An exaggerated accumulation of fibrous tissue seen as a diffuse increase in fibers (ie, interstitial fibrosis) and as a localized deposition (ie, perivascular fibrosis and microscopic scarring) is one of the key features of structural remodeling of the hypertrophied left ventricle in hypertensive heart disease (HHD) (Figure 1). Various studies performed in human heart postmortem specimens1,2 and endomyocardial human biopsy samples3–5 have shown that collagen volume fraction (CVF) is significantly increased in the hearts of patients with HHD compared with that in normotensive participants.
Changes in the composition of cardiac tissue develop in hypertensive patients with left ventricular hypertrophy (ie, hypertensive heart disease) and lead to structural remodeling of the myocardium. One of these changes is related to the disruption of the equilibrium between the synthesis and degradation of collagen types I and III molecules, which results in an excessive accumulation of collagen types I and III fibers within the myocardium. Myocardial fibrosis is the consequence of a number of pathologic processes mediated by mechanical, neurohormonal, and cytokine routes. The clinical relevance of fibrosis is that it may contribute to heart failure and other cardiac complications in patients with hypertensive heart disease. This brief review focuses on the mechanisms of hypertensive myocardial fibrosis.
The excess of collagen seen in hypertension is suggested to be the result of both increased collagen types I and III synthesis by cardiac fibroblasts and myofibroblasts and unchanged or decreased collagen types I and III degradation by matrix metalloproteinases.6 This notion is supported by experimental findings showing increased procollagen type I messenger RNA expression and diminished collagenase activity in the hypertrophied and fibrotic left ventricle of spontaneously hypertensive rats (SHRs).7,8 A number of factors might account for this disequilibrium (Figure 2).
Role of Mechanical Factors
As shown in in vivo experiments, pressure overload of the left ventricle is associated with increased collagen synthesis and reduced collagenase activity.9,10 In addition, in vitro studies have shown that collagen type I synthesis is stimulated and collagenase expression inhibited in cardiac fibroblasts submitted to mechanical load.9,10 Thus, hemodynamic overload of the left ventricle due to hypertension may contribute to ventricular fibrosis.
Several clinical observations support this possibility. Tanaka and colleagues1 reported that CVF increased from the outer to the inner third of the left ventricular free wall, probably reflecting transmural gradients of wall stress. Rossi2 found that the extent and severity of ventricular fibrosis paralleled the enlargement of cardiomyocytes. Finally, Querejeta and associates5 reported that CVF correlated with systolic blood pressure and pulse pressure in the myocardium of patients with HHD.
Role of Humoral Factors
Two types of findings suggest that nonhemodynamic factors also contribute to myocardial fibrosis in human hypertension. First, fibrosis has been identified in the left and right ventricles,11 the interventricular septum,5 and the left atria12 of patients with HHD. Second, it has been shown that the ability of antihypertensive treatment to regress fibrosis in hypertensive patients is independent of its antihypertensive efficacy.4,13 Thus, fibrosis could be the consequence of the loss of reciprocal regulation that normally exists between profibrotic and antifibrotic molecules (Table).6 Of particular importance are the effector hormones of the renin-angiotensin-aldosterone system (RAAS) and cytokines such as the transforming growth factor β (TGF-β).
|Vasoactive substances: angiotensin II, endothelin 1, norepinephrine|
|Adrenal hormones: aldosterone, deoxycorticosterone|
|Growth factors: TGF-β, connective tissue growth factor|
|Cytokines: cardiotrophin-1, interleukin 6|
|Other: osteopontin, thrombospondin, reactive oxygen species, prostaglandin E2, endogenous ligand of PPAR-γ, plasminogen activator inhibitor-1|
|Vasoactive substances: bradykinin, prostacyclin, nitric oxide, natriuretic peptides|
|Adrenal hormones: glucocorticoids|
|Cytokines: TNF-α, interleukin 1ß|
|Other: N-acetyl-seryl-aspartyl-lysyl-proline, endogenous ligands of PPAR-α, estrogens|
|Abbreviations: PPAR, peroxisome proliferator-activated receptor; TGF-ß, transforming growth factor β; TNF-α, tumor necrosis factor α.|
Pharmacologic interventions with angiotensin-converting enzyme inhibitors3,4 and angiotensin II type 1 receptor antagonists13,14 have underscored the importance of circulating or locally produced angiotensin II in the development of myocardial fibrosis in patients with HHD. This role is supported by a number of experimental findings, which indicate that the interaction of this peptide with the angiotensin II type 1 receptor exerts multiple profibrotic effects within the heart, including induction of fibroblast hyperplasia and differentiation to myofibroblasts, activation of collagen biosynthetic pathways, and inhibiton of collagen degradative pathways.15 Other data suggest that cross talk between some factors produced by cardiomyocytes (ie, osteopontin), macrophages (ie, plasminogen activator inhibitor-1), and fibroblasts (ie, TGF-β) mediates the profibrotic effects of angiotensin II.16 In addition, fibrosis might represent the reparative response to inflammation and oxidative stress induced by angiotensin II through the interaction with angiotensin II type 1 receptors located in cells from the cardiac microvasculature.15
Chronic aldosterone infusion in uninephrectomized rats on a high-salt diet is associated with marked accumulation of collagen fibers in the heart in both ventricles.17 Since cardiac fibrosis in this aldosteronism model is prevented by spironolactone,18 the mechanism of aldosterone and salt-induced cardiac fibrosis possibly involves stimulation of cardiac fibroblasts or myofibroblasts through the mineralocorticoid receptor. The profibrotic actions of aldosterone, interestingly, seem to be independent of blood pressure, since mineralocorticoid receptor inhibition with eplerenone, a selective aldosterone blocker, decreases oxidative stress, inflammation, and fibrosis in mice with chronic pressure overload in the absence of a decrease in systemic blood pressure.19
Overexpression of TGF-β in transgenic mice results in cardiac hypertrophy that is characterized by interstitial fibrosis.20 An association has been reported between an excess of TGF-β and stimulation of collagen type I synthesis and inhibition of collagen type I degradation in patients with HHD.21 In vitro, this cytokine exerts multiple profibrotic actions, including the phenotypic conversion of fibroblasts to myofibroblasts.22 Myofibroblasts arise from interstitial fibroblasts and/or pericytes, express α-smooth muscle actin, and are contractile.23,24 Myofibroblasts have a higher activity for collagen production than fibroblasts.22 Interestingly, it has been shown that cultured cardiac myofibroblasts express requisite components of the RAAS, including angiotensinogen, renin, and angiotensin converting enzyme, and are able to generate angiotensin II de novo.25
Role of Genetic and Environmental Factors
Some findings highlight the potential role of genetic and environmental factors in the modulation of ventricular fibrosis. A microsatellite marker in the rat angiotensin I-converting enzyme 1 (ACE) gene has been identified that allows the differentiation of ACE alleles among rat strains26 and their association with different levels of plasma angiotensin-converting enzyme activity.27 Rats carrying the B allele have been reported to exhibit higher left ventricular angiotensin-converting enzyme activity and to develop more extensive ventricular fibrosis in response to isoproterenol than rats carrying the L allele.28 In addition, the A1166→C polymorphism of the angiotensin II type 1 receptor gene has been found to be associated with exaggerated collagen type I synthesis and unchanged collagen type I degradation in patients with HHD.29 Although the molecular basis of these associations remains unclear, it is likely that they are related to changes in gene expression at a systemic or local level, activity of the RAAS, or both.
Many forms of experimental and clinical hypertension are exacerbated by salt loading. Not only is arterial pressure increased but there is also an increase in left ventricular mass that is complicated further by excessive collagen deposition.30 Recently, these findings have been extended by demonstrating that the sensitivity to salt loading in SHRs was also manifested by significant impairment of cardiac function and myocardial perfusion that were associated with marked myocardial fibrosis.31,32
Role of Sex
It has been shown that women with aortic stenosis display less fibrosis than men.33,34 The possibility exists that this sex-dependent different response to pressure overload may be due to the multiple antifibrotic actions of estrogens at both collagen synthesis and degradation levels.35 Whether this cardioprotective effect of estrogens is also operating in hypertensive women and whether it is lost with age deserves further investigation.
Role of Associated Conditions
A variety of clinical conditions such as diabetes, obesity, and chronic renal failure result in organ fibrosis, including cardiac fibrosis.36–38 The hypothesis has been advanced that elevated levels of circulating TGF-β are part of the molecular link between these conditions and their cardiac fibrogenic potential.39
HHD arises not only as the result of an increase in the quantity of myocardium but also because of alterations in its quality (ie, fibrosis). Data indicate that besides mechanical stress, a variety of cytokines, growth factors, and hormones (namely those belonging to the RAAS) might contribute to myocardial fibrosis in patients with HHD. Recent data support the notion that fibrosis could facilitate the transition from left ventricular hypertrophy to heart failure in these patients.40,41 In this conceptual framework, management of patients with HHD must focus on more than the diagnosis and correction of hypertension and left ventricular hypertrophy. A better approach is to include interventions aimed at detecting and targeting ventricular fibrosis.42