Heilzame intenties, schadelijke gevolgen. Factoren die de schadelijke gevolgen van hypertrofie van de linker hartkamer wijzigen
2003 - onbekend
- BACKGROUND: Many patients with left ventricular hypertrophy develop complications like heart failure and arrhythmias, yet a substantial number do not. It remains unknown why some are susceptible to progress to complications, while others are more resilient to develop heart failure or arrhythmias. The lack of proper understanding what renders an individual susceptible makes it very difficult to predict which patients will progress to complications. Understanding this individual susceptibility could greatly improve the early diagnosis and treatment of those susceptible subjects. - HYPOTHESIS: The most often advocated concept to explain why hypertrophied hearts develop complications focuses on the molecular changes and growth promoting mechanisms that cause or accompany the hypertrophic process itself. However, since these hypertrophic changes are uniform, while its outcome is not, we propose a different concept. We postulate that distinct molecular mechanisms, differing from the mechanisms underlying the hypertrophic process, cause these complications. Collectively we term these mechanisms the 'complication program'. We also propose that the 'complication program' is already activated before complication-prone hearts have developed failure or arrhythmias, making susceptible hearts identifiable at an early stage. Indeed, we have already successfully employed genomic approaches to identify some components of this 'complication program' and were able to predict heart failure susceptibility in a first study (Sharma et al, 2003a) demonstrating the validity of the concept and of our approach. - AIM: Our main aim is to combine genetic, genomic and proteomic approaches in both animal models and in human pathophysiology to uncover the major molecular mechanisms of the 'complication program'. To that extent we subdivided the program into four major projects: Project 1: (Heart Failure). Hypertensive TGR(mren2)27 rats diverge within the same progeny to either rapid heart failure or prolonged compensation. We will obtain serial cardiac biopsies during the compensated phase to test whether genomic and proteomic changes allow to predict rapid progression to heart failure. In well phenotyped human aortic stenosis, we will obtain myocardial tissue to obtain genomic and proteomic profiles. This project is expected to yield the gene expression and protein changes of the heart failure related 'complication program' in rats and humans. Project 2: (Arrhythmias). Here we will compare two different rat models, the hypertensive TGR(mRen2)27 and ascending aortic banding to assess model dependency of the genomic and proteomic changes. Apart from serial cardiac biopsies, here we will focus on telemetric cardiac rhythm monitoring and electrophysiologic changes. This project is expected to yield gene and cell signalling profiles of the 'complication program' in two rat models, particularly focused on arrhythmias. Project 3: (Susceptibility Genes). It is known that some mouse strains are very susceptible to the adverse effects of pressure loading. We will employ this difference in susceptibility to identify either 'complication-susceptible' or ' complication-resilient' strains of inbred mice. We will combine classical genetics with genomic strategies to identify which mechanisms cause the divergent response to pressure loading. This project is anticipated to yield novel arrhythmia or failure related candidate genes in mice. Project 4: (Humans Studies). Despite a similar disease burden, humans also differ with regard to their susceptibility to develop heart failure or lethal arrhythmias. Candidate genes derived from projects 1-3 will be analyzed to address whether variations in these genes modify the risk of heart failure or arrhythmias. We will study modifier genes in monogenetic trait (a large founder population of Dutch hypertrophic cardiomyopathy patients (>700 subjects)) and in polygenic traits in association studies in three large populations. This is expected to yield candidate genetic modifiers of hypertrophy complications in man. We expect to 1) find novel molecular components of the 'complication program', 2) assess whether these molecules are of pathophysiologic relevance and 3) establish whether these molecules are of importance in human disease. This can provide novel diagnostic markers to identify failure or arrhythmias susceptible patients at an early stage, and yield novel targets for treatment. - OBJECTIVES: This program aims to combine unbiased genetic, genomic and proteomic approaches to identify novel factors that determine the malign consequences of left ventricular hypertrophy: life threatening arrhythmias and heart failure. Specific objectives of subprojects are: P1: (Heart Failure). Predictive profile of changes in gene expression and protein status for heart failure in hypertrophied hearts from rats and humans. P2: (Arrhythmias). Predictive profile of changes in gene expression and protein status for sudden death in hypertrophied hearts from rats. P3: (Susceptibility). Genomic regions and candidate genes that convey the differences in susceptibility to pressure loading in inbred mice. P4: (Human Studies). Gene variations that modifies human susceptibility to the complications of cardiac hypertrophy. - RELEVANCE FOR CARDIOVASCULAR DISEASES: To uncover the molecular mechanisms that predispose a hypertrophied heart to heart failure or serious arrhythmias would mean a major stride ahead in understanding the pathophysiology of these complications. Important effects of this understanding would be the early recognition of such susceptible subjects, and potentially novel mechanisms to intervene in the process so that in susceptible patients we can prevent complications of cardiac hypertrophy.