ACE gene titration modulates acute myocardial infarction‐induced autonomic and functional changes in mice

Abstract

Acute myocardial infarction is one of the leading causes of mortality worldwide. The Angiotensin Converting Enzyme (ACE) act in the production of ANG II and in the degradation of bradykinin. It is believed that higher levels of ACE could modulate susceptibility to coronary occlusion. To investigate this possibility we used adult males mice genetically modified to express different concentrations of ACE similar to that found in humans. Animals (1, 2 or three copies; n = 6 each group) were subjected to acute myocardial infarction (AMI) and evaluated after 7 days. Systolic, diastolic and mean blood pressure as well as heart rate, heart rate (HRV) and blood pressure (BPV) variability and cardiac function by echocardiography were evaluated. Regarding hemodynamic data, AMI induced no difference in systolic, diastolic and mean blood pressure (ECA1: 74.02 ± 3.0; ACE2: 108.65 ± 2.8; ECA3: 102.07 ± 4.1mmHg). Regarding heart rate it was observed a reduction in 3 copies group (ECA1: 654.51 ± 26.34; ACE2: 668.22 ± 10; ECA3: 534.11 ± 33.4 BPM). HRV evaluated in the time domain by SDNN (ACE1: 5.16 ± 0.93; ACE2: 5.84 ± 1:32; ACE 3: 7.69 ± 1.4 ms) and RMSSD indexes (ECA1: 5.91 ± 0.69; ACE2: 5.7 ± 1:14; ECA3: 6.78 ± 1.2ms) was higher in the infarcted ACE3 group, as well as the total variance (ACE1: 30 ± 12.4; ACE2: 37 ± 13.8; ACE3: 69.9 ± 25.6 ms). Regarding the spectral analysis a higher sympathetic modulation (ACE1: 5.14 ± 3; ACE2: 7.2 ± 2.8; ACE3: 12.9 ± 4.1ms2) and lower parasympathetic modulation (ACE1: 7 ± 2; ACE2: 8.6 ± 3.2; ACE3: 9.5 ± 2.8 ms2) was observed in ACE 3 infarcted group. BPV (ACE1: 18.7 ± 6.2; ACE2: 14.85 ± 1.6; ACE3: 13.76 ± 4.2 mmHg2) and the Low Frequency (sympathetic) peripheral component of BPV were reduced in the ACE 3 AMI group (ACE1: 60.5 ± 6.2; ACE2: 54.6 ± 1.7; ACE3: 53 ± 3.3 mmHg2). Echocardiographic data showed a reduction in IRT isovolumetric relaxation time (ITR)(ACE1: 26.1 ± 3.1; ACE2: 32.3 ± 3.4; ACE3: 26.5 ± 3.1 ms), increased E/A ratio (ACE1: 3.40 ± 0.67; ACE2: 3:02 ± 1:36; ACE3: 2.0 ± 0.75) and an increase in FAC – Fractional Area Change (ACE1: 27.9 ± 4.5; ACE2: 26.4 ± 5.7; ACE3: 33.5 ± 1.3) in the ACE 3 group after AMI. Our data suggest that increasing the number of ACE gene copies may promote autonomic imbalance evidenced by increased sympathetic modulation of the cardiovascular system, reduction of parasympathetic modulation of HRV and impaired diastolic function.