Do Antihypertensives Differ In Their Ability To Regress Left Ventricular Hypertrophy?

Cardiac hypertrophy is a morphological adaptive increase in myocardial mass in response to chronic work overload. Although initially protective, the increase in myocardial mass requires an increase in coronary blood flow to maintain function; indeed, ventricular hypertrophy may cause myocardial ischemia even with angiographically normal coronary arteries. Left ventricular hypertrophy significantly increases the risk of myocardial infarction, congestive heart failure, and sudden cardiac death. It is also associated with more frequent arrhythmia and is an important risk factor for cardiac morbidity and mortality.

Clinicians have thus been concerned to identify the best drugs for regressing left ventricular hypertrophy or improving other surrogate markers of hypertensive target organ damage (eg, microproteinuria or endothelial dysfunction).

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In this regard, most studies have been relatively small, with additional limitations, including short duration, lack of comparators, unblinded echocardiogram readings, and absence of gender and ethnic diversity. On the other hand, the larger-scale trials have been confounded by concomitant nondrug therapy, high dropout, or absence of left ventricular hypertrophy b'efore therapy. One rigorous meta-analysis that only included double-blind randomized controlled studies with a parallel-group design (n=39) found more likelihood of regression of left ventricular hypertrophy with greater blood pressure reduction and longer-lasting therapy. Specifically, regression was seen in 13% of patients on angiotensin-converting enzyme (ACE) inhibitors, 9% on calcium channel blockers, 6% on (i-blockers, and 7% on diuretics, suggesting that ACE inhibitors were probably the effective drugs overall in this regard.

However, most antihypertensive drugs will eventually regress left ventricular hypertrophy, given time and sufficient blood pressure control. The meta-analysis by Dahlof et al, which also suggested that ACE inhibitors were the best drugs for regressing left ventricular hypertrophy, reported that diuretics too induced regression, but did so mainly by reducing the internal dimensions of the left ventricle. Even lifestyle changes or nonpharmacological methods reduce left ventricular hypertrophy. But the question arises: what are the prognostic implications of regressing left ventricular hypertrophy?

The recent Heart Outcomes Prevention Evaluation (HOPE) trial in patients with normal or controlled blood pressure showed that electrocardiographic (ECG) left ventricular hypertrophy regressed or was prevented in 91. 1% of patients treated with ramipril vs 90. 2% of those treated with placebo. Importantly, this effect was independent of hypertension or blood pressure reduction. Furthermore, regression/prevention of left ventricular hypertrophy using ramipril improved primary outcomes (cardiovascular death, myocardial infarction, and stroke) and prevented congestive heart failure (Figure 1). This was one of the first trials to provide convincing evidence that regression of left ventricular hypertrophy really does matter, even in normotensive patients. However, although ECG is a useful screening tool, it is relatively nonspecific and insensitive.

There are specific pathophysiological reasons why ACE inhibitors should not only be the best drugs for regressing left ventricular hypertrophy, but also, more generally, excellent drugs in vascular disease:

‚ Most obviously, they influence the renin-angiotensin-aldosterone system. ACE inhibitors presumably block the documented effects of angiotensin and aldosterone on myocardial and vascular remodeling, resulting in an antihypertrophic effect on the myocardium and an antiproliferative effect on smooth muscle.

‚ Despite blood vessels being exposed to high pressures, the complications of hypertension (myocardial infarction and stroke) are paradoxically thrombotic rather than hemorrhagic. The platelet and hemostasis abnormalities present in hypertension, together with endothelial damage/dysfunction, contribute to a prothrombotic or hypercoagulable state. These abnormalities, which are particularly associated with hypertensive target-organ damage, including left ventricular hypertrophy, respond to antihypertensive treatment, including with ACE inhibitors.

‚ Hypertension (and most vascular disease) is associated with endothelial dysfunction, which responds to ACE inhibitors.

Kaplan-Meier estimates of outcomes in patients with regression/prevention vs development/persistence of electrocardiographic left ventricular hypertrophy. A: Primary outcome events (cardiovascular death, myocardial infarction, stroke). B: Primary outcome events (cardiovascular death, myocardial infarction, stroke) plus secondary outcome events (revascularization, hospitalization for unstable angina, hospitalization for congestive heart failure, and complications of diabetes). C: Unexpected (sudden) death or cardiac arrest. D: All congestive heart failure, whether hospitalized or not.

Reproduced from: Mathew J, Sleight P, Lonn E, et al. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation. 2001;104: 1615-1621. Copyright ‚© 2001, American Heart Association.

‚ Recent attention has also been directed to abnormal angiogenesis in hypertension. Blood pressure reduction by an ACE inhibitor or angiotensin II receptor antagonist significantly reduces the elevated levels of vascular endothelial growth factor, an index of angiogenesis.

Other trials are ongoing that almost certainly will provide more information on left ventricular hypertrophy regression. Most are ECG-based, but a few (the smaller studies) are using echocardiography. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial vs atenolol in hypertensive patients with ECG markers of left ventricular hypertrophy should demonstrate the prognostic benefits, if any, of angiotensin II receptor antagonists and/or |3-blockers. Substudies from the megatrials, such as the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) comparing conventional agents (eg, P-blockers and thiazides) vs newer agents (eg, amlodipine and perindopril), should also provide data on the benefits of regressing left ventricular hypertrophy and on the differences, if any, between drug regimens in this regard.

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Keywords.

Drug; left ventricular hypertrophy; antihypertensive drug; LVH reversal; risk factor; left ventricular mass; ACEI; diuretic.

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