Clin. Cardiol. 15,711-714 (1992)

ACE Inhibitors and Regression of Left Ventricular Hypertrophy BRIANW. GILBERT, M.D.,F.R.c.P.,


Division of Cardiology, Mount Sinai Hospital, Toronto, Ontario, Canada

Summary: Left ventricular hypertrophy (LVH) is a common condition and a powerful independent risk factor for coronary heart disease, congestive heart failure, and other cardiac morbidity. It is associated with the male sex and advancing age. Its most common cause is hypertension, and many antihypertensive agents induce regression of LVH. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reverse LVH by a mechanism as yet unknown. Reduction in afterload and other hernodynamic abnormalities by reduction of blood pressure is clearly a factor, but ACE inhibitors also block adrenergic action and other sympathetic nervous system influences, and the reduction in angiotensin Il produces many effects. By inhibiting this potent vasoconstrictor and suppressing its degradation of the powerful vasodilator bradykinin, and by promoting sodium and water excretion, ACE inhibitors contribute to the restoration of normal ventricular function. Angiotensin I1 promotes protein synthesis in myocardial myocytes, and blocking this action may arrest the hypertrophic process. To determine the effect of angiotensin I1 on LVH and normalization of LV function, a study is now underway evaluating the effects of lisinopril, a new lysine analog of enalapril, and a diuretic agent in the treatment of hypertension LVH.

Key words: left ventricular hypertrophy, treatment of hypertension and left ventricular hypertrophy, regression of left ventricular hypertrophy

Introduction Left ventricular hypertrophy (LVH) is a common clinical problem with a prevalence far greater than is generally appreciated. Data from the Framingham Study suggest that one in 10 persons in the 65 to 69 year age group will manifest LVH on electrocardiogram (ECG), and that this condition increases with age. The study also found a close association between LVH and arterial blood pressure, with more than half of those with systolic blood pressure of 200 mmHg or greater demonstrating LVH on first examination.' Definite LVH on ECG, defined by the Framingham Study as a tracing showing prolongation of ventricular activation time associated with an increased R wave, depressed S-T segments and flattened to inverted T waves, is one of the potent risk factors for morbid cardiac events.' It is more potent than hypertension, diabetes, cigarette smoking, age, or sex. Even in the absence of coronary heart disease, congestive heart failure, or rheumatic heart disease, LVH results in mortality in 59% of patients within 12 years of its first detection.' Of all 264 cardiovascular deaths in the 14-year follow-up of the Framingham Study, 44% followed a finding of definite or possible LVH on ECG.' Since it has been demonstrated by many studies performed over the last decade that LVH can be reversed and high blood pressure normalized by antihypertensive therapy, it is appropriate to examine these conditions more closely.

Diagnostic Criteria Address for reprints: Brian W. Gilbert, M.D. Head, Division of Cardiology Deputy Physician-in-Chief Mount Sinai Hospital Room 632 600 University Avenue Toronto, Ontario, Canada M5GIX5 Received January 13, 1992 Accepted: February 20,1992

Left ventricular hypertrophy, defined as increased left ventricular mass, was demonstrated originally by radiography, a relatively insensitive and nonspecific modality of limited value. For some time electrocardiography(ECG) has been the most reliable diagnostic tool. There are, however, limitations to ECG detection of LVH. Tracings of precordial leads are sensitive but not very specific, leading to false positive results. On the other hand, limb tracings, such as that of the augmented left arm V lead, are more specific but less sensitive and can result in missed diagnoses. There


Clin. Cardiol. Vol. 15, October 1992

are, in fact, multiple ECG criteria for LVH which can complicate use of this modality. Nevertheless, ECG-detected mass has been shown to be a powerful predictor of cardiac morbidity and mortality. Because ECG lacks specificity and sensitivity, echocardiography (ECHO) has become the diagnostic procedure of choice, since it directly visualizes the septal and posterior walls and the internal radius of the ventricle. There are very good diagnostic criteria for ECHO-determined left ventricular mass, including the Penn and cube function geometry formulae, and the quantitative method described by Devereux and Reichert.* Ventricular mass greater than 130 g per meter squared in men and greater than 110 g per meter squared in women are generally accepted as diagnostic ECHO criteria for LVH.

the prevalence of LVH by ECG; the longer a patient has had hypertension, the greater the likelihood of ECG evidence of LVH. ECHO data over the last 10 years have supported these observations. Savage el al., using very strict ECHO criteria, examined the septum and posterior wall, and after taking into consideration the factors of age, gender, and body surface area, found LVH in up to 60% of patients with mild to moderate hypertension? Devereux et al. compared hypertensive patients with normotensive subjects and found a smaller but still significant proportion of patients with ECHO LVH.3 Almost 50 % of the patients manifested LVH, compared with 3-10 % of their normotensive subjects.

LVH: Adaptive or Pathologic? Multifactorial Nature of LVH Left ventricular hypertrophy is a single, specific end point to which there are many pathways. In some patients with ECHO- or ECG-diagnosed increased LV mass one can detect no clinical disease. Devereux ef a/. reported finding LVH in up to 10% of normal patient^.^ LVH commonly is found in patients with increased preload secondary to aortic insufficiency, mitral regurgitation, or ventricular septal defect. In these conditions the hypertrophy is manifested by an increase in the internal dimension of the ventricle, while the septum and posterior wall remain normal in size. LVH also may be secondary to decreased pump function, as in ischemic heart disease, myocarditis, and infiltrative cardiac diseases. This form of LVH is really a “pseudo” LVH, in that there is increased mass of nonfunctioning ventricular tissue but the functioning contractile elements are not increased. The most common cause of increased left ventricular mass is increased afterload produced by hypertension, aortic stenosis, or, less commonly, coarctation. In this form of LVH one finds concentric ventricular hypertrophy characterized by thickening of the septum and posterior wall, with the internal ventricular dimension unchanged. It is not uncommon for a combination of any of these factors to be present at the same time as underlying elements in LVH. In view of these manifold causative conditions, it should not be surprising that individual therapeutic agents may not produce LVH regression in all cases.

Prevalence Left ventricular hypertrophy, as previously indicated, is a very prevalent disorder and one associated with a high degree of mortality, a finding first reported by the Framingham Study and confirmed by subsequent studies. At any given elevation of blood pressure there is an increase in

The question as to whether LVH is a benign, adaptive, compensatory mechanism secondary to the increased afterload of hypertension or other cardiac stresses, a pathologic phenomenon, or both of these, has been posed by a number of investigators. Messerli and Devereux observe that the myocardium’s fundamental pump nature renders LVH both an adaptive and a pathologic manifestation in hypertensive patients, and that while in some it is well tolerated and “clinically silent,” in others with “a more marked deThis raises the gree” of hypertrophy it may be path~logic.~ additional question of the point at which LVH passes beyond its benign, adaptive stage and becomes pathologic. If one examines the constituents of myocardium and observes the effects of those influences that produce hypertrophy, one finds that these constituents undergo change. When the rat aorta is banded, stressing the heart, the myocytes are later found to have increased significantly in volume and in diameter in response to the increase in afterload. Increased cell volume requires more energy expense for nutrients to enter and wastes to leave the cell. Myocyte mitochondria increase in number, but not as much or as fast as the contractile cell elements, so that in hypertrophied ventricles there is a decreased concentration of mitochondria per myofibril, contributing further to decreased energy utilization. When ventricular mass increases, there is no corresponding increase in the number or length of myocardial capillaries, so that their density in LVH is decreased. This vascular decrease results in a decreased coronary reserve which, when combined with the increased myocardial oxygen needs of the hypertrophied ventricle, results in chronic ischemia, possibly contributing to the morbidity associated with LVH. Factor and others have described the changes in cardiac collagen matrix that accompany myocardial hypertrophy.”8 In patients with LVH there is an increase in collagen mass within the ventricle and increase in myocyte-tocapillary struts, in collagen weaves and in fiber coils, resulting in inefficient contraction due to increased stiffness


B.W. Gilbert: ACE inhibitors and regression of LVH of the ventricle. Other changes also occur in the hypertrophied ventricle, including decreases in the number of betaadrenergic receptors and in ATPase production. All these changes result in a ventricle that is not only large but is also essentially abnormal. If LVH is an adaptation compensating for the increased afterload imposed on the myocardium by hypertension, it is also a maladaptive response leading to a decline in cardiac performance. This is not just a theoretical construct; all the clinical, epidemiologic, and experimental evidence supports the conclusion that both ECG- and ECHO-detected LVH produce an increase in cardiac morbidity and mortality. The Framingham data show very clearly that in men 45 years of age or older with ECG LVH, with all other risk factors held constant, the death rate within 8 years of diagnosis is at least three times that of those in their age-gender groups with normal ECGs.' In comparison with the general population, both men and women with an ECG pattern of definite LVH have an approximately threefold increased risk of developing coronary heart disease, and those with "possible" ECG LVH have about a twofold increased riskg (Table I). ECHO studies have confirmed these findings. In a series of 73 patients with hypertension evaluated by ECHO, 37 demonstrated LVH and 36 had normal posterior wall thickness.IOSix patients with hypertrophy and three with normal wall thickness experienced stroke. Left ventricular hypertrophy has a striking association with cardiac arrhythmias. A number of studies have shown that increased LV mass is associated with an increased frequency of ventricular ectopic beats and of complex ventricular ectopic beats as well as of couplets, triplets, multifocal ventricular premature beats, and nonsustained ventricular tachycardia. Messerli and colleagues monitored 14 normotensive subjects, 10 hypertensive patients without LVH, and 16 hypertensive patients with ECG-confirmed LVH by continuous ambulatory ECG and arterial pressure for 24 h." They reported that patients with LVH had significantly more ventricular (but not atrial) premature contractions than those without LVH or those who were normotensive subjects, and that these were frequent and complex (Table 11). McLenachan et al. investigated the frequency of complex ventricular arrhythmias in 50 hypertensive patients with LVH, 50 hypertensive patients without LVH, and 50 normotensive controls by 48-h ambulatory ECG monitoring.I2They found nonsustained ventricular tachycardia in 28% of the patients with LVH but in only 8% of those without LVH and 2% in the controls. Of the patients with LVH, 16% had episodes longer than five complexes, while none of the non-LVH patients or controls had such episodes. The cause of this association of LVH with a high frequency of ventricular arrhythmias is unknown and may be due to underlying chronic ischemia resulting from the decrease in capillary density in the hypertrophied mass, decreased coronary reserve, and/or increased myocardial oxygen needs. Messerli et al. suggest that one reason may be

TABLEI Factor of increased risk of developing coronary heart disease after first appearance of electrocardiographic left ven-

tricular hypertrophy (ECG-LVH) Time after first

appearance of ECG-LVH (years)

Relative risk" of acquiring coronary heart disease Men


30-44 45-54 55-62 3-44 45-54 55-62

Definite ECG-LVH 2 6 12

3.8 1.2 1.7

3.6 2.4 3.0

5.1 3.7 2.2


9.0 3.8 4.1

1.5 1.6 2.0

2.0 0.9 1.1

2.7 2.1 1.2



5.2 2.1

1.2 2.0


2.7 2.5

Possible ECG-LVH 2 6 12

2.2 1.7 1.3

Relative to population as a whole in the same age-sex cohort coming at risk in the same examination as the first appearance of ECG-LVH. Reproduced with permission from Ref. 9.

TABLE II Prevalence of premature atrial and ventricular contractions (mean f SD)

Hypertensive Without

APCs per 24 h VPCs per 24 h Mean heart rate (beatdmin)



With LVH

1.08 f 1.78 8.17 f 20.1 77 f 3.0

1.0 f 1.5 10.0 f 22.1 75 f 2.6

9.3 f 25 475 f 852" 74 f 3.6

a p

ACE inhibitors and regression of left ventricular hypertrophy.

Left ventricular hypertrophy (LVH) is a common condition and a powerful independent risk factor for coronary heart disease, congestive heart failure, ...
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