Ventricular remodelling in cardiomyopathy – impact on ventricular physiology and cardiovascular outcome

Abstract

Ventricular remodelling, defined as changes in ventricular structure and/or function in response to haemodynamic load and/or cardiac injury, is a feature of cardiomyopathy. Patterns of remodelling vary according to the specific type of cardiomyopathy, and also between individuals. Ventricular remodelling is linked to the development of systolic and diastolic heart failure as well as other adverse outcomes, including death. There is increasing interest in the potential role of novel strategies, including anti-fibrotic therapies, to enhance the treatment of patients with ventricular dysfunction. In this thesis, several cardiac imaging modalities, including cardiac magnetic resonance (CMR) imaging, are used to further evaluate both the physiological effects and clinical outcomes of ventricular remodelling in a variety of cardiomyopathies. In particular, the significance of myocardial fibrosis is explored in detail. Chapter 1 of this thesis provides an introduction and literature review encompassing current concepts of cardiomyopathy, ventricular remodelling and heart failure. Chapter 2 investigates the link between post-contrast T1 time, a CMR-derived index of diffuse myocardial fibrosis, and invasively determined measures of ventricular diastolic function in cardiac transplant recipients. For the first time, a significant correlation is revealed between post-contrast T1 time and β, the load-independent passive LV stiffness constant. The ability to non-invasively evaluate ventricular stiffness using T1 mapping may enhance our understanding of cardiomyopathies, and facilitate therapeutic trials of anti-fibrotic agents. Chapters 3 and 4 explore ventricular remodelling and the influence of genotype on phenotype in hypertrophic cardiomyopathy (HCM). Significantly more diffuse myocardial fibrosis is found in patients with HCM compared to healthy subjects, and is associated with both diastolic dysfunction and dyspnoea. Correlations between regional myocardial fibrosis by late gadolinium enhancement (LGE) and both left ventricular ejection fraction and outflow tract obstruction are also demonstrated. The presence of an identifiable pathogenic HCM mutation is associated with significantly more regional, but less diffuse myocardial fibrosis. Further research may identify links between specific pathogenic mutations and particular HCM phenotypes, and facilitate more individualised management strategies in this complex condition. Chapter 5 addresses whether peripheral byproducts of collagen metabolism can be utilised as indicators of myocardial fibrosis in HCM. Importantly, levels of these biomarkers are not found to reliably reflect either myocardial collagen metabolism or content. Chapter 6 prospectively compares electrocardiography, echocardiography and CMR for predicting response to cardiac resynchronisation therapy (CRT). While all three modalities are found to predict improvements in markers of response, only CMR is observed to predict both symptomatic and survival benefits in CRT candidates with shorter, non-LBBB QRS complexes, a subgroup known to derive less benefit from CRT. Finally, Chapter 7 explores whether novel approaches to coronary artery disease (CAD) risk stratification can predict plaque characteristics in asymptomatic, intermediate risk subjects. Plasma lipidomic profiling is shown to predict the burden of non-calcified coronary plaque in these patients. Re-stratification by this technique may enable more appropriate and effective preventative strategies against CAD, a major cause of cardiomyopathy.