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Association between polymorphisms of genes involved in the Renin-Angiotensin-Aldosterone System and the adaptive morphological and functional responses to essential hypertension.

ABSTRACT: Hypertensive cardiac remodeling is illustrated by increased left ventricular (LV) mass index values and/or relative wall thickness (RWT) values >0.42, and functionally by isolated alteration of LV diastole (abnormal relaxation). The aim of the present study was to establish differentiated models of anatomical and functional adaptation to essential hypertension (EHT), in relation to the genetic variants of genes involved in the Renin-Angiotensin-Aldosterone System (RAAS). The M235T-AGT, I/D-ACE, A1166C-R1AngII, A3123C-R2AngII and G83A-REN genotypes were determined using PCR-Restriction Fragment Length Polymorphism in 139 hypertensive subjects. The relationship between the studied RAAS gene polymorphisms with morphological and functional cardiac remodeling was assessed by multiple logistic regression analysis. Patients carrying the C/C, A/C genotypes (A3123C-R2AngII polymorphism) had a 2.72-fold (P=0.033) increased risk of exhibiting an RWT value <0.42; in the multivariate model the risk was 4.02-fold higher (P=0.008). Analysis of LV diastolic dysfunction (LVDD) revealed that hypertensive patients carrying the T/T, M/T genotypes (M235T-AGT polymorphism) had a 2.24-fold (P=0.037) increased risk of developing LVDD and a 2.42-fold increased risk (P=0.039) after adjustment for confounders. Similarly, carriers of the G/G, A/G genotypes (G83A-REN) had a 2.32-fold (P=0.021) increased risk of developing LVDD, and this remained an independent risk factor based on the multivariate model (P=0.033). The results of the present study showed that no particular gene was associated with increased LV mass, but the A3123C-R2AngII polymorphism was associated with a non-concentric type of cardiac response in hypertensive patients. Conversely, the M235T-AGT and G83A-REN polymorphisms were found to be statistically significantly associated with LVDD when assessing abnormal relaxation.

SUBMITTER: Mocan O

PROVIDER: S-EPMC8372125 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationalePatients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are up-regulated, but this may have long-term negative effects on the progression of iPAH.ObjectivesAssess systemic and pulmonary RAAS activity in patients with iPAH and determine the efficacy of chronic RAAS inhibition in experimental PAH.MethodsWe collected 79 blood samples from 58 patients with iPAH in the VU University Medical Center Amsterdam (between 2004 and 2010) to determine systemic RAAS activity.Measurements and main resultsWe observed increased levels of renin, angiotensin (Ang)I, and AngII, which were associated with disease progression (P < 0.05) and mortality (P < 0.05). To determine pulmonary RAAS activity, lung specimens were obtained from patients with iPAH (during lung transplantation, n = 13) and control subjects (during lobectomy or pneumonectomy for cancer, n = 14). Local RAAS activity in pulmonary arteries of patients with iPAH was increased, demonstrated by elevated angiotensin-converting enzyme activity in pulmonary endothelial cells and increased AngII type 1 (AT(1)) receptor expression and signaling. In addition, local RAAS up-regulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT(1) receptor signaling in patients with iPAH compared with control subjects. Finally, to determine the therapeutic potential of RAAS activity, we assessed the chronic effects of an AT(1) receptor antagonist (losartan) in the monocrotaline PAH rat model (60 mg/kg). Losartan delayed disease progression, decreased right ventricular afterload and pulmonary vascular remodeling, and restored right ventricular-arterial coupling in rats with PAH.ConclusionsSystemic and pulmonary RAAS activities are increased in patients with iPAH and are associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.

Project description:PurposeThis study examined the effects of plasma renin activity (PRA), angiotensin II (Ang II) and aldosterone (PAC) concentrations as well as common polymorphisms in the β1-Adrenoceptor gene (ADRB1) and the G-protein α-Subunit (Gαs) protein gene the G protein α-Subunit 1 gene (GNAS) on the blood pressure (BP) and heart rate (HR) response to bisoprolol in Chinese patients with hypertension.MethodsPatients with sitting clinic systolic BP (SBP) 140-169 mmHg and/or diastolic BP (DBP) 90-109 mmHg after placebo run-in were treated with open-label bisoprolol 2.5 mg daily for 6 weeks. Patients diagnosed as having primary aldosteronism or renal artery stenosis were excluded. PRA, Ang II and PAC concentrations were measured after the placebo run-in and after 6 weeks of treatment. The Ser49Gly and Arg389Gly polymorphisms in ADRB1 and the c.393C > T polymorphism in GNAS were genotyped by the TaqMan® assay.ResultsIn 99 patients who completed the study, baseline PAC levels were significantly associated with baseline DBP and plasma potassium on univariate but not on multivariate linear regression analysis. PRA, Ang II, and PAC concentrations at baseline were not associated with changes in BP with bisoprolol treatment, but the values were all significantly reduced (PRA -0.141 ± 0.595 ng/mL/h, Ang II -2.390 ± 5.171 pmol/L and aldosterone -51.86 ± 119.1 pg/mL; all P < 0.05) following 6 weeks of bisoprolol treatment. There were no significant differences in BP or HR responses in patients with baseline PRA above or below the PRA cut-point of 0.65 ng/mL/h or the median value of 0.9 ng/ml/hour. There were no significant associations of the ADRB1 and GNAS polymorphisms with the clinic and ambulatory BP and HR responses to bisoprolol.ConclusionBaseline PRA, PAC and Ang II concentrations showed no significant association with the BP response to bisoprolol treatment, but all these parameters were reduced after 6 weeks of treatment with bisoprolol. The two common polymorphisms in ADRB1 and the c.393C > T polymorphism in GNAS had no significant association with the BP and HR response to bisoprolol in these patients.

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Association between polymorphisms of genes involved in the Renin-Angiotensin-Aldosterone System and the adaptive morphological and functional responses to essential hypertension.

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