Abstract

Abstract There is increasing evidence that fibro-inflammatory changes play a role in variety of cardiovascular diseases. We created new rat models to investigate the role of fibro-inflammatory changes in the pathophysiology of systolic and diastolic dysfunction in hypertensive heart. (1) a model of a blood pressure (BP) surge was created by performing abdominal aortic constriction in Wistar-Kyoto rats. Aortic constriction rapidly increased BP and the high BP levels sustained. A BP surge transiently induced MCP-1 and TGF-beta induction, angiotensin converting enzyme activation, and macrophage infiltration, followed by left ventricular (LV) hypertrophy and perivascular reactive fibrosis. Echocardiography showed diastolic, but not systolic, LV dysfunction in this model. A sub-depressor dose of candesartan, angiotensin II type-1 receptor antagonist, prevented the fibro-inflammatory changes, cardiac remodeling, and diastolic LV dysfunction. (2) A model of hypertension with large short-term BP variability (BPV) by performing sino-aortic denervation (SAD) in spontaneously hypertensive rats (SHRs). In this model, SAD exaggerated BPV without affecting mean BP and the activity of sympathetic nerve system and systemic renin-angiotension-aldosterone system. Large BPV induced chronic fibro-inflammatory changes (macrophage infiltration, MCP-1, TGF-beta, and angiotensinogen upregulations) and aggravated hypertensive LV hypertrophy and reparative myocardial fibrosis, resulting in systolic LV dysfunction. A sub-depressor dose of candesartan prevented the large BPV-induced fibro-inflammatory changes and cardiac remodeling, as well as systolic LV dysfunction, without changing BPV itself. In conclusion, a BP surge induces transient fibro-inflammatory changes leading to cardiac hypertrophy with diastolic dysfunction. In contrast, large short-term BPV caused the local angiotensin-mediated chronic fibro-inflammatory changes which aggravates hypertensive cardiac remodeling and myaocardial damages, resulting in systolic dysfunction.

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