125 At the same time, sustained pressure and/or volume overload favour arrhythmogenesis. 25,124,126,127 Application of SAC-blockers such as GsMTx-4 has been shown to reversibly reduce the preload dependent increase in both incidence and duration of burst-pacing induced atrial fibrillation in isolated heart experiments. 28 In patients, igf-1r it can be difficult to distinguish stretch-induced changes in electrophysiology

from other chronically occurring aspects of structural and functional remodelling. However, an impressive illustration of acute effects of ventricular loading has been provided by Waxman et al., 128 who showed that performing the Valsalva manoeuvre may terminate ventricular tachycardia by temporary reduction of ventricular filling. The Valsalva manoeuvre, an attempt to forcefully exhale against the closed glottis, increases intrathoracic pressure, favouring a net reduction of intravascular volume in the chest (i.e. impeding venous return and favouring arterial drainage to other parts of the body). In this study, the reduction in cardiac dimensions was confirmed radiographically. Cessation of ventricular

tachycardia coincided with removal of ventricular strain, while arrhythmia resumption occurred upon refilling after the end of the manoeuvre. Since this type of response can be seen not only in neurologically intact, but also in pharmacologically 128 or surgically 7 denervated patients (transplant recipients), it is not attributable to a nervous reflex. This highlights how removal of strain may unmask the presence of stretch-induced arrhythmias, even in a chronic setting. Various SAC have

been implicated in the heart’s (patho-)physiological responses to mechanical stimuli, but in the absence of firm identification of molecular substrates for cardiac SAC, successful mechanistic exploration of cardiac mechanosensitivity is a challenging task. Conceptually, it is pragmatic to subdivide SAC into two categories, SACNS and Anacetrapib SACK. For both, there are several candidate proteins. SACNS were initially thought to be formed by TRP proteins and, most convincingly, TRPC6 antibodies inhibit whole-cell ISAC,NS in mouse ventricular myocytes. 58 However, subsequent heterologous expression studies yielded conflicting results. 50,56 More recently, attention has turned towards the newly discovered Piezo1 channels. 46 Although there is no published data yet on specific electrophysiological effects of Piezo1 in cardiomyocytes, comparative kinetic analysis suggests that these proteins may function as cardiac SACNS. In as far as cardiac SACK are concerned, recombinant TREK-1 has remarkably similar properties to endogenous SACK, 78 but the protein has yet to be identified in human heart.