Hypertension Myocardial Fibrosis

Adverse effects of hypertension on the heart include left ventricular hypertrophy and increased myocardial fibrosis, which can lead to impaired systolic and diastolic dysfunction. ¹ As reviewed by Díez ² in this issue of The Journal of Clinical Hypertension, the histologic characteristics of hypertensive cardiac remodeling are myocyte hypertrophy and reactive myocardial fibrosis that extends from the perivascular space into the intermuscular interstitium. These are adaptive changes to pressure overload from elevated pressure and associated hormonal actions. Díez notes that an important element in this structural remodeling involves relative increases in synthesis vs degradation of collagen type I and II molecules with their consequent accumulation. ² As noted by this author and others, there is increasing evidence that enhanced activation of the renin‐angiotensin‐aldosterone system in addition to pressure overload play important roles in this maladaptive modeling of the heart.

Díez and others have noted that circulating and/or locally produced angiotensin II acts through angiotensin II type 1 (AT₁) receptors on the cardiomyocyte and myofibers to exert multiple profibrotic effects, including induction of fibroblast hyperplasia and differentiation to myofibroblasts, activation of collagen biosynthetic pathways, and inhibition of collagen degradative pathways. Indeed, there is accumulating evidence that both angiotensin II and aldosterone mediate many of these effects by increasing both inflammation and oxidative stress. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ The role of angiotensin in mediating cardiac fibrosis and hypertrophy has been extensively reviewed, ¹ but the role of mineralocorticoids in these processes is less well appreciated.

Both cardiomyocytes and cardiac fibroblasts express mineralocorticoid receptors (MR) with high affinity for aldosterone and corticosterone. ⁵ Indeed, the effects of mineralocorticoids in the heart include an interaction with the renin‐angiotensin system. In aldosterone salt‐treated rodents, AT₁ receptor and angiotensin‐converting enzyme expression are increased in cardiomyocytes. ² , ³ , ⁴ , ⁵ , ⁶ Recently, data from several laboratories indicate that MR activation potentiates the proinflammatory/fibrotic effects of AT₁ receptor signaling by enhancing the cardiac oxidative stress induced by angiotensin II. ² , ³ , ⁴ , ⁵ , ⁶ These adverse effects of mineralocorticoids may be independent of blood pressure, since treatment with low doses of MR blockers in rodents decreases oxidative stress, inflammation, and fibrosis with chronic pressure overload. ⁶ , ⁷ Thus, it is not surprising that MR antagonism, similar to AT₁ antagonism, has improved cardiovascular outcomes in clinical trials.