Stretch pulses and cardiac arrhythmias in rat hearts: is it a good model?

The article by Huang et al. (2009) in this issue of Experimental Physiology adopted and adapted a patch-clamp stretch mechanism to the rat heart to investigate the myocardial electrical response to stretch and resulting arrhythmias, i.e. ectopic beats. The phenomenon of cardiac cells to react to mechanical stimuli with an electrical response is known as mechanoelectrical coupling (MEC). The role of MEC in physiology and pathophysiology is increasingly under investigation as a mechanism for both adaptive responses and arrhythmias (Kohl et al. 2005). Cells responding to mechanical stimuli were among the first cells on earth. An amoeba does not have many senses but when it encounters an obstacle in its path, it reacts. We now know that mechanosensitive cells exist in almost every part of the body, from brain cells to digestive tract cells to bone cells to cardiac cells. While some of these mechanosensitive properties make sense at first sight (for instance, bone cells adjusting to the force of gravity, or intestinal cells responding to filling of the gut, or blood vessels responding to volume and pressure), the mechanosensitive role or purpose of other cells in the body is less obvious, especially in cardiac cells. Cardiac cells respond to mechanical stimuli almost as readily as to electrical stimuli. In 1992, Franz et al. showed in isolated rabbit hearts with atrioventricular block, instrumented with an intraventricular fluid-filled balloon connected to a computer-driven piston, that volume pulses of low amplitude cause membrane depolarizations during diastole. When volume pulses (amplitude of stretch) were gradually ramped up, a threshold was seen beyond which each volume pulse triggered a beat (mechanical pacing). This is surprisingly similar to electrical pacing. Mechanical pacing has been known also to work in the human heart. Zoll (Estes et al. 1989) and other inventors have devised mechanical trans-thoracic pacing by applying mechanical stimuli to the asystolic heart to revive beating in emergency situations. Chest thumps also have been shown to start up an asystolic human heart, and sometimes but rarely even during ventricular fibrillation. Clinical electrophysiologists know that even a casual but sudden contact of a catheter with the endocardium usually elicits an ectopic beat at the site of contact. There is therefore little doubt that heart tissue (including human myocardium) is electrically responsive to mechanical stimuli. Clinically, the field of MEC is in its early stages of exploration. It is very difficult to relate regional stretch events to regional electrophysiological responses, owing to the invasive nature of such studies. In the study by Huang et al. (2009) in this issue of Experimental Physiology, the stretchproducing instrument was miniaturized to be applicable in small hearts (rat hearts). They were able to replicate some earlier findings from rabbit hearts, such as stretch-induced depolarizations and stretch-related ectopic ventricular beats (Franz et al. 1992), and extended this research by applying stretch pulses of varying amplitudes and timing and in different cardiac loading conditions. In addition, the authors tested the stretchactivated channel (SAC) hypothesis by adding gadolinium or streptomycin to the perfusate, both of which are known as SAC blockers and both of which significantly reduced the incidence of stretch-induced extra beats. There are some caveats that need to be addressed. The investigators used solenoidactivated pulses that bear little resemblance to the haemodynamic forces occurring in hearts in situ, even when pathophysiological conditions are present. Furthermore, some extra beats commenced with a delay after the mechanical stimulus, which is in contrast to the relatively swift response to electrical stimuli and even mechanical stimuli. The ‘destretch’ hypothesis offered for these ‘out of sync’ MEC responses has no foundation in experiments reported to date. Sudden diastolic relaxation and the associated release of calcium ions from the disengaging myofilaments may lead to subtle membrane depolarizations. However, these events are part of the normal cardiac cycle and are not arrhythmogenic. Further research needs to be done to verify that this can happen under pathophysiological stretch conditions. The miniaturization of a stretch mechanism in intact hearts as shown in this paper (Huang et al. (2009)) has significant potential. If further reduced to become applicable in murine hearts, it could become a valuable tool in the study of transgenically mutated hearts and could lead to clinically applicable discoveries in a variety of arrhythmia models, especially those with pre-existing (congenital) mechanical disorders. For instance, researchers in the laboratory of Fabritz and Kirchhof (Kirchhof et al. 2006) have used plakoglobin-deficient mice to study the arrhythmogenic mechanism that may also occur in arrhythmogenic right ventricular cardiomyopathy. There are many other models that could be explored (including long QT syndromes), as well as the testing of new pharmacological agents. Thus, while the data presented in the study by Huang et al. (2009) do not yet warrant drawing major clinical conclusions, further fine-tuning of the stretch apparatus to mimic clinical haemodymanic mechanical loads and stress more faithfully, especially when administered to regionally susceptive myocardium, could lead to important insights into MEC.