Prevention and Reduction of Left Ventricular Hypertrophy in the Elderly

CORONARY ARTERY DISEASE IN THE ELDERLY

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PREVENTION A N D REDUCTION O F LEFT VENTRICULAR HYPERTROPHY IN THE ELDERLY Carl J. Lavie, MD, Richard V. Milani, MD, and Franz H. Messerli, MD

Although risk factor modification and advances in therapeutic modalities have resulted in a welcome decline in cardiovascular and particularly coronary artery disease (CAD) mortality during the past two decades, recent statistics indicate that this decline is less notable in the elderly, the fastest growing segment , ~ ' with the aging of the population, recent statistics suggest of ~ o c i e t y . ~In~ fact, that the overall prevalence, mortality, and cost of CAD will increase. Therefore, emphasis on the prevention and treatment of CAD risk factors is imperative in the elderly. An important but often overlooked risk factor for CAD in the elderly is left Although LVH is a target organ response to ventricular hypertrophy (LVH).3,38 arterial hypertension, substantial evidence indicates that it increases cardiovascular events. The fundamental response to an isolated increase in arterial pressure or afterload is LVH of the concentric type, which represents an increase in ventricular wall thickness without chamber dilatation; on the other hand, obesity and other conditions that increase preload (systolic ventricular failure or regurgitant valvular heart disease) lead to eccentric LVH, which consists of chamber dilatation 35, 37, 39, 50 with only a minimal increase in ventricular wall thickness (Fig. According to Laplace's equation, this ventricular dilatation increases ventricular wall stress and leads to an increase in muscle mass. Because both obesity and arterial hypertension tend to increase with age, LVH becomes a particular problem for the elderly, who have a prevalence of LVH as high as 50% in some studies,25.38, 39 This article emphasizes modalities available to detect and quantify LVH, risk factors for developing LVH, the morbid sequelae of LVH, as well as nonpharmaco-

From the Department of Cardiovascular Diseases, Ochsner Heart and Vascular Institute (CJL, RVM); and the Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner Clinic and Alton Ochsner Medical Foundation (FHM), New Orleans, Louisiana

CLINICS IN GERIATRIC MEDICINE

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VOLUME 1 2 . NUMBER I FEBRUARY 1996

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Lean normotensive

Obese normotensive

Lean hypertensive

hypertrophy

Figure 1. Cardiac structural adaptation to obesity, essential hypertension, and a combination of obesity and hypertension. (From Messerli FH: Cardiovascular effects of obesity and hypertension. Lancet 1:1165-1168, 1982; O by The Lancet Ltd, with permission.)

Obese hypertensive

Congestive heart failure

logic and pharmacologic strategies to prevent and reduce LVH, particularly in an elderly patient population.

IDENTIFICATION OF LVH

Although severe LVH can be identified by either radiograph imaging of the chest or even on physical examination, in general these techniques are neither sensitive nor specific for evaluating LVH.39Electrocardiography (ECG) is considerably more sensitive and specific for LVH than these other techniques, but considerable limitations in both sensitivity and specificity still exist. When LVH is identified by both ECG voltage criteria and repolarization abnormalities (strain pattern), the specificity is considerably greater, but these ECG markers are not common in either the general population or subgroups of elderly patients. The sensitivity and specificity for detecting LVH, as well as for predicting new CAD events, are considerably improved by using echocardiographic criteria for LVH, particularly 25* 39 Criteria for LVH using LV mass should criteria using LV mass calc~lation.~, r . n - ~. r t~ c ! fnr -.. ho;rrht --.- !rr/m! \of ---,nr .-hndv 5~ a-n-1-r -....-. -I .-rnrisr --...-, 2nd .....- 1,l7 m -.-.--. ~ ---. ~qh n ? ? ! r ! .....::.. surface area (g/m2).17,39,4262 Correction of the LV mass by body mass index is not as useful because it largely excludes increased LV mass seen in obesity. The upper limits of normal for LV mass determinations have been validated in the Framingham cohort44as well as other population^.'^^'^^'^ Using echocardiographic criteria obtained from a large Framingham cohort, Levy and colleagues40demonstrated that echocardiographic evidence of LVH is present in 16% of men and 19%of women in the general population. In the elderly, however, the prevalence of LVH is nearly 50% compared to only 5% in subjects under 30 years of -

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RISK FACTORS FOR LVH

Advancing age is a very important risk factor for the development of LVH.25,27,37,39,41 However, even in the elderly, increasing levels of arterial pressure and increasing obesity lead to progressive increases in the prevalence and severity of LVH. The risk factors for LVH include: Age Weight Arterial pressure Race Sodium intake Catecholamines Renin-angiotensin system Various growth factors In general, hypertension is more common and more severe in blacks,6O who also have more LVH and other target organ disease. Although numerous studies demonstrated that sodium intake is related to the pathogenesis of hypertension, particularly in sodium-sensitive patients (e.g., those with low renin hypertension), data from our laboratory and elsewhere indicate that sodium intake independently increases the risk of LVH.39,63 In addition, LVH correlates better with exercise blood pressure at submaximal or maximal workloads and with blood pressure recordings at the worksite, as well as with average blood pressure recordings during 24-hour ambulatory blood pressure monitoring, than with casual pressure recordings in the physician's office.15,22, 34 Finally, various neurohumoral factors, including the renin-angiotensin-aldosterone and adrenergic systems, insulin, and various growth factors also play some role in the development and progression of LVH.39

SEQUELAE OF LVH

Although LVH may initially be compensatory by reducing LV wall stress, clearly as LVH progresses, it is not benign but is associated with serious cardiovascular sequelae, including contributing to cardiac morbidity and mortality (Fig.2).39

Decreased Coronary Perfusion

Coronary flow reserve refers to the ability of the coronary arteries to dilate and increase its blood flow under stress or vasodilatory stimuli (e.g., exercise, adenosine, dipyridamole). In patients with LVH either due to an elevated arterial pressure load or LV obstruction (e.g., aortic stenosis or some hypertrophic cardiomyopathies), coronary flow reserve is markedly reduced, thus leading to relative myocardial ischemia. This result has also been demonstrated in hypertensive but patients without LVH and with normal macrovascular coronary arteries,'2,38,39 it is more severe in the elderly patients who not only have more severe LVH but who also have concomitant macrovascular coronary atherosclerosis. Studies have also demonstrated that LVH not only affects the microcirculation but also is associated with increased prevalence of macrovascular CAD. In patients with LVH and repolarization abnormalities on the ECG (or LVH with "strain"), significant CAD is particularly prevalent.59

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Figure 2. Consequences of left ventricular hypertrophy.(From Lavie CJ, Ventura HO, Messerli FH: Regression of increased left ventricular mass by antihypertensives. Drugs 42:945-961, 1991; with permission.)

Dysrhythmias

The Framingham Heart Study has previously demonstrated that ECGdetected LVH is associated with a nearly 10-fold increase in the risk of sudden death.26Studies that we have performed at the Ochsner Clinic in New Orleans over the past decade have demonstrated that all types of LVH, including concentric LVH,33,53 isolated septa1 hypertr0phy,5~and eccentric LVH in obesity37,39, are not only associated with more frequent but also with more complex (e.g., couplets, multifocal, and nonsustained ventricular tachycardia) ventricular dysrhythmias; we beleive that this increased ventricular ectopic activity may in part account for the markedly increased risk of sudden death associated with LVH.36,39 In the elderly, particularly those with LVH on the ECG with "strain" pattern, these ventricular dysrhythmias seem to be more prevalent.33Several other investigators have confirmed the strong association between LVH and the prevalence and complexity of ventricular ectopic activity.36We have also demonstrated that sub:::^^__:^? --.-^-.:^-?-. ?-^-.^ :--..,,,.,. 2 ?-:..:,.,.:..-:,. ..,.::.,::., & I U U ~ VVLLLI l a u l a L c u a c y L a k ILY ~ C L I IV ~ I L Y lllClcaacu including more runs of atrial tachycardia, in comparison with hypertensives without LVH or those with other forms of LVH? The prognostic significance of these ventricular dysrhythmias associated with LVH are not known, and other evidence suggests that ventricular ectopic activity does not markedly influence prognosis in CAD patients with preserved left ventricular systolic function. However, Aronow and colleagues7showed that in 468 elderly nursing home patients, the risk of sudden cardiac death was increased by 3.3 fold in those with echocardiographic evidence of LVH; in fact, sudden :^^:_L^_?

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PREVENTION AND REDUCTION O F LEFT VENTRICULAR HYPERTROPHY

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death was increased 2 fold in elderly with nonsustained ventricular tachycardia on the Holter monitor, 3 fold in those with echocardiographic evidence of LVH, and 10 fold in those with both complex ventricular ectopy and echocardiographic LVH. Ventricular Dysfunction

Diastolic ventricular abnormalities are known to occur in both aging and hypertension, particularly in those with LVH.37,39 This diastolic dysfunction may contribute to symptoms of dyspnea, exercise intolerance, angina, and dysrhythmias in elderly patients with LVH, significantly affecting their cardiac morbidity. These diastolic ventricular relaxation abnormalities were demonstrated in early M-mode echocardiographic studies and more recently in studies using radionuclide angiography and particularly pulsed Doppler evaluation of mitral valve inflow.39,57 Elderly patients usually have a reduced early diastolic filling and greater dependence on atrial systole to fill the left ventricle, thus producing a reduced E/A ratio. In addition, the isovolumic relaxation time is usually increased, as is the deceleration time.56All of these diastolic abnormalities are accentuated in elderly hypertensive patients with LVH. As with increased ventricular ectopic activity, we have also demonstrated that diastolic left ventricular dysfunction accompanies all types of LVH, including con~entric?~ eccentric LVH,23,28 as well as isolated septa1 h y p e r t r ~ p h yThe . ~ ~most significant diastolic abnormalities seem to occur in patients with both obesity and essential hypertension, two conditions (along with LVH) that increase with advancing age. Not surprisingly, these diastolic abnormalities are particularly problematic in the elderly. Using various indices of systolic function (e.g., shortening fraction, ejection fraction, etc.), resting systolic function is usually in the normal range in healthy elderly patients and early in the course of hypertension. In the elderly, however, a reduction in ventricular functional reserve occurs fairly early in the course of hyperten~ion.~" We have also demonstrated that with progression of obesity in hypertensive patients, as is frequently present in the elderly, intrinsic ventricular contractility assessed by a preload independent index (end-systolic stress/endsystolic volume index) progressively decline^.^' In addition, data from the Framingham study indicates that LVH is a very strong risk factor for congestive heart failure (CHF). In fact, when LVH is present on the ECG, particularly with strain pattern, the relative increased risk for CHF is considerably greater than for CAD, even though coronary events are considerably more prevalent in the elderl~.~~ Major Cardiac Events

Numerous studies have now documented the markedly increased risk of cardiac morbidity, cardiac mortality, and all-cause mortality associated with LVH, including several studies in elderly population^.^,^^ In a study of 1141 elderly patients followed prospectively for 4 years in the Framingham Heart Study, Levy and colleagues43showed that echocardiographic-determined LV mass (corrected for height) was the strongest independent predictor of CAD events and was the only independent predictor of events in the men. Although this study and others cannot determine if LVH contributed to the cardiac events or is simply a marker of target organ involvement in hypertension and other cardiovascular disorders,

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for every 50 g/m increase in LVH corrected for height, there was a greater than 1.5 fold increase in the relative risk of new CAD events. In another study of 1220 elderly Framingham subjects, Bikkina et al" recently demonstrated that echocardiographically-determined LVH was also strongly and independently associated with the risk of stroke. In fact, even after adjusting for other known risk factors, the risk of cerebrovascular events was nearly three times greater in those with the highest quartile of LV mass/height ratio compared with those in the lowest quartile. Aronow and colleagues3have performed an extensive evaluation of a large number of elderly nursing home patients, which has contributed to our understanding of various risk factors for cardiovascular events in the elderly. In a prospective study of 557 elderly patients, they demonstrated that those elderly with known CAD and echocardiographic evidence of LVH had 2.2 times greater risk of new CAD events than those without LVH.8 In a prospective study of 84 elderly blacks and 326 elderly whites with hypertension, Aronow and colleagues4 demonstrated that those with ECG-detected LVH had approximately 1.5 times greater risk of a new CAD event than those without LVH on the ECG, but those with LVH detected echocardiographically had a more than 3-fold increased risk of major CAD events. By using multivariate analyses with 15 variables, they demonstrated that the odds ratio for LVH determined echocardiographically in elderly with hypertension was 3.2 (1.7-6.2, 95% CI) for new CAD events. Finally, as mentioned previously, data from both the Framingham Heart ~,~ that echocardiographic LVH Study" and Aronow and c o l l e a g ~ e sdemonstrated is a strong predictor of stroke in the elderly. Although cerebrovascular events are not nearly as prevalent as CAD events in the elderly, these events are often quite disabling and frequently fatal. Previous studies have demonstrated that extracranial carotid artery disease is also a risk factor for stroke in the elderly.6,'0In addition, recent evidence suggests that LVH is not only associated with increased risk of stroke but is also a risk factor for significant carotid artery disease in elderly patient^.^ REDUCTION IN LVH

Based on considerable evidence previously discussed, we strongly believe that efforts to prevent and reduce LVH, including both nonpharmacologic and pharmacologic strategies, are warranted (Table 1). In addition, we briefly review the effects of LVH on ventricular performance. Table 1. Measures associated with prevention and reduction of left ventricular hv~ertro~hv

Weight reduction Sodium restriction

---------:.. ACE inhibitors Calcium antagonists Alpha blockers Beta blockers lndapamide Chlorthalidone (in one major study) Centrally acting agents Serotonin uptake inhibition

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Nonpharmacologic Modalities

Various nonpharmacologic modalities are available that may reduce LVH, including weight reduction, sodium restriction, and increased dynamic exercise. Although weight reduction lowers arterial pressure, numerous studies, discussed previously, demonstrate that obesity independently contributes to LVH.29,37, 38, 50 Weight reduction also reduces preload, afterload, and sympathetic drive, and studies have demonstrated considerable reductions in LVH with both vigorous In addition, although we know that sodium or mild weight reduction strategies.'~~~ intake is important in the pathogenesis of hypertension, particularly in patients with low renin hypertension (e.g., elderly, blacks, obese, and diabetic hypertensives), data from our laboratory and elsewhere demonstrate that sodium intake is directly related to the development of LVH, independent of its effect on arterial pressure.39,63 Therefore, along with weight reduction, sodium restriction should be encouraged for both the treatment of hypertension and for reduction of LVH. However, many elderly hypertensives have elevated peripheral vascular resistance, low intravascular volume (despite low plasma renin activity), and reduced cardiac output. Therefore, too vigorous sodium restriction, particularly if combined with the current recommended diuretic therapy, may exacerbate symptoms of volume depletion in elderly hypertensive patients. Drug Strategies

Recent recommendations from the joint National Committe in Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V) support the use of either diuretics or beta blockers as a first-line treatment for hypertension, even in the elderly population.I8 Diuretic therapy has resulted in nearly 40% reduction in the risk of stroke, but most studies with this therapy indicate only 10% to 15% reductions in the risk of major CAD events, much less than the 35% reduction that is predicted based on control of arterial pressure. In addition, most studies with diuretics (indapamide being the exception)39do not demonstrate significant reductions in LVH. However, recent trials in the elderly using low doses of diuretics and beta blockers demonstrate nearly 20% reductions in CAD events.'4,38,47,55,61 In addition, a recent large study (The Trial of Mild Hypertension Study or TOMHS) showed, although mostly in younger patients, that LVH was reduced with several different therapeutic modalities, including beta adrenergic blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, and alpha blocker^.^^,^^,^^ Surprisingly, however, the greatest reduction in LV mass occurred with low doses of the diuretic chlorthalidone, which was significantly greater than the LV mass reduction with placebo, as well as with beta blockers and ACE inhibitors, after 12 months of treatment?6 Despite these results, however, we feel that optimal doses of other agents will also reduce LVH more so than diuretics. In addition, diuretic therapy may worsen preexisting volume depletion, frequency, and complexity of ventricular dysrhythmias (if not given with potassium supplements or in combination with potassium sparing agents), and lipid abnormalities in the elderly hypertensive population.38,39 Beta adrenergic blocking agents are also recommended as first-line therapy for hypertension. Beta blockers have inconsistent effects on LVH, but various studies, including some from our laboratory, demonstrate modest reductions in LVH with beta blockers but usually less of a reduction than that produced with ACE inhibitors and calcium blockers.39Although this therapy may be particularly effective in patients with known CAD, elderly patients with relative bradycardia

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and decreased baseline cardiac output may experience side effects with this therapy, as well as adverse lipid effects. In a study of 245 elderly patients with prior myocardial infarction or hypertensive heart disease, complex ventricular ectopic activity, and a relatively preserved global systolic function (ejection fraction greater than 40%),Aronow and colleaguessdemonstrated that propranolol therapy was associated with reductions in sudden cardiac death, total cardiac death, and total mortality of 47%, 37%, and 20%, respectively, compared with no antiarrhythmic therapy. Therefore, beta blockers can be considered for elderly with CAD, LVH, and complex ventricular dysrhythmias. Although beta blockers with intrinsic sympathomimetic activity (e.g., pindolol and acebutolol) cause less resting bradycardia and may actually improve the plasma lipid profile, these agents have not been "cardioprotective" in acute ischemic heart disease and are not routinely recommended for cardioprotection. Most studies suggest that ACE inhibitors are the most potent for reduction in LVH, and recent evidence suggests that ACE inhibitors reduce ventricular dysrhythmias in hypertensive patient^.^, 36, 39, 49 However, in the TOMHS study discussed previously, low doses of ACE inhibitors (enalapril5 mg/day) did not reduce LVH as much as did diuretic therapy.46In addition, although these agents have beneficial effects in nearly all hypertensive patients, they are generally not as effective in subgroups with low plasma renin activity (e.g., the elderly, obese, black, and diabetic hypertensives). Based on considerable evidence, however, ACE inhibitors should be considered the drugs of first choice for treatment of elderly with LVH who have systolic LV dysf~nction.3.~~ Calcium-channel blocking agents have been demonstrated to reduce LVH in many studies with various medications in the ~lass.3~. 39 In addition, they reduce several of the major consequences of LVH, including decreased coronary flow reserve, diastolic ventricular dysfunction, myocardial ischemia, and ventricular 39, Unl'ike the ACE inhibitors, which are not as effective in ectopic acti~ity.3~~ patients with low plasma renin activity (e.g., the elderly), calcium antagonists are particularly effective in hypertensive patients with low plasma renin activity. Therefore, these agents may be particularly effective in the elderly. In addition, the calcium blockers seem to have no adverse metabolic effects and may have anti-atheroscleroticeffects, particularly by reducing the formation of new coronary In elderly with preserved systolic function, the lesions in patients with CAD.38,39,4s rate slowing calcium blockers (e.g., verapamil or diltiazem) would be reasonable choices, although these agents (especially verapamil) may worsen constipation in the elderly. However, in elderly with relative bradycardia or those taking a beta blocker, a dihydropyridine drug may be more appropriate. In patients with systolic ventricular dysfunction, who need a calcium blocker (usually in addition to ACE inhibitors and/or nitrates) to treat ischemia or severe hypertension, a dihydropyridine with less negative inotropic effects (e.g., isradipine, felodipine, or amlodipine) may be appropriate. Alpha blockers reduce LVH in many studies, have beneficial lipid effects (partic;larly reducing triglycerides and increasing levels of high-density lipopro+?<= ~ ~ + 2-.A ~ - . q ~,). q7 T-;-.-..:!: ?..-?., ----- ~ h 5 ~ ____,, - . - "< - ~ : : l ; ~ ii; 2.?,?:!;.-.~-, yul appropriate to elderly men, these agents also significantly reduce the symptoms of prostatic hypertrophy. Therefore, alpha adrenergic blockers can be considered in the elderly, particularly those with hypertension, LVH, and prostatic hypertrophy. 39; however, the Centrally acting agents may also markedly reduce LVH38~ central side effects with these agents, particularly sedation, are troublesome in elderly patients. In addition, we have recently noted reductions in arterial pressure and LVH with serotonin uptake inhibition with sertraline in obese patients with -2TT

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hyperten~ion.'~ Therefore, this therapy, which is frequently used for depression, may be appropriate for elderly obese hypertensives with LVH, particularly if concomitant depression is present. Some concern has been expressed, however, that if treatment for hypertension is abruptly discontinued (as is seen in many elderly patients for various reasons) and blood pressure returns to pretreatment levels or higher after LVH is reduced, LV wall stress will be increased, which may predispose to severe CHF.I9, 39 However, we and others have recently demonstrated the safety and efficacy of reducing LVH.54,h4, 65,6R Even after LVH is reduced and antihypertensive therapy is withdrawn, resulting in return of blood pressure to pretreatment levels, both systolic and diastolic function remain enhanced. CONCLUSION

These data suggest that emphasis needs to be placed not only on reducing arterial pressure but also on reducing LVH in elderly hypertensive patients. Although most data appear particularly promising regarding calcium antagonists and ACE inhibitors, some recent studies with low doses of diuretics also appear promising and suggest that these agents may be efficacious and cost effective for treating hypertension, reducing LVH, and reducing cardiovascular disease events, including CAD events. Further large scale prospective trials are needed to determine whether a reduction in LV mass and ventricular dysrhythmias is associated with major reductions in cardiovascular morbidity and mortality in the elderly population, exceeding that produced by adequate blood pressure reduction alone.

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10. Aronow WS, Schoenfeld MR, Gutstein H: Extracranial carotid arterial disease:A prognostic factor for atherothrombotic brain infarction and cerebral transient ischemic attack. NY State J Med 92424-425, 1992 11. Bikkina M, Levy D, Evans JC, et al: Left ventricular mass and risk of stroke in an elderly cohort. The Framingham Heart Study. JAMA 272:33-36,1994 12. Brush JE, Cannon RO, Schenke WH, et al: Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med 319:13021307, 1988 13. Casale PN, Devereux RB, Milner M, et al: Value of echocardiographic measurement of left ventricular mass i n predicting cardiovascular morbid events in hypertensive men. Ann Intern Med 105:173-178, 1986 14. Dahlof B, Lindholm LH, Hansson L, et al: Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-Hypertension).Lancet 338:1281-1285, 1991 15. Devereux RB: Does increased blood pressure cause left ventricular hypertrophy or vice versa? [editorial] Ann Intern Med 112157-159,1990 16. Devereux RB, Lutas EM, Casale PN, et al: Standardization of M-mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol4:1222-1230,1984 17. Devereux RB, Reichek N: Echocardiographic determination of left ventricular mass in man: Anatomic validation of the method. Circulation 55:613-618, 1977 18. The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, Bethesda, MD: US Department of Health and Human Services, 1993. National High Blood Pressure Education Program, National Institutes of Health, Heart, Lung and Blood Institute, NIH Publication no. 93-1088 19. Frohlich ED: Cardiac hypertrophy in hypertension. N Engl J Med 317:831-833, 1987 20. Garavaglia GE, Lavie CJ, Messerli FH: Systemic hemodynamics. In Amery A, Staessen J (eds): Handbook of Hypertension: Hypertension in the,Elderly, vol 12. Amsterdam, Elsevier Science Publishers, 1989, p 63-69 21. Garavaglia GE, Messerli FH, Nunez BD, et al: Myocardial contractility and left ventricular function in obese patients with essential hypertension. Am J Cardiol 62:592-597, 1988 22. Gottdiener JS, Brown J, Zoltick J, et al: Left ventricular hypertrophy in men with normal blood pressure: Relation to exaggerated blood pressure to exercise. Ann Intern Med 112:161-166, 1990 23. Gross E, Oren S, Messerli FH: Left ventricular filling in the systemic hypertension of obesity. Am J Cardiol 68:57-60,1991 24. Jordan J, Messerli FH, Lavie CJ, et al: Reduction of weight and left ventricular mass with serotonin uptake inhibition in obese patients with systemic hypertension. Am J Cardiol 75:743-744, 1995 25. Kannel WB: Hypertension in the elderly: Epidemiologic appraisal from the Framingham study. Cardiol Elderly 1:359-363, 1993 26. Kannel WB: Prevalence and natural history of electrocardiographic left ventricular hypertrophy. Am J Med 75(suppl3A):4-11,1983 27. Lauer MS, Anderson KM, Kannel WB, et al: The impact of obesity on left ventricular mass and geometry: The Framingham Heart Study. JAMA 266:231-236,1991 28. Lavie CJ, Amodeo C, Ventura HO, et al: Left artrial abnormalities indicating diastolic ventricular dysfunction in cardiopathy of obesity. Chest 92:1042-1046, 1987 29. Lavie CJ, Messerli FH: Cardiovascular adaptation to obesity and hypertension. Chest 90:275-279,1986 30. Lavie CJ, Milani RV: Cardiac rehabilitation, exercise training and risk factor modification i n t h PldPrl~7. ~ CARDIO S~p47-52.1993 31. Lavie CJ, Milani RV, Littman AB: Benefits of cardiac rehabilitation and exercise training in secondary coronary prevention in the elderly. J Am Coll Cardiol22678-683, 1993 32. Lavie CJ, Milani RV, Messerli FH: How antihypertensives affect lipid levels. IM 12:3646, 1991 33. Lavie CJ, Nunez BD, Garavaglia GE, et al: Hypertensive concentric left ventricular hypertrophy: When is ventricular ectopic activity increased? South Med J 81:696-700, 1988 34. Lavie CJ, Schmieder RE, Messerli FH: Ambulatory blood pressure monitoring: Practical considerations. Am Heart J 116:1146-1151,1988

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