Opportunities in the failing heart

Abstract

Heart failure (HF) is a syndrome with typical signs and symptoms that can result from abnormal cardiac structure or function. It can lead to impaired quality of life, decreased functional capacity, hospital admissions and mortality. Heart failure has been associated with focal and diffuse myocardial fibrosis and arrhythmias. The aim of this thesis was to provide opportunities from bench-to-bedside to elucidate pathways associated with the failing heart and ultimately to improve clinical outcome for patients. In the first part of this thesis, we observed that in the current era a substantial amount of patients develop HF after a first myocardial infarction (MI) and identified several important risk factors for HF following MI. In the second part of this thesis, we developed a novel systematic digital histological quantification method to compare histology with imaging techniques. For late gadolinium enhancement (LGE) imaging, we found that the full width at half maximum (FWHM) technique is preferred for the detection of fibrosis. While LGE cardiovascular magnetic resonance imaging (CMR) provides an accurate qualitative measure of replacement fibrosis, it has potential adverse effects and does not provide a quantitative or direct measurement of cardiac collagen. Therefore, we reviewed endogenous contrast methods to assess fibrosis with CMR including non-contrast T1 and T1rho mapping and although these methods seem promising, more research is required before a large-scale application for clinical decision-making can be recommended. Phospholamban (PLN) is a crucial regulator of cardiac contractility. Within the Netherlands a relatively large population of patients exists with the PLN R14del mutation causing HF. In a systematic histological analysis of PLN R14del patients heart slices, fibrosis was mainly observed in the posterolateral wall of the left ventricle, whilst adipose tissue was more pronounced in the outer myocardium of the right ventricle. We also found a characteristic distribution of fibrosis in genetic cardiomyopathies related to the mutation group. In the third and final part of this thesis, epigenetic and therapeutic pathways in HF are investigated. In an epigenetic study we found multiple PLN R14del mutation specific regulated genes, which could be used in future as a biomarker for risk stratification. Regarding the translational axis of cell therapy, we found that the results of cell therapy for dilated cardiomyopathy seem promising, but we have methodological recommendations for future studies before implementation in clinical practice. Finally, we performed a randomized, placebo controlled study with intracoronary infusion of cardiomyocyte progenitor cells (CMPCs) in a large preclinical model of ischaemic HF. While this method seems feasible and safe, we did not find significant positive effects on left ventricular performance or infarct size. Therefore translation of the current CMPCs towards a first-in-man trial is presently not justified. In summary, in this thesis we have shed light on opportunities to identify the clinical picture, visualize pathophysiology, elucidate underlying mechanisms and pave the way for future therapeutic strategies in the failing heart.