Cardiac-restricted ACE overexpression in mice resulted in low-voltage electrical activity, conduction defects, and induced ventricular tachycardia in 83% of mice compared to 0% in wild-type controls.
Does cardiac-restricted ACE overexpression cause electrophysiological abnormalities and connexin dysregulation in mice?
Cardiac-specific ACE overexpression in mice leads to conduction defects, reduced connexin expression, and increased susceptibility to ventricular arrhythmias, providing a potential mechanism for sudden death in states of RAS activation like heart failure.
Absolute Event Rate: 83% vs 0%
Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na(+) channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca(2+) channel, Kv4.2 K(+) channel alpha-subunit, and Cx45 mRNA abundances and the peak ventricular Na(+) current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure.
Kasi et al. (Sat,) conducted a other in Renin-angiotensin system activation and arrhythmia. Cardiac-restricted angiotensin-converting enzyme (ACE) overexpression vs. Wild-type (WT) controls was evaluated on Ventricular tachycardia inducibility with burst pacing. Cardiac-restricted ACE overexpression in mice resulted in low-voltage electrical activity, conduction defects, and induced ventricular tachycardia in 83% of mice compared to 0% in wild-type controls.