The Protective Effects of Remote Ischaemic Preconditioning on Pressure Overload-Induced Myocardial Remodelling

Remote ischaemic conditioning (RIC) is known to protect the myocardium from ischemia/reperfusion injury. More recently, sustained bouts of RIC have shown a potential to attenuate maladaptive remodelling post myocardial infarction (MI) associated with the development of heart failure. The drivers for myocardial remodelling include mechanical stretch and neurohormonal stimulation (e.g. ET-1, Ang-II and alpha-adrenoceptor stimulation) which are also involved in the pressure overload-induced remodelling (e.g. systemic hypertension). So, we have hypothesized that RIC will ameliorate/prevent pathological remodelling from pressure overload.

Using cellular models of cyclic stretch- and agonist (e.g. ET-1)- driven adult rat ventricular cardiomyocytes (ARVC) hypertrophy and human cardiac fibroblasts proliferation, I looked for any anti-hypertrophic or anti-fibrotic role of serum collected from healthy human volunteers who have undergone a standard RIC protocol. Cell hypertrophy was assessed by measuring cell size (length width ratio) and proliferation was assessed using BrdU chemiluminescence. Furthermore, I investigated the functional effects of RIC on blood pressure using both in vivo and in vitro models.

Unlike normal serum, RIC-serum proved to have strong anti-hypertrophic effects. The cardioprotection afforded by RIC on ET-1-induced hypertrophy was blocked by adenosine and opioid receptor blockers. Both adenosine and endogenous opioids are known to be humoral mediators of RIC protection. Moreover, the antihypertrophic effect RIC serum on stretched ARVCs was also blocked by the use of selective inhibitors of the eNOS/cGMP/sGC/PKG signalling pathway, which is proposed to exert the anti-hypertrophic action of RIC in response to pressure overload. RIC serum, however, did not attenuate fibroblast proliferation induced by either ET-1 or cyclic stretch.

RIC resulted in significant, yet transient, drop in blood pressure and shortening of electrocardiographic QT interval. In vitro, RIC-serum caused a sustained vasodilation in a rat mesenteric model of resistance arteries. Unconditioned serum from the same volunteers did not.