Aerobic exercise training differentially affects ACE C- and N-domain activities in humans: Interactions with ACE I/D polymorphism and association with vascular reactivity.

INTRODUCTION: Previous studies have linked angiotensin-converting enzyme ( ACE) insertion (I)/deletion (D) polymorphism (II, ID and DD) to physical performance. Moreover, ACE has two catalytic domains: NH2 (N) and COOH (C) with distinct functions, and their activity has been found to be modulated by ACE polymorphism. The aim of the present study is to investigate the effects of the interaction between aerobic exercise training (AET) and ACE I/D polymorphism on ACE N- and C-domain activities and vascular reactivity in humans. MATERIALS AND METHODS: A total of 315 pre-selected healthy males were genotyped for II, ID and DD genotypes. Fifty completed the full AET (II, n = 12; ID, n = 25; and DD, n = 13), performed in three 90-minute sessions weekly, in the four-month exercise protocol. Pre- and post-training resting heart rate (HR), peak O2 consumption (VO2 peak), mean blood pressure (MBP), forearm vascular conduction (FVC), total circulating ACE and C- and N-domain activities were assessed. One-way ANOVA and two -way repeated-measures ANOVA were used. RESULTS: In pre-training, all variables were similar among the three genotypes. In post-training, a similar increase in FVC (35%) was observed in the three genotypes. AET increased VO2 peak similarly in II, ID and DD (49±2 vs. 57±1; 48±1 vs. 56±3; and 48±5 vs. 58±2 ml/kg/min, respectively). Moreover, there were no changes in HR and MBP. The DD genotype was also associated with greater ACE and C-domain activities at pre- and post-training when compared to II. AET decreased similarly the total ACE and C-domain activities in all genotypes, while increasing the N-domain activity in the II and DD genotypes. However, interestingly, the measurements of N-domain activity after training indicate a greater activity than the other genotypes. These results suggest that the vasodilation in response to AET may be associated with the decrease in total ACE and C-domain activities, regardless of genotype, and that the increase in N-domain activity is dependent on the DD genotype. CONCLUSIONS: AET differentially affects the ACE C- and N-domain activities, and the N-domain activity is dependent on ACE polymorphism.

Genetic polymorphism, medical therapy and sequential cardiac function in patients with heart failure.

BACKGROUND: Functional variants of angiotensin-converting enzyme (ACE) gene may be associated with response to therapy in patients with heart failure (HF). OBJECTIVE: To test the hypothesis of differences in sequential echocardiographic evaluations of left ventricular ejection fraction in patients with HF on medical therapy, including ACE inhibitors in relation to insertion (I) / deletion (D) polymorphism of the ACE gene. METHODS: We studied 168 patients (mean age 43.3+/-10.1 years), 128 (76.2%) men, with HF and sequential echocardiograms. The I/D polymorphism was determined by polymerase chain reaction. Left ventricular ejection fraction (LVEF) was analyzed comparatively to genotypes. More than 90% of patients were on ACE inhibitors. RESULTS: There was a significantly greater increase in mean LVEF in patients with the D allele compared to patients with the II genotype (p=0.01) after a mean follow-up of 38.9 months. The D allele was associated with an increase of 8.8% in mean LVEF over the same period. Furthermore, there was a tendency toward a D allele "copy number" effect on the increase of mean LVEF over time: a 3.5% difference in LVEF variation between patients with the II and the ID genotypes (p = 0.03) and a 5% difference between patients with the II and DD genotypes (p=0.02). CONCLUSION: ACE gene deletion polymorphism may be operative in response to medical treatment that included ACE inhibitors in patients with HF. Further controlled studies may contribute to better understanding of genetic influences on response to therapy.

Polimorfismo genético, terapia farmacológica e função cardíaca seqüencial em pacientes com insuficiência cardíaca / Genetic polymorphism, medical therapy and sequential cardiac function in patients with heart failure

FUNDAMENTO: Variantes funcionais do gene da enzima conversora da angiotensina (ECA) podem estar associados com a resposta à terapia em portadores de insuficiência cardíaca (IC). OBJETIVO: Testar a hipótese de diferenças na avaliação ecocardiográfica seqüencial da fração de ejeção do ventrículo esquerdo de pacientes com IC em tratamento farmacológico, inclusive com inibidores da ECA, em relação ao polimorfismo de inserção (I) e deleção (D) do gene da ECA. MÉTODOS: Estudamos 168 pacientes (média de idade 43,3±10,1 anos), 128 (76,2 por cento) dos quais homens, com IC e ecocardiogramas seqüenciais. O polimorfismo I/D foi determinado por reação em cadeia da polimerase. A fração de ejeção do ventrículo esquerdo (FEVE) foi analisada comparativamente aos genótipos. Mais de 90 por cento dos pacientes estavam tomando inibidores da ECA. RESULTADOS: Houve um aumento significantemente maior na FEVE média em pacientes com o alelo D, em comparação com pacientes com genótipo II (p = 0,01) após um seguimento médio de 38,9 meses. O alelo D foi associado com aumento de 8,8 por cento na FEVE média no mesmo período. Além disso, observou-se uma tendência para um efeito do "número de cópias" do alelo D sobre o aumento da FEVE média com o tempo: uma diferença de 3,5 por cento na variação da FEVE entre os pacientes com genótipos II e ID (p = 0,03) e de 5 por cento entre os pacientes com genótipos II e DD (p = 0,02). CONCLUSÃO: O polimorfismo de deleção do gene da ECA pode estar associado com a resposta ao tratamento farmacológico com inibidores da ECA em portadores de IC. Outros estudos controlados poderão contribuir para uma melhor compreensão das influências genéticas sobre a resposta à terapia.

BACKGROUND: Functional variants of angiotensin-converting enzyme (ACE) gene may be associated with response to therapy in patients with heart failure (HF). OBJECTIVE: To test the hypothesis of differences in sequential echocardiographic evaluations of left ventricular ejection fraction in patients with HF on medical therapy, including ACE inhibitors in relation to insertion (I) / deletion (D) polymorphism of the ACE gene. METHODS: We studied 168 patients (mean age 43.3±10.1 years), 128 (76.2 percent) men, with HF and sequential echocardiograms. The I/D polymorphism was determined by polymerase chain reaction. Left ventricular ejection fraction (LVEF) was analyzed comparatively to genotypes. More than 90 percent of patients were on ACE inhibitors. RESULTS: There was a significantly greater increase in mean LVEF in patients with the D allele compared to patients with the II genotype (p=0.01) after a mean follow-up of 38.9 months. The D allele was associated with an increase of 8.8 percent in mean LVEF over the same period. Furthermore, there was a tendency toward a D allele "copy number" effect on the increase of mean LVEF over time: a 3.5 percent difference in LVEF variation between patients with the II and the ID genotypes (p = 0.03) and a 5 percent difference between patients with the II and DD genotypes (p=0.02). CONCLUSION: ACE gene deletion polymorphism may be operative in response to medical treatment that included ACE inhibitors in patients with HF. Further controlled studies may contribute to better understanding of genetic influences on response to therapy.