doi: 10.1161/01.CIR.0000018901.71457.10
(Circulation. 2002;105:e194.)
© 2002 American Heart Association, Inc.
Correspondence |
Ramipril and Cardiovascular Risk Reduction
Department of Medicine/Cardiology, Box 100277, University of Florida, Gainesville, FL 32610, nichoww@medicine.ufl.edu
University of New South Wales, Sydney, Australia
To the Editor:
Mathew el al1 reported that in the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril causes regression of electrocardiographic (ECG) left ventricular hypertrophy (LVH) independent of blood pressure reduction, with changes associated with reduced risk of death, myocardial infarction, stroke, and congestive heart failure. This conclusion is based on the false assumptions that blood pressure is the same in the brachial artery and central aorta and that neither changes with vasodilator medication. This same mistake was made in the original HOPE study and other clinical trials that investigated the cardiovascular effects of ramipril.2 Apparently our earlier letter to the editor in The New England Journal of Medicine3 in response to the HOPE study was totally disregarded by Mathew et al.1
We do not question the beneficial affects of ramipril, but we do question the mechanism of LVH regression. It cannot be concluded from measurements of sphygmomanometric cuff brachial artery blood pressure that LVH regression is independent of aortic or left ventricular systolic blood pressure reduction. ACE inhibitors have been shown to reduce arterial wave reflection, and so to reduce central aortic pressure and left ventricular afterload to a far greater degree than would be apparent from measurements of pressure in a peripheral artery.4 Similar effects have been demonstrated at cardiac catheterization with drugs that reduce wave reflection, such as nitroglycerin and nitroprusside, and noninvasively, using applanation tonometry, with nitrates, ACE inhibitors, calcium antagonists, and a vasodilating ß blocker.5
The cuff sphygmomanometer is an important instrument, but cannot be relied on exclusively for interpretation of hemodynamic benefit in trials such HOPE. We contend that regression of ECG-LVH is explicable on the basis of reduction in wave reflection amplitude and central aortic systolic pressure, and we urge that this possibility be explored in addition to the other mechanisms proposed by the HOPE investigators.
References
1.
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.
2.
Lievre M, Gueret P, Gayet C, et al. Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. HYCAR Study Group. Hypertension. 1995; 25: 92–97.
3.
O’Rourke MF, Nichols WW. Effect of ramipril on cardiovascular events in high-risk patients. N Engl J Med. 2000; 343: 64–65.
4.
Mitchell OF, Pfeffer MA, Finn PV, et al. Equipotent antihypertensive agents variously affect pulsatile hemodynamics and regression of cardiac hypertrophy in spontaneously hypertensive rats. Circulation. 1996; 94: 2923–2929.
5. Nichols WW, O’Rourke W. McDonald’s Blood Flow in Arteries. 4th ed. London: Arnold 1998.
Response
University of Iowa College of Medicine, Iowa City, Iowa, manthi@galesburg.net
John Radcliffe Hospital, Oxford, United Kingdom
McMaster University, Hamilton, Canada
Dalhouse University, Halifax, Nova Scotia, Canada
Memorial University of Newfoundland, St John’s, Newfoundland, Canada
Washington University, Seattle, Wash
According to Nichols and colleagues, the conclusion in our study1 that ramipril causes regression of electrocardiographic markers of left ventricular hypertrophy (LVH) independent of blood pressure reduction is based on the false assumptions that blood pressure is the same in the brachial artery and in the central aorta and that neither changes with vasodilator medication. We did not make these assumptions, nor did we make such statements. It is common knowledge that central and peripheral blood pressures are different in amplitude and waveform and that they differ as a function of distance from the heart.2 It is also common knowledge that both central and peripheral blood pressures change with vasodilator treatment. However, what is relevant is that hypertension in humans is diagnosed by cuff pressure in the arm, and major epidemiological studies and randomized trials in hypertension use this method to measure blood pressure.
Nichols and colleagues also ask if changes in blood pressure and waveform by ramipril in the central aorta could have contributed to LVH regression. The answer is yes; several hemodynamic mechanisms, including the favorable effect of ramipril on vessel wall compliance and wave reflection, might have contributed to afterload reduction and LVH regression. It is also probable that ACE inhibitors cause LVH regression through neurohormonal mechanisms independent of their hemodynamic properties. Angiotensin II promotes the growth of myocytes independent of loading conditions,3 and ACE inhibitors block the hypertrophic effect of angiotensin II without affecting blood pressure.4 In the Heart Outcomes Prevention Evaluation (HOPE) study, the beneficial effect of ramipril on LVH was seen in patients with or without hypertension by history and across various blood pressure levels; the change in blood pressure by ramipril during the study was small (3.3 mm Hg systolic and 1.4 mm Hg diastolic), and LVH regression was independent of blood pressure change. Additionally, vasodilators in general reduce blood pressure, improve arterial compliance, and diminish wave reflection.5 Yet, direct-acting vasodilators may not be effective in causing LVH regression6 or in reducing clinical events in patients with normal blood pressure, which thus reinforces the view that ACE inhibitors might cause LVH regression and reduction in clinical events by mechanisms beyond blood pressure reduction.
References
1. 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.
2.
Murgo JP, Westerhof N, Giolma JP, et al. Aortic input impedance in normal man: relationship to pressure wave forms. Circulation. 1980; 62: 105–116.
3.
Aceto JF, Baker KM. [Sar1]angiotensin II receptor-mediated stimulation of protein synthesis in chick heart cells. Am J Physiol. 1990; 258: H806–H813.
4. Linz W, Schaper J, Weimer G, et al. Ramipril prevents left ventricular hypertrophy with myocardial fibrosis without blood pressure reduction: a one- year study in rats. Br J Pharmacol. 1992; 107: 970–975.[Medline] [Order article via Infotrieve]
5.
Laskey WK, Kussmaul WG. Arterial wave reflection in heart failure. Circulation. 1987; 75: 711–722.
6. Sen S, Tarazi RC, Bumpus FM. Cardiac hypertrophy and antihypertensive therapy. Cardiovasc Res. 1977; 11: 427–433.[Medline] [Order article via Infotrieve]
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