Demonstrating the pharmacogenetic effects of angiotensin-converting enzyme inhibitors on long-term prognosis of diastolic heart failure

Abstract

The objective of this study was to evaluate the effects of angiotensin-converting enzyme (ACE) inhibitors and pharmacogenetic interaction on the survival of the patients with diastolic heart failure (DHF). A total of 285 subjects with DHF confirmed by echocardiography were recruited in the period between 1995 and 2003. Baseline characteristics (age, sex, prior history, medication, and echocardiographic findings) and genetic polymorphisms (ACE gene insertion/ deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen (AGT) gene; and A1166C polymorphisms of the angiotensin II type I receptor (AT1R)) were collected and matched (by propensity score) in those who received and those who did not receive ACE inhibitors. The patients were followed up to 10 years. Kaplan-Meier curves and Cox regression models were used to demonstrate the survival trend. The 85 patients who received ACE inhibitors and the other 85 patients who did not were found to have comparable baseline characteristics and polymorphism distribution. Prescription of ACE inhibitors was associated with a significant decrease in overall mortality (hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.24-0.83; P ¼ 0.01), and a lower rate of cardiovascular events at 4000 days (HR, 0.53; 95% CI, 0.32-0.90; P ¼ 0.02). In addition, ACE I/D gene D allele was associated with higher overall mortality as compared with the I allele (HR, 2.04; P ¼ 0.003). This effect was diminished in those who received ACE inhibitors. The use of ACE inhibitor was associated with a significant decrease in long-term mortality and cardiovascular events in the patients with DHF. Genetic variants in the renin-angiotensin system genes were also associated, but their effects could be modified by the use of ACE inhibitors.

Genetic variation-optimized treatment benefit of angiotensin-converting enzyme inhibitors in patients with stable coronary artery disease

“…Although ACE inhibitors work on multiple pathways in the RAAS, single SNP analysis may generate less useful data and fail to clarify the clinical significance of RAAS gene variation for the use of ACE inhibitors. The genetic influence of RAS gene polymorphisms on cardiovascular disease, especially on the susceptibility and progression of CAD or heart failure, has been studied widely [17,30]. Recently, the PERindopril GENEtic (PERGENE) study examined the genetic determinants of the treatment benefits of ACE inhibitor therapy and concluded that genetic variants modifying the treatment effect of perindopril were particularly located in the AGT1R and bradykinin 1 receptor genes [30].…”

“…An insertion/ deletion (I/D) polymorphism in the ACE gene on chromosome 17 has been found to be a major determinant of the ACE serum level, which may influence the extent of vasoconstriction [11]. This polymorphism on chromosome 17 also predicts the clinical outcome in cardiovascular disease, including CAD, myocardial infarction, left ventricular hypertrophy, atrial fibrillation, diastolic heart failure, and hypertension [12][13][14][15][16][17]. It is unclear whether this genetic variation modifies the clinical efficacy of ACE inhibitors.…”

Up-to-date clinical approaches of biomarkers’ use in heart failure

“…Indeed, it is well known that angiotensin-converting enzyme (ACE) I/D gene D allele was associated with higher overall mortality as compared with the I allele in HF patients and that the effect could be modified by ACE inhibitors' given (Kolder et al, 2012). Additionally, ACE DD and angiotensin-1-receptor 1166 CC genotypes may synergistically increase the predisposition to HFpEF (Wu et al, 2010).…”

Genetic Predictive Scores in Heart Failure: Possibilities and Expectations

“…Indeed, some early studies have reported interested results with respect to genetic precursors of HFpEF and HFrEF [16][17][18][19][20][21][22]. As biomarkers particularly used to scrutiny single nucleotide polymorphisms (SNPs) of genes encoding enzymes related to oxidative stress [16], genotype of guanine nucleotide-binding proteins (G-proteins) β-3 subunit (GNB3) [17], transcription factor Islet-1 gene [18], troponin T [19], CYP2D6 polymorphism [20], cardiac myosin binding protein-C mutations [19], renin-angiotensin-aldosterone system polymorphism [21] etc.…”

“…As biomarkers particularly used to scrutiny single nucleotide polymorphisms (SNPs) of genes encoding enzymes related to oxidative stress [16], genotype of guanine nucleotide-binding proteins (G-proteins) β-3 subunit (GNB3) [17], transcription factor Islet-1 gene [18], troponin T [19], CYP2D6 polymorphism [20], cardiac myosin binding protein-C mutations [19], renin-angiotensin-aldosterone system polymorphism [21] etc. Indeed, it is well known that angiotensin-converting enzyme (ACE) I/D gene D allele was associated with higher overall mortality as compared with the I allele in HF patients and that the effect could be modified by ACE inhibitors' given [22]. Additionally, ACE DD and angiotensin-1-receptor 1166 CC genotypes may synergistically increase the predisposition to HFpEF [23].…”