(Circulation. 2001;104:1582.)
© 2001 American Heart Association, Inc.
Editorial |
Regression of Left Ventricular Hypertrophy and Improved Prognosis
Some HOPE Now...or Hype?
From the University Department of Medicine, City Hospital, Birmingham, UK.
Correspondence to Professor G.Y.H. Lip, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK. E-mail g.y.h.lip{at}bham.ac.uk
Key Words: Editorials • prognosis • hypertrophy • trials • hypertension
It has been well recognized that the presence of left ventricular hypertrophy (LVH) is an adverse feature in hypertension, with such patients having a substantially higher risk of cardiovascular events, including mortality and morbidity from heart failure, atrial fibrillation, and sudden death.1 Indeed, LVH is probably the most visible manifestation of hypertensive target organ damage.
See p 1615
For many years, clinicians have been interested in finding the best drugs to regress LVH or improve other surrogate markers of hypertensive target organ damage (such as microproteinuria or endothelial dysfunction), without knowing whether or not such actions actually did any good in the long term. Furthermore, the scientific community has long been provided with data from LVH regression studies that have generally been suboptimal in design, with small numbers of subjects, unrepresentative populations, short study duration, lack of comparison between agents, unblinded echocardiographic readings, and inappropriate statistical methods.2 Using the criteria proposed by Devereaux and Dahlof,2 future studies that avoid the above limitations should be related to the question(s) that need to be answered. These could be categorized as follows: (1) relatively small studies (n=40 to 60) to investigate pathophysiology in detail or explore the effects of new agents; (2) medium-sized ones (n=300 to 400; duration 
1 year) to determine definitively whether interagent differences in the reduction of left ventricular mass exist; and (3) large, long-term trials (n>1200; duration 4 years) to determine whether LVH reversal improves prognosis, over and above blood pressure reduction and the type of treatment used.
One "strict" meta-analysis, including only double-blind, randomized, controlled clinical studies with parallel-group design (39 trials) found that more LVH regression occurred with greater blood pressure reduction and a longer duration of therapy.3 Specifically, LVH regression occurred in 13% of patients treated with the ACE inhibitors, 9% treated with calcium channel blockers, 6% treated with ß-blockers, and 7% treated with diuretics,3 suggesting that overall, the ACE inhibitors were probably the best drugs for LVH regression.
The cynic would argue that because LVH is "bad," regression to normal left ventricular mass is "good." However, most antihypertensive drugs will eventually regress LVH, given time and good enough blood pressure control.3 The meta-analysis by Dahlof et al,4 which also suggests that the ACE inhibitors are the best drugs for LVH regression, reported that diuretics did cause LVH regression but that this was mainly by a reduction in left ventricular internal dimensions. Even lifestyle changes or nonpharmacological methods reduce LVH.5,6 The question then arises regarding whether LVH regression does really matter and, if so, why and how.
In the current issue of Circulation, the LVH regression substudy from the Heart Outcomes Prevention Evaluation (HOPE) trial, 7 which studied a broad range of patients with normal or controlled blood pressure, convincingly shows that ECG-LVH was prevented/regressed in 91.9% patients treated with ramipril compared with 90.2% of those treated with placebo. Importantly, this effect was independent of hypertension or blood pressure reduction. Furthermore, LVH prevention/regression using ramipril resulted in a reduction of the primary outcomes (cardiovascular death, myocardial infarction, or stroke) and the prevention of congestive heart failure.7 This study represents one of the first trials that convincingly shows that LVH regression really does matter, even in patients without hypertension. Unfortunately, the study depends on ECG criteria of LVH, and it is certainly recognized that although the ECG is a useful screening tool for LVH, it has a relatively low specificity and sensitivity.1 The logistics of undertaking echocardiography, which still remains the gold standard for diagnosing LVH, in the 9541 patients in a large, multicenter international study such as HOPE7 would, of course, be difficult.
If all drugs (eventually) regress LVH, is it possible that intrinsic properties of particular antihypertensive agents provide the beneficial effect(s)? The ACE inhibitors seem to be a "pill for every ill"; their use is well-established for the treatment of hypertension, heart failure, left ventricular systolic dysfunction, and perhaps for all patients with myocardial infarction, diabetic nephropathy, diabetic retinopathy, and possibly even diabetic neuropathy.8 Recent data from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) also point toward the beneficial effects of the ACE inhibitor, perindopril, in patients after stroke. However, the possibility arises that ACE inhibitors may be the best drugs for regressing LVH and result in corresponding improvements in prognosis through their benefits in concomitant comorbidity, including underlying left ventricular dysfunction, diabetes, renal dysfunction, cerebrovascular disease, etc.7
Perhaps insights into pathophysiology may help us understand why the ACE inhibitors provide therapeutic hope to the many patients with cardiovascular disease. Clearly the most obvious system influenced by the ACE inhibitors is the renin-angiotensin-aldosterone system, and because angiotensin and aldosterone have effects on myocardial and vascular remodelling, the beneficial effect(s) of these drugs may come through the blockade of these neurohormones, resulting in an antihypertrophic effect on the myocardium and an antiproliferative effect on smooth muscles.8 Furthermore, despite blood vessels being exposed to high pressures, the complications of hypertension (that is, myocardial infarction and stroke) are paradoxically thrombotic rather than hemorrhagic; this is now referred to as the "thrombotic paradox" of hypertension or the "Birmingham paradox."8,9 Indeed, abnormalities of hemostasis, platelets, and endothelial damage/dysfunction are present in hypertension, contributing to a prothrombotic or hypercoagulable state.9 These abnormalities have also particularly been associated with hypertensive target organ damage, including LVH,10,11 and furthermore, they can be beneficially improved with antihypertensive treatment, including ACE inhibitors.12 Indeed, satisfactory blood pressure lowering by different nonpharmacological and pharmacological means does not necessarily translate into an equal reduction in cardiovascular outcomes, which may be due in part to unfavorable effects on the prothrombotic state in hypertension (and vascular disease, in general), and drugs with particular effects in improving the prothrombotic state in vascular disease may have an additional advantages in reducing the occurrence of stroke and other thromboembolic events.
Furthermore, hypertension (and most vascular disease) is associated with endothelial dysfunction, and the ACE inhibitors improve endothelial function.1,8 There is also some evidence that the ACE inhibitors may also improve insulin resistance; indeed, in one trial, this property was associated with LVH regression.13 Recent attention has also been directed to abnormal angiogenesis in hypertension, 14,15 and blood pressure reduction by an ACE inhibitor or angiotensin II receptor antagonist significantly reduced the elevated levels of vascular endothelial growth factor, an index of angiogenesis.15 Thus, a multitude of pathophysiological benefits indicate why the ACE inhibitors may be good in hypertensives, especially if LVH is present, and more generally, in vascular disease.
Nevertheless, unanswered questions remain. For example, the Afro-Caribbean ethnic group are at particular risk of developing LVH, and it remains uncertain whether LVH regression in this group (or other nonwhite ethnic groups, for that matter) would translate into a prognostic benefit. Ethnic differences in cardiovascular disease are increasingly important considerations, and (in the United Kingdom, at least) blacks are at high risk of hypertension and hypertension-related complications such as stroke and renal damage, whereas south Asians (from the Indian subcontinent) are at a high risk of coronary artery disease.16 Indeed, the recent analysis from the Studies of Left Ventricular Dysfunction (SOLVD) investigators suggests that black patients with left ventricular dysfunction do not respond well to ACE inhibitors, especially if they have a past history of hypertension.17 Limited data on LVH regression and other hypertensive target organ damage are available in south Asians per se, although it is perceived that they respond to antihypertensive drugs similarly to whites.8
Second, does the "strain pattern" on the ECG matter? In the study by Mathew et al,7 202 of the 676 participants had ECG-LVH and strain, but we do not have information on this important subgroup of patients. Another interesting observation is that there was prevention/regression of ECG-LVH in 90.2% of the patients who were taking placebo. This again raises the recurrent question of how "typical" is the population entered into trials, where motivated patients and research staff with regular, careful follow-up get a good package of care that includes education, advice on nonpharmacological measures to reduce cardiovascular risk, etc. Thus, a placebo-control group may not be truly "untreated" and, as previously mentioned, lifestyle modification may itself result in LVH regression, at least in mild hypertensives.6
Finally, are the benefits of LVH regression on prognosis exclusive to the ACE inhibitors? Despite the theoretical pathophysiological advantages highlighted above (hype?) for the ACE inhibitors, the answer is "possibly not," especially because most agents regress LVH and even the recent outcome trials with the newer agents (calcium antagonists and ACE inhibitors) have suggested that the clinical end points are probably reduced to the degree that would be expected.8 Some disappointments are nevertheless likely, as seen with the recent report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) that the 
-blocker doxazosin actually increased cardiovascular events by 25%, with the most events related to heart failure, when compared with chlorthalidone.18 It should be remembered that 50% of hypertensives require 2 drugs and nearly a third require 3 drugs to control blood pressure. It would thus be difficult be fully confident that the benefits are exclusive to a single agent (or drug class).
Other trials are ongoing that almost certainly would provide more information on LVH regression, mostly by ECG and occasionally (on smaller numbers) by echocardiography. For example, the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial comparing losartan with atenolol in hypertensive patients with ECG-LVH would demonstrate the prognostic benefits, if any, of angiotensin II receptor antagonists and/or ß-blockers.19 Substudies of large megatrials, such as the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which compares "conventional" agents (eg, ß-blockers and thiazides) with "new" agents (eg, amlodipine and perindopril),20 should also address the benefits of LVH regression and the differences, if any, between different drug regimes.
For now, the 12-lead ECG must be part of the routine evaluation of patients with vascular disease in general (and hypertensives, in particular), because it is a simple, cost-effective screening test, at least for LVH. Beyond the hype, LVH regression does bring some hope...in terms of improved prognosis.
Acknowledgments
Dr Lip has received funding for research, educational symposia, and lecturing from different manufacturers of antihypertensive drugs and is a local coprincipal investigator for the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Lip GYH, Felmeden DC, Li-Saw-Hee FL, et al. Hypertensive heart disease: a complex syndrome or a hypertensive ‘cardiomyopathy’? Eur Heart J. . 2000; 21: 1653–1665.
2. Devereux RB, Dahlof B. Criteria for an informative trial of left ventricular hypertrophy regression. J Hum Hypertens. . 1994; 8: 735–739.[Medline] [Order article via Infotrieve]
3.
Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension: a meta-analysis of randomized double-blind studies. JAMA. . 1996; 275: 1507–1513.
4. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients: a metaanalysis of 109 treatment studies. Am J Hypertens. . 1992; 5: 95–110.[Medline] [Order article via Infotrieve]
5.
Liebson PR, Grandits GA, Dianzumba S, et al. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation. . 1995; 91: 698–706.
6. MacMahon SW, Wilcken DE, Macdonald GJ The effect of weight reduction on left ventricular mass: a randomized controlled trial in young, overweight hypertensive patients. N Engl J Med. . 1986; 314: 334–339.[Abstract]
7.
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.
8. Beevers G, Lip GYH, O’Brien E. ABC of Hypertension. 4th ed. London: BMJ Books; 2001.
9. Lip GYH. Hypertension and the prothrombotic state. J Hum Hypertens. . 2000; 14: 687–690.[Medline] [Order article via Infotrieve]
10. Lip GYH, Blann AD, Jones AF, et al. Relation of endothelium, thrombogenesis, and hemorheology in systemic hypertension to ethnicity and left ventricular hypertrophy. Am J Cardiol. . 1997; 80: 1566–1571.[Medline] [Order article via Infotrieve]
11.
Sechi LA, Zingaro L, Catena C, et al. Relationship of fibrinogen levels and hemostatic abnormalities with organ damage in hypertension. Hypertension. . 2000; 36: 978–985.
12. Lee AJ. The role of rheological and haemostatic factors in hypertension. J Hum Hypertens. . 1997; 11: 767–776.[Medline] [Order article via Infotrieve]
13.
Kuperstein R, Sasson Z. Effects of antihypertensive therapy on glucose and insulin metabolism and on left ventricular mass: a randomized, double-blind, controlled study of 21 obese hypertensives. Circulation. . 2000; 102: 1802–1806.
14. le Noble FA, Stassen FR, Hacking WJ, et al. Angiogenesis and hypertension. J Hypertens. . 1998; 16: 1563–1572.[Medline] [Order article via Infotrieve]
15. Belgore FM, Blann AD, Li-Saw-Hee FL, et al. Plasma levels of vascular endothelial growth factor and its soluble receptor (SFlt-1) in essential hypertension. Am J Cardiol. . 2001; 87: 805–807.[Medline] [Order article via Infotrieve]
16. Cruickshank JK, Beevers DG, Osbourne VL, et al. Heart attack, stroke, diabetes, and hypertension in West Indians, Asians, and whites in Birmingham, England. BMJ. . 1980; 281: 1108.
17.
Exner DV, Dries DL, Domanski MJ, et al. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med. . 2001; 344: 1351–1357.
18.
ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA. . 2000; 283: 1967–1975.
19.
Dahlof B, Devereux RB, Julius S, et al. Characteristics of 9194 patients with left ventricular hypertrophy: the LIFE study: Losartan Intervention For Endpoint Reduction in Hypertension. Hypertension. . 1998; 32: 989–997.
20. Sever PS, Dahlof B, Poulter NR, et al. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial: ASCOT investigators. J Hypertens. . 2001; 19: 1139–1147.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  O. H. Cingolani, X.-P. Yang, Y.-H. Liu, M. Villanueva, N.-E. Rhaleb, and O. A. Carretero Reduction of Cardiac Fibrosis Decreases Systolic Performance Without Affecting Diastolic Function in Hypertensive Rats Hypertension, May 1, 2004; 43(5): 1067 - 1073. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Swan, J. Mathew, P. Sleight, E. Lonn, D. Johnstone, J. Pogue, Q. Yi, J. Bosch, B. Sussex, J. Probstfield, et al. A Pill for Every Ill * Response Circulation, April 9, 2002; 105 (14): e82 - e82. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||