From the Department of Medicine, State University of New York, Stony Brook
Left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular morbidity and mortality independent of other known risk factors, including hypertension. Only left ventricular mass and age have been shown to be independent factors of cardiovascular death, all-cause death, and cardiovascular events.1,2 Hypertension is the strongest independent risk factor for LVH. Other important determinants of LVH are age, obesity, and race.3 LVH is associated with an increased risk of coronary heart disease, angina, myocardial infarction (MI), stroke, congestive heart failure, and sudden death.2,3
The prevalence of LVH varies, depending on the patient population and the diagnostic method and criteria used. Electrocardiography (ECG) has poor sensitivity and specificity for diagnosing LVH; LVH shown on ECG, however, predicts significant cardiovascular mortality and all-cause death. In the elderly, ECG-LVH portends increased risk of stroke mortality. Overall, 45% of cardiovascular disease deaths observed in the Framingham Heart Study were preceded by ECG-LVH.3 The appearance of ECG-LVH should be regarded as cardiovascular end-organ damage from hypertension. The prevalence of ECG-LVH in hypertensive patients varies from 1% to 8%, depending on the severity of hypertension.4 Echocardiography (echo) is
the diagnostic procedure of choice for LVH. The widely used threshold is 134 g/m2 for men and 110 g/m2 for women.5 In the general population, the prevalence of echo-LVH has been reported to be 16% in men and 19% in women3 and ranges from 22% to 62% among patients with hypertension.5,6
Studies suggest that regression of LVH is associated with improved prognosis in hypertensive patients.5,7-9 Verdecchia and colleagues reported in a recent meta-analysis that the regression of LVH with antihypertensive treatment was associated with a 59% reduced risk of subsequent cardiovascular disease compared with the persistence or new development of LVH.7 Thus, prevention or reversal of LVH has emerged as a desirable treatment goal.
Pathogenesis of LVH
LVH is an adaptive response to hemodynamic and neurohormonal stresses. Hemodynamic stress, both afterload and preload, is important to the development of LVH; however, several nonhemodynamic factors, including the renin angiotensin system, sympathetic nervous system, and genetic factors, also contribute to the hypertrophic response.10,11 Among these, renin angiotension system ac-tivation via angiotensin II plays a crucial role. Angiotensin II mediates its effects through the angiotensin II type 1 (AT1) receptor, causing vasoconstriction, an increase in sympathetic outflow, and myocardial cell and vascular smooth muscle cell hypertrophy.10-12 The angiotensin II type 2 (AT2) receptor appears to down-modulate actions mediated by the AT1 receptor.11
Experimental evidence suggests that the local production of angiotensin II in the myocardium through a number of different pathways may be important in promoting cardiovascular restructuring and remodeling via an autocrine or paracrine effect.11,13 Angiotensin II stimulates growth, inhibits apoptosis, and causes smooth muscle cell growth and migration, oxidative stress, and endothelial dysfunction,11 thus increasing atherosclerotic risk.
When left ventricular mass increases, there is no corresponding increase in the number or length
of myocardial capillaries; therefore, their density in LVH is decreased.
As a result, hypertrophied myocardium may be more susceptible to ischemic events,2 and this might be a contributing factor to the increased morbidity and mortality associated with LVH.
Angiotensin-converting enzyme inhibitors and LVH
Angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to angiotensin II, inhibiting the action of angiotensin II at the AT1 and AT2 receptors while blocking the degradation of bradykinin. Data from
animal models showed that ACE
inhibitors improved cardiac function and metabolism (decreasing lactate dehydrogenase, creatine kinase, and lactate, and increasing myocardial tissue levels of glycogen, adenosine triphosphate, and creatine phosphate), even at a low dose that did not affect the hypertension or LVH.10,12 These observed effects seemed to be mediated by ACE
inhibitor-induced potentiation of bradykinin because the changes could be prevented by bradykinin B2 receptor blockade.12
Numerous clinical trials and experimental studies have determined the effects of ACE inhibitors on left ventricular mass and compared ACE inhibitors with other antihypertensive agents. In a recent meta-analysis, Klingbeil and colleagues evaluated the efficacy of different antihypertensive agents to reverse LVH in hypertensive patients.14 They analyzed 80 double-blind, randomized trials that included 3,767 patients in 146 active treatment arms and 346 patients in 17 placebo arms. Angiotensin receptor blocking agents (ARBs), calcium channel blocking agents, and ACE inhibitors reduced left ventricular mass index (left ventricular mass/body surface area) by 10% to 13%, whereas the reduction with beta blocking agents and diuretics was 6% to 8%. Their analysis suggests that the blockade of the renin angiotension system reduced left ventricular mass beyond the effects of blood pressure reduction.14
Several other meta-analyses concluded that ACE inhibitors were more potent than diuretics and beta blocking agents for the reduction of left ventricular mass,15-17 and calcium antagonists were nearly equal to ACE inhibitors in potency.15,16 Trials with various ACE inhibitors have shown greater reductions in left ventricular mass index compared with beta blocking agents, diuretics, and calcium antagonists.8,18-20 Regression of myocardial fibrosis, with accompanying improvement in diastolic dysfunction, has also been shown with ACE inhibitors,21 as well as reversal of hypertension-related changes in vascular structure and improvement in vascular compliance.19
In a study by Mathew and colleagues, ramipril caused regression of ECG-LVH independent of blood pressure reduction. This reduction in left ventricular mass was associated with decreased risk of death, MI, stroke, and chronic heart failure.8 Clinical studies suggest that treatment with antihypertensive agents should be of long enough duration to appreciate the maximum effect of left ventricular mass regression.9,20,22 In a study by Oren and colleagues, LVH regression was not associated with deterioration in left ventricular systolic performance, and improvement in diastolic dysfunction was observed only in patients who had a reduction in left ventricular mass.18
ARBs and LVH
Although clinical trials have shown that ACE inhibitors are effective in the reduction of LVH, this therapy has limitations. Alternative pathways in converting angiotensin I to angiotensin II (ie, chymase), bradykinin accumulation with possible side effects of cough and angioedema, and ACE inhibitors reduce the activity of both receptor types (AT1 and AT2) by inhibiting angiotensin II formation.4,11
ARBs selectively block AT1 receptors and therefore directly prevent the binding of angiotensin II to the AT1 receptor (regardless of angiotensin II origin). However, ARBs do not inhibit the binding of angiotensin II to the AT2 receptor; thus, the AT2 receptor is stimulated through excessive angiotensin II.10,11 ARBs, therefore, may have a greater effect on LVH regression compared with ACE inhibitors because of the more complete inhibition of the proliferative effects mediated via the AT1 receptor and the stimulation of the AT2 receptor through increased concentration of angiotensin II.4,10 ARBs increase the level of angiotensin II through a negative feedback mechanism (whereas ACE inhibitors decrease the angiotensin II level) and lack the bradykinin-potentiating capability of ACE inhibitors.
Numerous trials with ARBs have suggested that the drugs are effective in LVH regression. In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial, which compared losartan with atenolol for the treatment of hypertensive patients with ECG-LVH, losartan produced significant reductions in left ventricular mass compared with atenolol and improved left ventricular systolic function.9
Losartan induced reductions in myocardial fibrosis, with an associated decrease in myocardial stiffness.23 Results from the LIFE trial showed that losartan prevented more cardiovascular morbidity and mortality than atenolol, with a similar reduction in blood pressure, and was better tolerated.9
Trials with other ARBs have shown significant LVH regression and improved left ventricular ge-
ometry, vascular structure, and en-
dothelial function.6,10,22,24 Dandona and colleagues showed that val-
sartan inhibited reactive oxygen species generation, reduced oxidative stress, and suppressed plasma C-reactive protein concentrations.25 These actions were consistent with anti-inflammatory and potential
antiatherogenic effects, and the anti-inflammatory response with valsartan was much faster compared with ACE inhibitors and HMG—CoA reductase inhibitors (statins).
Studies comparing ACE inhibitors and ARBs suggest that both agents are equally effective in reducing blood pressure and left ventricular mass.12,26-28 ARBs were consistently associated with fewer adverse effects and greater compliance.27 The combination of ACE inhibitors and ARBs appeared to be more effective in preventing left ventricular dilation and suppressing neurohormonal activation than either drug alone.12 Animal studies showed greater improvement of coronary flow and systemic hemodynamics with combination therapy with ACE inhibitors and ARBs compared with a single agent alone4,29 and improved cardiac function and metabolism.12
LVH is associated with increased cardiovascular morbidity and mortality, independent of hypertension. Blood pressure is the strongest risk factor for LVH. Several studies have suggested improved outcome with LVH regression. Clinical and experimental evidence has indicated the effectiveness of ACE inhibitors and ARBs in LVH regression. Trials have shown that combination therapy with ACE inhibitors and ARBs is more effective than either agent alone. Further clinical research is needed to determine which drug is more efficacious and whether combination therapy is preferred.