Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Abstract

To investigate the local effects of angiotensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the ␣-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death. The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. A critical component of this system is angiotensin-converting enzyme (ACE), which produces the eight amino acid peptide angiotensin II, the effector molecule of the RAS. 1 ACE is a zinc metallopeptidase located on the cell surface of endothelium. In this location, ACE produces angiotensin II adjacent to vascular smooth muscle, a critical target organ for this vasoconstrictor. ACE is also produced by a variety of other tissues including renal tubular epithelium, activated macrophages, proximal gut epithelium, and areas of the brain. Endothelium and these other tissues make the isozyme of ACE, termed somatic ACE, which consists of two catalytic domains that are independently capable of producing angiotensin II. Studies of knockout mice established that somatic ACE influences blood pressure and other cardiovascular functions. 2,3 In contrast, within the testis, developing male germ cells produce a different ACE isozyme called testis ACE, which plays an important role in normal male reproduction. 4 In addition to regulating normal physiology, substantial evidence suggests that the RAS plays an important role in disease, including heart disease. 5 Genetic studies reported a link between somatic ACE polymorphisms and the incidence of cardiac hypertrophy, sudden cardiac death, and acute coronary events. 6 This is consistent with the clinical effectiveness of ACE inhibitors in treating heart failure. 7 The beneficial effects of ACE inhibitors may not be solely the result of blood pressure reduction since other antihypertensive drugs do not produce the same effect. Rather, ACE may directly influence heart function through the local production of angiotensin II. Studies have found that angiotensinogen, renin, and ACE exist in the heart, implying that local generation of angiotensin II

Cardiac corticosteroid receptors mediate the enlargement of the ovine fetal heart induced by chronic increases in maternal cortisol

“…In adult hearts, both the MR and the RAS have been implicated in cardiac fibrosis and hypertrophy after injury (Fraccarollo et al 2003, Xiao et al 2004. We propose that corticosteroid receptors also play a role in cardiac enlargement in the fetal heart, although by mechanisms independent of cardiac injury and fibrosis.…”

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

“…Despite these limitations, there are some genetically modified mouse models that are susceptible to AF. These include gene disruption/mutation of connexin40, KCNE1, or nuclear core component NUP155, [5][6][7] overexpression of RhoA, 8 basic leucine zipper inhibitor protein: JDP2, 9 angiotensin converting enzyme, 10 tumor necrosis factor ␣, 11 Rac1, 12 and MURC. 13 AF often occurs in combination with heart failure, although the factors that precipitate the onset of AF in patients with (or without) pre-existing heart disease remain unclear.…”

The Effect of Renal Sympathetic Denervation (RSD) in Atrial Fibrillation (AF) Inducibility

“…It is well-known that renal sympathetic stimu-lation induces renin release; conversely, Ang II appears to have important actions in modulating sympathetic nerve activity. The RAAS is involved in myocardial fibrosis and increased Ang II production causes marked atrial dilation with focal fibrosis and AF [8] [20]. Under AF, development and persistent sympathetic nerve and RAAS are activated and each condition predisposes to the other.…”