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Elevated intracardiac angiotensin II leads to cardiac hypertrophy and mechanical dysfunction in normotensive mice

journal contribution
posted on 2003-01-01, 00:00 authored by Catherine Huggins, A Domenighetti, T Pedrazzini, S Pepe, L Delbridge
Introduction
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.

Methods
Normotensive heterozygous TG1306/1R mice harbouring multiple copies of a cardiac-specific rat angiotensinogen gene 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, Langendorffmounted hearts ( at a perfusion pressure of 80 mmHg, 37°C) using a fluid-filled PVC balloon interfaced to a pressure transducer and digital data acquisition system.

Results
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).

Conclusion
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.

History

Journal

Journal of the renin-angiotensin-aldosterone system

Volume

4

Issue

3

Pagination

186 - 190

Publisher

Sage

Location

Thousand Oaks, Calif.

ISSN

1470-3203

eISSN

1752-8976

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal