Role of Activated Renin-Angiotensin System in Myocardial Fibrosis and Left Ventricular Diastolic Dysfunction in Diabetic Patients Reversal by Chronic Angiotensin II Type 1A Receptor Blockade

Abstract

ype 2 diabetes mellitus is associated with an increased risk of cardiovascular disease. 1 In particular, diabetic patients have a higher incidence of congestive heart failure compared with age-matched non-diabetic subjects. 2 Although left ventricular (LV) systolic dysfunction occurs only infrequently, diastolic dysfunction is a commonly observed cardiovascular manifestation even in the absence of ischemic or hypertensive heart diseases in diabetic patients. 3,4 The pathogenesis of LV diastolic dysfunction is not fully clarified in the diabetic heart, but myocardial fibrosis is one of the most important mechanisms for the diastolic dysfunction. 5-7 Activation of the local reninangiotensin system is likely to contribute to the development of myocardial fibrosis because its importance has been demonstrated in a number of animal models of LV diastolic dysfunction. 8,9 The renin-angiotensin system is certainly upregulated in the diabetic myocardium, 10 and locally produced angiotensin II might well facilitate the myocardial fibrosis. 11 Thus, we might expect angiotensin II type 1A receptor blockade (ARB) working towards cardioprotection by reducing myocardial fibrosis in diabetic patients.Myocardial fibrosis has been only assessable via the histological examination of the myocardial specimen; however, this requires biopsy and should not be justified from the ethical view in most of the diabetic patients. Most recently, the use of serological markers of collagen turnover was shown to provide estimates of collagen types I and III turnover, that is, production and degradation, for the noninvasive monitoring of myocardial fibrosis. [12][13] In contrast, LV diastolic filling is non-invasively assessable by analyzing pulsed Doppler mitral flow velocity patterns. Even LV chamber stiffness (KLV) may be assessed from the measurement of the deceleration time of the early diastolic mitral filling wave. 14 Thus, we repeatedly assessed collagen turnover and LV diastolic filling in diabetic patients to test the hypothesis that chronic ARB alters myocardial collagen turnover leading to an improvement of diastolic dysfunction in diabetic patients. Methods Subjects and Study ProtocolCandidates of the study were 148 patients with type 2 diabetes mellitus but without moderate to severe hyperten- Background We attempted to test the hypothesis that chronic angiotensin II type 1A receptor blockade (ARB) alters myocardial collagen turnover leading to an improvement of diastolic dysfunction in diabetic patients. Methods and Results Forty-eight type 2 diabetic patients were divided into 2 groups: 38 treated with candesartan for 6 months, and 10 without candesartan, as controls. Doppler mitral flow velocity pattern and biomarkers of collagen type I turnover were assessed before and after ARB during a 6-month period. The mitral E/A ratio increased from 0.65±0.11 to 0.75±0.19. The carboxy-terminal propeptide of procollagen type I (PIP), an index of collagen type I synthesis, decreased and the carboxy-terminal telopeptide of collagen type I (CI...

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

“…24) Activation of the cardiac renin-angiotensin system, myocardial stiffening associated with fibrosis, and abnormal microvascular function have been suggested as contributing to cardiac diastolic dysfunction in humans and animal models with diabetes and hypertension. 10,25,26) We reported that impairment of coronary microcirculation associated with activation of angiotensin type I receptor occurred in SHRSP-fatty. 8) In the present study, we found that collagen type I accumulated in the ventricles along with diastolic dysfunction in SHRSPfatty.…”

Hemodynamic Effects of Fenofibrate and Coenzyme Q10 in Type 2 Diabetic Subjects With Left Ventricular Diastolic Dysfunction

“…However, few studies have investigated potential therapies. In type 2 diabetic subjects with LVDD, 6 months' treatment with candesartan improved one index of diastolic filling (E/A), but not another (DT) (15). In hypertensive patients with LVDD, 12% of whom had diabetes, BP reduction over 38 weeks improved myocardial relaxation (EЈ) irrespective of the agent used, but the independent effect of diabetes was not assessed (16).…”

Angiotensin II Receptor Blocker, Valsartan, Increases Myocardial Blood Volume and Regresses Hypertrophy in Hypertensive Patients

“…[13][14][15] It is an important question to be solved whether the beneficial effects of valsartan on the MBV imply clinically relevant vascular protection for patients with HT, which will translate into improved outcomes, reduced morbidity and mortality. [22][23][24] We measured MBV during MCE as a noninvasive index of structural alterations of the myocardial microvasculature in vivo. There are several other techniques that also allow assessment of microvascular disease in the clinical setting.…”