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Symptomatic heart failure is accompanied by diastolic ventricular dysfunction due largely to an extensive reactive and reparative fibrosis. Experimental evidence suggests a clear association between myocardial fibrosis and chronic inappropriate elevations in circulating angiotensin II (Ang II) and/or aldosterone. Although not entirely elucidated, injury follows Ang II-associated release of adrenal medullary catecholamines and aldosterone-induced myocardial potassium depletion. Increasing evidence indicates locally produced cardiac Ang II plays an important role in tissue repair that may underlie myocardial remodelling, the fibrous tissue accumulation both at and remote to the site of myocardial infarction (MI). Angiotensin converting enzyme (ACE) binding density markedly increases at these fibrous tissue sites after experimental MI, indicating an involvement in wound healing regardless of the cause and location of fibrosis; cells expressing Ang II receptors are primarily myofibroblasts. Therapy with ACE inhibitors and aldosterone receptor antagonist have each been shown to attenuate development of fibrosis.

Chronic activation of the circulating renin-angiotensin-aldosterone system (RAAS), as can occur with unilateral renal ischemia (URI), is associated with an adverse structural remodeling of the right and left ventricles characterized by reparative (i.e., microscopic scars) and reactive (i.e., perivascular/interstitial) fibrosis. The time course and cells involved in fibroplastic and fibrogenic phases of these events are unclear. Hearts were examined over the course of 8 weeks in rats infused with either angiotensin II or aldosterone, and compared to rats with URI. Tissue sections from the same heart were stained with hematoxylin and eosin, collagen specific picrosirius red, or immunolabeled with PCNA or alpha smooth muscle actin antibody. With angiotensin II or renal ischemia, fibroblast proliferation, presenting as focal accumulations at both sites of myocyte necrosis and widespread perivascular locations, was present in each ventricle on days 2 and 4, but not thereafter, alpha-Smooth muscle actin containing cells (myofibroblasts) appeared at day 2 and persisted through week 2 with renal ischemia and week 6 with angiotensin II. Macrophages, neutrophils and lymphocytes were transiently found at sites of necrosis between day 2-4 of renal ischemia. AngII-induced necrotic sites were characterized by macrophages and lymphocytes from day 2 through week 6, and neutrophils at day 2-4. Increased collagen volume fraction, presenting as immature scars associated with fibroblast clusters and interstitial/perivascular fibrosis, was evident on day 14 in both ventricles. In contrast, fibroblast proliferation during aldosterone infusion did not appear in both ventricles until week 3 and was associated with a subsequent reparative and reactive fibrosis as early as 4 weeks. Myofibroblasts became evident between 3-6 weeks; macrophages and lymphocytes were seen between 3-8 weeks. Neutrophils were not seen at any time point with aldosterone. Thus, the temporal cellular response and appearance of myocardial fibrosis associated with chronic elevations in angiotensin II and/or aldosterone differ. We conclude that separate pathogenic mechanisms are operative with these effector hormones of the RAAS.

Circulating mineralocorticoid hormones are so named because of their important homeostatic properties that regulate salt and water balance via their action on epithelial cells. A broader range of functions in nonclassic target cellular sites has been proposed for these steroids and includes their contribution to wound healing following injury. A chronic, inappropriate (relative to intravascular volume and dietary sodium intake) elevation of these circulating hormones evokes a wound healing response in the absence of tissue injury--a wound healing response gone awry. The adverse remodeling of vascularized tissues seen in association with chronic mineralocorticoid excess is the focus of this review.

Chronic mineralocorticoid (MC) excess, whether due to elevated plasma aldosterone (ALDO) or deoxycorticosterone (DOC), is associated with a perivascular fibrosis of systemic and coronary arterioles. This remodeling of resistance vessels contributes to the appearance of hypertension. Chronic MC excess is also accompanied by cardiac myocyte necrosis, secondary to myocardial potassium depletion, and a subsequent reparative fibrosis that appears in the normotensive, nonhypertrophied right and hypertensive, hypertrophied left ventricles. Fibrosis contributes to the appearance of ventricular arrhythmias and dysfunction. Herein, clinical and experimental evidence linking chronic, inappropriate (relative to dietary sodium) elevations in circulating ALDO and DOC with these reactive and reparative forms of fibrous tissue formation in the heart and other tissues is presented.

Vascular permeability of the coronary and mesenteric circulation is increased in association with the arterial hypertension that accompanies either endogenous activation of the renin-angiotensin-aldosterone system (RAAS) or exogenous administration of angiotensin II (AII). Whether this occurs as a result of increased intravascular pressure or of elevations in plasma concentrations of AII or aldosterone (ALDO) (or both) is unclear. This acute study of filtration-independent coronary fluid exchange and macromolecular permeability was undertaken to address these issues in open-chest, anesthetized dogs. The influence of arterial hypertension, with or without associated elevations in plasma AII or ALDO (or both), on coronary permeability was examined by monitoring the response in cardiac lymph flow, protein concentration, and capillary and intramural coronary artery structure. Experimental groups received a 90-minute intravenous infusion of either AII (n = 8), methoxamine (MX; n = 7), or ALDO plus MX (n = 5) in equipotent doses that raised arterial pressure to comparable levels. When we compared these animals with normotensive, instrumented controls (n = 5), we found that (1) lymph flow was a function of arterial and microvascular pressures in each group; (2) increased protein permeability, myocardial edema, extravasated red cells, and infused colloidal carbon were found in both ventricles with AII, together with endothelial discontinuities and enhanced abluminal capillary endothelial vesicle formation, when plasma ALDO had risen significantly in response to AII; and (3) macromolecular permeability was no different from that in controls after MX or ALDO plus MX. Based on this short-term study of acute arterial hypertension, we would conclude that acute elevations in microvascular pressure increase fluid flux, whereas increased circulating effector hormones of the RAAS, not plasma ALDO or hypertension alone, alter coronary microvascular structure and permeability to macromolecules Responsible mechanisms remain to be defined.

In this report we review the replacement (i.e., scarring) and reactive (i.e., perivascular and interstitial fibrosis) fibrous tissue responses found in the myocardium in response to effector hormones of the renin-angiotensin-aldosterone system. Experimental data are presented to indicate: a) endogenous or exogenous elevations in plasma angiotensin II are associated with acute cardiac myocyte necrosis and subsequent microscopic scarring; b) chronic elevations in plasma aldosterone (ALDO), relative to Na+ intake, are associated with a perivascular and interstitial fibrosis of the coronary and systemic circulations and are also seen in response to chronic administration of the mineralocorticoid hormone deoxycorticosterone (DOC); and c) chronic mineralocorticoid excess, due to ALDO or DOC, is associated with enhanced urinary K+ excretion, cardiac myocyte necrosis and scarring. Pharmacologic agents which interfere with these effector hormones (e.g., ACE inhibition and ALDO receptor antagonism) protect the myocardium against this pathologic structural remodeling created by the reactive and replacement (reparative) fibrosis. Evidence is also presented to indicate that chronic ACE inhibition is associated with a regression in reactive myocardial fibrosis. Based on these experimental findings we would suggest that clinical trials are indicated to address the prevention and regression of myocardial fibrosis--an important determinant of pathologic structural remodeling and abnormal myocardial stiffness.

The myocardium contains myocyte and non-myocyte cells. A disproportionate growth of the nonmyocyte cell population can alter myocardial structure and lead to pathologic hypertrophy. Myocardial fibrosis, the result of cardiac fibroblast growth or abnormal accumulation of fibrillar collagen within the interstitial space, can adversely influence myocardial stiffness and ultimately ventricular function. We have examined the relative importance of ventricular systolic and arterial pressures and the effector hormones of the renin-angiotensin--aldosterone system in mediating this reactive fibrous tissue response in the hypertensive left and normotensive right ventricles in various experimental models of arterial hypertension. To date, our findings implicate arterial hypertension, together with an elevation in plasma aldosterone, as being contributory to the fibrosis in renovascular hypertension that creates tissue heterogeneity in either ventricle and impaired diastolic function. The endocrine properties of aldosterone in this nonclassical mineralocorticoid target tissue, the myocardium, requires further investigation.