Volume overload and heart failure risk: insights from high frequency echocardiography and cardiovascular genetics

Volume overload can occur in disease states (e.g. valvular regurgitation, shunts) as well as other conditions associated with a hyperdynamic, high cardiac output state during an individual’s lifetime (e.g. pregnancy or regular endurance exercise). Titin truncating mutations are a highly prevalent genetic risk factor for dilated cardiomyopathy, present in 1 – 3% of the population. The effects of volume overload in titin truncating mutation carriers represent a relatively commonly occurring gene-environmental interaction. This thesis investigated whether chronic volume overload is an important risk factor for heart failure in heterozygous carriers of this heart failure genetic susceptibility factor.Zebrafish models of titin truncation provide a unique approach for examining the physiological consequences of this genetic condition and the potential deleterious effects of volume overload. Echocardiography studies in genetically engineered zebrafish offer fundamental insights into the key systolic and diastolic features of titin truncation in-vivo, in the context of the univentricular cardiovascular system of this lower-order vertebrate.This thesis reports a world-first development and validation of a standardised method of high frequency echocardiography, adapted from clinical cardiology for use in adult zebrafish models of cardiac disease. This method was then used to characterise, for the first time, the adult phenotype of four different lines of zebrafish carrying titin truncating mutations, and the impact of volume overload on the myocardial properties of a zebrafish model of an A-band titin truncating variant.Adult heterozygous zebrafish mutation carriers exhibited mutation position-dependent propensity for dilated cardiomyopathy, prolonged ventricular relaxation and abnormal late-diastolic ventricular passive stiffness. These zebrafish also displayed impaired tolerance of volume overload, similar to the human patients from whom they were modelled, a phenomenon that appeared to be conserved despite 400 million years of vertebrate evolution.These zebrafish models therefore provide tantalising insights into the propensity for dilated cardiomyopathy and the increased susceptibility to the effects of volume overload in titin truncation. The altered ventricular compliance seen in zebrafish titin truncating models may also help explain the occurrence of atrial fibrillation often observed in human heterozygous carriers. Collectively, these studies have demonstrated an innovative means of investigating the physiological consequences of genetic heart disease.