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Is Angiotensin II a Direct Mediator of Left Ventricular Hypertrophy?: Time for Another Look

Hypertensive cardiac remodeling, characterized by left ventricular hypertrophy (LVH) and increased fibrosis, increases the workload of the heart and is a significant risk factor for cardiovascular morbidity and mortality.1 There is a continuous relationship between left ventricular mass and the likelihood of cardiovascular events, including stroke, heart failure, and coronary artery disease, leading to myocardial infarction (MI).2 Virtually all of the clinical trials have demonstrated that antihypertensive treatment achieves some reversal of LVH,3 and reduction of left ventricular mass during antihypertensive treatment has repeatedly emerged as a goal of paramount importance in reducing risk.4,5 Nevertheless, the interpretation of certain clinical trials has led to the widely held view that inhibition of the renin–angiotensin system (RAS) has favorable effects on cardiac remodeling that go beyond its blood pressure–lowering effects. This view has been supported by the experimental finding that cultured cardiomyocytes hypertrophy in response to exogenously added angiotensin II and has led to the model of the heart as a direct target of the RAS. In the current review, we critically analyze these arguments in light of recent clinical and experimental data with a particular emphasis on genetically modified animals designed to test for the role of a local cardiac RAS in the development of LVH.

Although an extensive discussion of clinical trials that tested the role of the RAS in cardioprotection is beyond the scope of this review (the reader is referred to recent reviews in References 6 and 7), the results of most clinical studies suggest that the absolute reduction in blood pressure is the primary determinant of long-term outcome in patients. The Heart Outcomes Prevention Evaluation (HOPE) Trial8 initially demonstrated that an angiotensin-converting enzyme (ACE) inhibitor given to high-risk patients with vascular disease or diabetes reduced rates of death, MI, and stroke, and …