Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction

Animal models have suggested a role of renin-angiotensin system (RAS) activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF). Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs), F2-isoprostanes (IsoPs), and ratios of oxidized to reduced glutathione (EhGSH) and cysteine (EhCyS) were measured. Angiotensin converting enzyme (ACE) levels and activity were measured. On univariate analysis, HFpEF was associated with male sex(p=0.04), higher body mass index (BMI)(p=0.003), less oxidizedEhCyS(p=0.001), lower DROMs(p=0.02), and lower IsoP(p=0.03). Higher BMI (OR: 1.3; 95% CI: 1.1–1.6) and less oxidizedEhCyS (OR: 1.2; 95% CI: 1.1–1.4) maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01–1.05), ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF.

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Angs (Angiotensins) of the Alternative Renin-Angiotensin System Predict Outcome in Patients With Heart Failure and Preserved Ejection Fraction

Hypertension ◽

10.1161/hypertensionaha.119.12786 ◽

2019 ◽

Vol 74 (2) ◽

pp. 285-294 ◽

Cited By ~ 8

Author(s):

Christina Binder ◽

Marko Poglitsch ◽

Asan Agibetov ◽

Franz Duca ◽

Caroline Zotter-Tufaro ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Renin Angiotensin System ◽

Preserved Ejection Fraction ◽

Angiotensin System ◽

Renin Angiotensin ◽

Patients With Heart Failure

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The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00424.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. R26-R32 ◽

Cited By ~ 40

Author(s):

J. C. B. Ferreira ◽

A. V. Bacurau ◽

F. S. Evangelista ◽

M. A. Coelho ◽

E. M. Oliveira ◽

...

Keyword(s):

Heart Failure ◽

Renin Angiotensin System ◽

Collagen Content ◽

Ang Ii ◽

Male Adult ◽

Angiotensin System ◽

Sympathetic Hyperactivity ◽

Renin Angiotensin ◽

Ras Activation

Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking α2A and α2C adrenoceptor knockout (α2A/α2CARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, α2A/α2CARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, α2A/α2CARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT1 receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.

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