End-stage heart failure and left ventricular mechanical support : clinical and fundamental aspects

Abstract

This thesis deals about mechanical support in en-stage heart failure. The introduction provides an overview of some clinical aspects of heart failure and the pathofysiology, focussing on remodeling. Chapter 2 reports the results of 38 patients undergoing implantation of a left ventricular assist device (LVAD) as a bridge to heart transplantation. 87 % survived the first postoperative month, and 76 % of the patients were successfully transplanted after a mean duration of support of 206±129 days. In chapter 3 exercise performance of patients supported by a LVAD is reported. Twelve weeks after LVAD implantation peak VO2 is comparable to that at 12 weeks and one year after heart transplantation (peak VO2: 22.8±5.3, 24.6±3.3 and 26.2±3.8 ml/kg/min, respectively). Therefore, with regard to exercise capacity an LVAD is fully compatible with activities of normal daily life. Chapter 4 describes the histologic features of cardiomyocytes, with emphasis on the contractile proteins. At the time of LVAD implantation widespread distortion of the staining pattern of the thin contractile proteins and titin was seen. In contrast, myosin staining pattern was preserved. After LVAD support, during a period of 213±135 days, the thin contractile proteins and titin showed improvement, but no normalization. Cardiomyocyte cross-sectional area decreased 36% after LVAD support, but also did not normalize. The persistence of severe structural myocyte damage in this study group does not support complete recovery of myocyte histologic features after a period of unloading of the heart by LVAD support. Chapter 5 focuses on cardiomyocyte cell death in patients with end-stage heart failure, before and after LVAD support. Before LVAD support apoptosis incidence was low (0.8% of cardiomyocytes), further decreasing after support (0.1% of cardiomyocytes). The apoptosis inducing mediators and their receptors were all present before and after LVAD support. The apoptosis inhibitory protein FLIP was widely expressed in cardiomyocytes before and after LVAD support, with m-RNA levels comparable to that in normal controls. This may suggest that FLIP is an important factor in the prevention of cardiomyocyte apoptosis. Chapter 6 reports the comparison of the morphology of the contractile proteins in biopsies of the left- and right ventricle and the interventricular septum to investigate if right ventricular biopsies might be used to monitor reverse remodeling in the left ventricle. The staining pattern of all these biopsies was identical. Furthermore, small biopsies taken with a diagnostic bioptome were representative for the histologic findings of the myofilaments in larger biopsies. With regard to the morphology of the contractile proteins, prospective biopsies of the right ventricle may be a way of monitoring reverse remodeling of the left ventricle during LVAD support. Chapter 7 is a general discussion of the results of the investigations included in this thesis. Probably, mechanical circulatory support can be used in the near future as an alternative to heart transplantation. The use of mechanical support as a bridge to recovery of cardiac function in end-stage heart failure is presently highly experimental and unpredictable