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The aged myocardium - response to hypertrophic and fibrotic stimuli

Objective



Aged patients suffer more frequently from systemic hypertension and heart failure after myocardial infarction as reflected by increased morbidity and mortality. A diminished arterial compliance, a compromised capacity of myocardial adaptation due to altered electrophysiological and mechanical properties of the myocardium and changes in the molecular response during stress-induced signalling, all concur to worsen cardiac pathophysiology in ageing.
Chronic haemodynamic stress initiates a complex programme at the cardiovascular level. This 'ventricular remodelling' features a progressive increase of surviving cardiomyocyte dimension (cellular hypertrophy), an enlargement of chamber volume (dilatation), an augmented deposition of extracellular matrix proteins in replacement of necrotic cardiac cells (reactive fibrosis), around vessels (perivascular fibrosis) and in the interstitium (interstitial fibrosis).
The specific responses of the senescent heart to hypertrophic and fibrotic stimuli remain still poorly defined in terms of hormonal homeostasis, regulation of transcription for the proteins involved in ventricular remodelling and functional evolution after insult. Therefore, in the present project, the relative importance of haemodynamic factors versus circulating hormones in promoting myocyte hypertrophy or fibrosis in cardiac pathologies will be evaluated. This will be investigated by submitting animals to hypertrophic stimuli of prevalently hormonal origin (continuous Beta-adrenergic stimulation) or experimental models combining hypertension and hormonal stimuli (coarctation of abdominal aorta).The response will be analysed in terms of level and velocity of transcription of some selected genes activated during ventricular remodelling, collagen deposition in the ventricles, cardiac performance, hormonal state and compared for young mature and aged animals.
In EC countries, the median age of the population tends to increase The specificity of the aged cardiovascular system response to hypertrophic stress and the mortality associated with chronic heart failure in the senescent population (important cause of mortality in the western population aged over 65) clearly delineate the socioeconomic relevance of the present project. It appears now likely that the nature of the cardiovascular adaptation to haemodynamic stresses depends not only on age, but also on the nature of the induced stress. The development of specific therapeutic approaches to the failing ageing heart needs to be first validated with animal models

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

Consorzio Mario Negri Sud
Address
Via Nazionale
66030 Santa Maria Imbaro Chieti
Italy

Participants (1)

Not available
France