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The Genetic Variants in the Renin-Angiotensin System and the Risk of Heart Failure in Polish Patients.

ABSTRACT: (1) Background: Heart failure (HF) is a complex disease and one of the major causes of morbidity and mortality in the world. The renin-angiotensin system (RAS) may contribute to the pathogenesis of HF. (2) Aim: To investigate the association of RAS key genetic variants, rs5051 (A-6G) in the gene encoding angiotensinogen (AGT), rs4646994 (I/D) in the gene for angiotensin I converting enzyme (ACE), and rs5186 (A1166C) in the gene encoding type 1 receptor for angiotensin II (AGTR1), with the HF risk in the cohort of Polish patients. (3) Methods: The study group consisted of 415 patients that were diagnosed with HF, while the control group comprised of 152 healthy individuals. Genomic DNA were extracted from blood and genotyping was carried out using either PCR or PCR-RFLP for ACE or AGT and AGTR1 variants, respectively. (4) Results: No association has been found between the I/D ACE and heart failure. The HF risk was significantly higher for AG AGT heterozygotes (overdominance: AG versus AA + GG) and for carriers of the G AGT allele in codominant and dominant modes of inheritance. However, the risk of HF was significantly lower in the carriers of at least one C AGTR1 allele (AC or CC genotypes) or in AC AGTR1 heterozygotes (overdominant mode). There was a significant relationship for AGT and HF patients in NYHA Class I-II for whom the risk was higher for the carriers of the G allele, and for the AG heterozygotes. There was also a significant interaction between heterozygote advantage of AGT and BMI increasing the risk for HF. (5) Conclusion: Our results suggest that the A(-6)G AGT polymorphism may be associated with HF in the Polish population and the HF risk seems to be modulated by the A1166C AGTR1 polymorphism.

SUBMITTER: Goracy I

PROVIDER: S-EPMC9319667 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale & objectiveHeart failure treatment relies on loop diuretics to induce natriuresis and decongestion, but the therapy is often limited by diuretic resistance. We explored the association of renin-angiotensin-aldosterone system (RAAS) activation with diuretic response.Study designObservational cohort.Setting & populationEuvolemic ambulatory adults with chronic heart failure were administered torsemide in a monitored environment.PredictorsPlasma total renin, active renin, angiotensinogen, and aldosterone levels. Urine total renin and angiotensinogen levels.OutcomesSodium output per doubling of diuretic dose and fractional excretion of sodium per doubling of diuretic dose.Analytical approachRobust linear regression models estimated the associations of each RAAS intermediate with outcomes.ResultsThe analysis included 56 participants, and the median age was 65 years; 50% were women, and 41% were Black. The median home diuretic dose was 80-mg furosemide equivalents. In unadjusted and multivariable-adjusted models, higher levels of RAAS measures were generally associated with lower diuretic efficiency. Higher plasma total renin remained significantly associated with lower sodium output per doubling of diuretic dose (β = -0.41 [-0.76, -0.059] per SD change) with adjustment; higher plasma total and active renin were significantly associated with lower fractional excretion of sodium per doubling of diuretic dose (β = -0.48 [-0.83, -0.14] and β = -0.51 [-0.95, -0.08], respectively) in adjusted models. Stratification by RAAS inhibitor use did not substantially alter these associations.LimitationsSmall sample size; highly selected participants; associations may not be causal.ConclusionsAmong multiple measures of RAAS activation, higher plasma total and active renin levels were consistently associated with lower diuretic response. These findings highlight the potential drivers of diuretic resistance and underscore the need for high-quality trials of decongestive therapy enhanced by RAAS blockade.

Project description:ObjectivesThe purpose of this study was to assess the relationship between biomarkers of renin-angiotensin-aldosterone system (RAAS) activation and decongestion strategies, worsening renal function, and clinical outcomes.BackgroundHigh-dose diuretic therapy in patients with acute heart failure (AHF) is thought to activate the RAAS; and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation.MethodsThis study analyzed 427 AHF patients enrolled in the DOSE-AHF (Diuretic Optimization Strategies in Acute Heart Failure) and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trials. We assessed the relationship between 2 markers of RAAS activation (plasma renin activity [PRA] and aldosterone) from baseline to 72 h and 96 h and decongestion strategy: high- versus low-dose and continuous infusion versus bolus furosemide for DOSE-AHF and UF versus stepped pharmacologic care for CARRESS-HF. We determined the relationships between RAAS biomarkers and 60-day outcomes.ResultsPatients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium levels, and higher blood urea nitrogen (BUN) concentration. Continuous infusion furosemide and UF were associated with greater PRA increases (median: +1.66 vs. +0.66 ng/ml/h with continuous vs. bolus infusion, respectively, p = 0.021; +4.05 vs. +0.56 ng/ml/h with UF vs. stepped care, respectively, p = 0.014). There were no significant differences in RAAS biomarker changes with high- versus low-dose diuretic therapy (both: p > 0.5). Neither baseline log PRA nor log aldosterone was associated with increased death or HF hospitalization (hazard ratio [HR] for a doubling of 1.05; 95% confidence interval [CI]: 0.98 to 1.13; p = 0.18; and HR: 1.13; 95% CI: 0.99 to 1.28; p = 0.069, respectively). The change in RAAS biomarkers from baseline to 72 and 96 h was not associated with outcomes (both: p > 0.5).ConclusionsHigh-dose loop diuretic therapy did not result in RAAS activation greater than that with low-dose diuretic therapy. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. (Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure [DOSE-AHF]; NCT00577135; Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome [CARRESS]; NCT00608491).

Project description:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The progression and pharmacological response of heart failure-affected patients are subject to interindividual variability. It is also acknowledged that the genotype frequency of certain gene polymorphisms varies across different ethnic groups and that a difference in gene polymorphism frequencies between healthy and heart failure patients seems to exist. WHAT THIS STUDY ADDS: This study investigated associations between 10 gene polymorphisms of RAAS-related genes with an individual's susceptibility to heart failure. Our data suggest that the angiotensinogen (AGT) 235 single nucleotide polymorphism (SNP) may be associated with heart failure in our population and that the AGT(M174)-AGT(T235) haplotype, as well as the AGT/angiotensin-converting enzyme (ACE) gene combination, may play an important role in disease predisposition. AIMS: Racial differences in survival outcomes point towards a genetic role in the pathophysiology of heart failure. Furthermore, contemporary evidence links genetics to heart failure (HF) predisposition. We tested for a difference in prevalence of 10 renin-angiotensin-aldosterone system (RAAS)-related gene polymorphisms between a homogenous population of HF patients and healthy controls. METHODS: One hundred and eleven healthy volunteers and 58 HF patients were included in this study. The healthy control group consisted of males aged between 18 and 35 years old. The HF group consisted of patients (89.7% male) who were 63.8 +/- 7.9 years old, were in New York Heart Association (NYHA) class II-III and had a documented left ventricular ejection fraction (LVEF) <or= 40% within the previous 6 months. Despite being treated maximally for their condition with angiotensin-converting-enzyme (ACE)-inhibitors and beta-adrenoceptor blockers, they continued to be symptomatic and, as such, were a highly specialized and homogeneous patient population. Both groups were composed of Canadian Caucasians. The analyzed polymorphisms were: ACE (I/D), angiotensin-II-receptor-type-1 (AGTR1)(A1166C), angiotensinogen (AGT)(M235T and T174M), endothelial-nitric-oxide-synthase (eNOS)(T-786C and Glu298Asp), adrenergic-receptor-â2 (ADRB2)(Gln27Glu), bradykinin-receptor-beta2 (BDKRB2)(+9/-9), aldosterone-synthase (CYP11B2)(T-344C) and adducin-1 (ADD1)(Gly460Trp). RESULTS The AGT (T235) allele (P = 0.0025, OR 2.02, 95% CI 1.24, 3.30) was found to be more prevalent in our HF group. The AGT (174M)-AGT (235T) haplotype was also associated with the HF phenotype (P = 0.0069). Exploratory evaluation of gene-gene combinations revealed an indicative association of the AGT (T235)/ACE(D) combined polymorphisms in the HF group (P = 0.02, OR 2.12, 95% CI 1.11, 4.06). CONCLUSIONS: This study demonstrates that the SNPs of AGT may be associated with HF in our population and that the AGT/ACE gene combination may play an important role in disease predisposition.

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The Genetic Variants in the Renin-Angiotensin System and the Risk of Heart Failure in Polish Patients.

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