vivo. Taken together, danicamtiv improves cardiac systolic function, but it can also limit diastolic performance, especially at high drug concentrations.