angiotensinogen and Tachycardia--Ventricular

Rats harboring the human renin and angiotensinogen genes (dTGR) feature angiotensin (ANG) II/hypertension-induced cardiac damage and die suddenly between wk 7 and 8. We observed by electrocardiogram (ECG) telemetry that ventricular tachycardia (VT) is a common terminal event in these animals. Our aim was to investigate electrical remodeling. We used ECG telemetry, noninvasive cardiac magnetic field mapping (CMFM) at wk 5 and 7, and performed in vivo programmed electrical stimulation at wk 7. We also investigated whether or not losartan (Los; 30 mg x kg(-1) x day(-1)) would prevent electrical remodeling. Cardiac hypertrophy and systolic blood pressure progressively increased in dTGR compared with Sprague-Dawley (SD) controls. Already by wk 5, untreated dTGR showed increased perivascular and interstitial fibrosis, connective tissue growth factor expression, and monocyte infiltration compared with SD rats, differences that progressed through time. Left-ventricular mRNA expression of potassium channel subunit Kv4.3 and gap-junction protein connexin 43 were significantly reduced in dTGR compared with Los-treated dTGR and SD. CMFM showed that depolarization and repolarization were prolonged and inhomogeneous. Los ameliorated all disturbances. VT could be induced in 88% of dTGR but only in 33% of Los-treated dTGR and could not be induced in SD. Untreated dTGR show electrical remodeling and probably die from VT. Los treatment reduces myocardial remodeling and predisposition to arrhythmias. ANG II target organ damage induces VT.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Cardiac Pacing, Artificial; Cardiomegaly; Connexin 43; Death, Sudden, Cardiac; Disease Models, Animal; Electrocardiography; Heart Conduction System; Hypertension; Losartan; Male; Myocardium; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Shal Potassium Channels; Tachycardia, Ventricular; Telemetry; Time Factors; Ventricular Remodeling

Angiotensin II (Ang II) is known to induce cardiac growth and modulate myocardial contractility. It has been reported that elevated levels of endogenous Ang II contribute to the development of cardiac hypertrophy in hypertensives. However, the long-term functional effects of cardiac exposure to Ang II in normotensives is unclear. A recently developed transgenic mouse (TG1306/1R), in which cardiac-specific overproduction of Ang II produces primary hypertrophy, provides a new experimental model for investigation of this phenotype. The aim of the present study was to use this model to investigate whether there is a functional deficit in primary hypertrophy that may predispose to cardiac failure and sudden death. We hypothesised that primary cardiac hypertrophy is associated with mechanical dysfunction in the basal state.. Normotensive heterozygous TG1306/1R mice harbouring multiple copies of a cardiac-specific rat angiotensinogen gene1 were studied at age 30-40 weeks and compared with age-matched wild-type littermates. Left ventricular function was measured ex vivo in bicarbonate buffer-perfused, Langendorff- mounted hearts (at a perfusion pressure of 80 mmHg, 37 degrees C) using a fluid-filled PVC balloon interfaced to a pressure transducer and digital data acquisition system.. There was no difference in the mean (+SEM) intrinsic heart rate of TG1306/1R and wild-type control mice (357.4 +/- 11.8 vs. 367.5 +/- 20.9 bpm, n=9 & 7). Under standardised end-diastolic pressure conditions, TG1306/1R hearts exhibited a significant reduction in peak developed pressure (132.2 +/- 9.4 vs. 161.5 +/- 3.1 mmHg, n=9 & 7, p<0.05) and maximum rate of pressure development (3566.7 +/- 323.7 vs. 4486.3 +/- 109.4 mmHg, n=9 & 7, p<0.05). TG1306/1R mice show a significant correlation between incidence of arrhythmia and increasing heart size (Spearman s correlation coefficient 0.61).. These data demonstrate that chronic in vivo exposure to elevated levels of intra-cardiac Ang II is associated with significant contractile abnormalities evident in the ex vivo intact heart. Our findings suggest that endogenous overproduction of cardiac Ang II, independent of changes in blood pressure, is sufficient to induce ventricular remodelling that culminates in impaired cardiac function which may precede failure.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Heart Rate; Mice; Mice, Transgenic; Myocardial Contraction; Myocardium; Rats; Tachycardia, Ventricular; Ventricular Remodeling