A computational model of age-dependent cardiomyocyte apoptosis.

Abstract

Hypertension and ageing are risk factors for arterial stiffness, which increases cardiac overload and causes left ventricular (LV) hypertrophy. Cardiomyocyte apoptosis acts as a regulatory mechanism that participates in the adaptive response of the heart to pressure overload. Anti-hypertensive drugs can exert anti-apoptotic effects on cardiomyocytes, which are important therapeutic targets for cardio protection. The angiotensin II receptor blocker losartan, used in hypertension and cardiac remodelling, may inhibit cardiomyocyte apoptosis, possibly by reducing Bax expression. To study the effect of apoptotic signals in LV myocytes on patient survival with and without losartan treatment we used a previously developed mathematical model of the human cardiovascular and renal systems. Here we extended this model to include mechanisms of CD95-induced cardiomyocyte apoptosis. Our model is the first to integrate a mechanistic view of cardiorenal processes with biochemical mechanisms of cell death. The model predicted that therapeutic intervention on cardiac apoptotic pathways could significantly improve the survival in patients with cardiac pressure overload pathology. Although the modelling results showed that losartan suppresses cardiomyocyte apoptosis primarily through its effects on LV haemodynamic function, the model demonstrated that in diseases that promote water and sodium accumulation in the body, the therapeutic effect of losartan on molecular apoptotic processes may be more significant than its effects on LV haemodynamics. KEY POINTS: Therapeutic interventions that target cardiac apoptotic pathways have the potential to markedly improve the survival of patients with cardiac pressure overload pathology. The findings of the modelling suggest that losartan suppresses cardiomyocyte apoptosis primarily through its effect on left ventricular haemodynamic function. In diseases that result in the accumulation of water and sodium within the body the therapeutic efficacy of losartan on molecular apoptotic processes may prove to be more significant than its effects on left ventricular haemodynamics.