Left Ventricular HvDertroDhv J

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Wilbert S. Aronow, MD Objective: To review the pathophysiology, epidemiology, patterns, diagnosis, and treatment of left ventricular hypertrophy with emphasis on the elderly. Data Sources: A computer-assisted search of the Englishlanguage literature (MEDLINE database) followed by a manual search of the bibliographies of pertinent articles. Study Selection: Studies on the pathophysiology, epidemiology, patterns, diagnosis, and treatment of left ventricular hypertrophy were screened for review. Studies on left ventricular hypertrophy in the elderly and recent studies were emphasized. Data Extraction: Pertinent data were extracted from the reviewed articles. Emphasis was on studies involving the elderly. Relevant articles were reviewed in depth. Data Synthesis: Available data about the pathophysiology,

epidemiology, patterns, diagnosis, and treatment of left ventricular hypertrophy with emphasis on studies involving the elderly were summarized. Conclusions: Left ventricular hypertrophy caused by hypertension or other cardiovascular disease is not only a marker for but also a contributor to cardiovascular morbidity and mortality in elderly and young patients. The question of whether regression of left ventricular mass in patients with hypertension will decrease cardiovascular morbidity and mortality needs to be answered by prospective studies using different types of antihypertensive drugs. Future studies on the efficacy of antihypertensive drugs and on stratification of therapy should include echocardiographic estimates of left ventricular mass index. J Am Geriatr SOC4 0 71-80,1992

eft ventricular (LV) hypertrophy is an abnormal increase in LV mass if it is due to hypertension or other cardiovascular disease. LV hypertrophy may also be a physiologic response to exercise training. Physiologic aging is associated with the development of an increase in LV mass.1r2Data from the Baltimore Longitudinal Aging population without evidence of hypertensive or ischemic heart disease suggest that the increase in LV wall thickness associated with aging is mediated via an increase in systolic blood pressure.' Aging is also associated with an increase in systemic hypertension and with an increase in the prevalence of cardiovascular disease. The prevalence of echocardiographic LV hypertrophy increases with age.'-3 In the Framingham Heart Study, echocardiographic LV hypertrophy was found in 49% of women and 33% of men older than 70 years.3 In an unselected elderly population in a long-term health care facility, echocardiographic LV hypertrophy was demonstrated to occur in 195 of 469 patients (42%)with systemic hypertension, coronary artery disease, valvular heart disease, or cardiomyopathy and in two of 88 patients (2%)without hypertension or cardiac d i ~ e a s e . ~ 6-12 LV Electro~ardiographic~-~ or echo~ardiographic~, hypertrophy in the elderly population is associated with an increased incidence of cardiovascular events. This review article on LV hypertrophy will discuss factors predisposing to LV hypertrophy, patterns of LV hypertrophy, the effect of LV hypertrophy on LV function, the effect of LV hypertrophy on myocardial oxygen demand and supply, the diagnosis of LV hypertrophy, the effect of LV hypertrophy on ventricular arrhythmias, the prognosis of electrocardiographic and echocardiographic LV hypertrophy, and the effect of

treatment on LV hypertrophy. Information available on LV hypertrophy in the elderly population will be emphasized.

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From Hebrew Hospital for Chronic Sick and the Department of Medicine, Albert Einstein College of Medicine, Bronx, New York. Address correspondence and reprint requests to Wilbert S. Aronow, MD, Medical Director, Hebrew Hospital for Chronic Sick, 2200 Givan Avenue, Bronx, NY 10475.

1AGS 40:71-80, 1992 0 1992 by the American Geriatrics Society

PATHOPHYSIOLOGY Hemodynamic Factors Hemodynamic and nonhemodynamic factors predispose to LV hypertrophy. LV hypertrophy may be caused by increased afterload, increased preload, impaired LV function or may be multifactorial or idiopathic. LV hypertrophy may be caused by systolic or diastolic h y p e r t e n ~ i o n , ~ aortic -~~ valvular ~ t e n o s i saortic , ~ ~ reg~rgitation,~~ mitral regurgitation,26coronary artery di~ease,~, 6,9,11,33,38*39 cardiom y ~ p a t h y ? ~~besity,~, , ~ ~ , ~ 13-15 ~ h yperthyroidism;' endstage renal disease,42T43 or exercise training.44LV hypertrophy is caused by an increase in the volume, but not the number, of the cardiac myocytes. Fibroblasts undergo hyperplasia, and collegen is deposited in the myocardial interstitium. LV hypertrophy caused by renovascular hypertension in rats is associated with decreased contractile function, decreased myosin ATPase activity, and a shift to the V3 isozyme of m y ~ s i n . On ~ ~the - ~ other ~ hand, LV hypertrophy caused by a forced swimming program in rats improves contractile function and myosin bioReversal of renovascular hypertensioninduced LV hypertrophy in rats causes a regression of the mechanical and biochemical abnormalities associated with pressure overload LV hypertrophy.*' All of these hemodynamic factors are applicable to the increased LV mass that occurs in the elderly. Trophic and Cellular Factors Non-hemodynamic factors also contribute to LV hypertrophy. Activation of the sympathetic nervous system and renin-angiotensin system are involved. Increased norepinephrine and angiotensin I1 levels increase LV hypertrophy. Growth factors and molecular biologcal mechanisms also contribute to the pathogenesis of LV hypertrophy. Cardiac hypertrophy involves initiating signals, cou-

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IAGS-JANUARY 1992-VOL. 40,NO. 1

pling mechanisms, and regulation of gene e x p r e ~ s i o n . ~hypertrophy ~ of the myocytes occurs in exercise-inInitiating signals include ventricular wall stretch, alpha duced LV hypertrophy; there is thus no adverse cardiac 1- and beta-adrenergic agonists, thyroid hormone, and risk. On the other ‘hand, an inadequate increase in the renin-angiotensin system (Ang II).49 Coupling myocardial vascularity occurs in LV hypertrophy mechanisms include ion channels, phospholipase C, caused by LV pressure overload (eg, hypertension or adenylyl cyclase, inositol phosphates, diacylglycerol, aortic stenosis), leading to reduced coronary vascular cyclic AMP, protein kinase C, and cyclic AMP-depend- reserve.56 ent protein k i n a ~ e Regulation .~~ of gene expression LV hypertrophy increases myocardial oxygen deincludes nuclear enhancer-binding proteins (AP-1 mand. At the same time, hypertrophy of the media in transcription factor and AP-2 transcription factor), coronary resistance vessels due to increased proliferacyclic AMP response-elements, contractile protein tion of vascular smooth muscle in patients with hypergenes (beta myosin light chain and alpha-skeletal ac- tension and LV hypertrophy causes an increase in tin), atriope tin, angiotensinogen, ribosomal DNA, and coronary vascular resistance and a reduction in corooncogenes. nary vascular r e ~ e r v e . The ~ ~ -greater ~ ~ the degree of LV In vitro tissue culture studies have shown develop- hypertrophy, the greater the decrease in coronary vasment of cardiac hypertrophy and myocardial protein cular reserve. The ratio of subendocardial to epicardial synthesis when norepinephrine, isoproterenol, or an- blood flow in the LV becomes abnormal. Intraventricgiotensin I1 was added to the tissue c ~ l t u r e . ~Studies ~-~’ ular compressive forces may cause a decrease in coroof proto-oncogene message levels have been per- nary blood supply to the myocardium while myocardial formed in various models of cardiac hypertrophy. Var- oxygen demand is increased. This may result, especially ious forms of LV hypertroph can be characterized not during episodes of tachycardia, in subendocardial hy only by isomyosin content46?47 but also by transcrip- poperfusion and ischemia. If blood pressure is detional patterns for both contractile and growth regula- creased without a concomitant reduction in LV mass, tory gene^.^'-^^ Starksen et a15’ demonstrated that the coronary perfusion will be reduced, leading to a deinduction of cardiac myocyte hypertrophy is associated crease in coronary blood flow to a hypertrophied LV with augmented expression of the c-myc gene and which has an increased myocardial oxygen demand. suggested hormonally induced cell hypertrophy and Reduced ability of the coronary arterioles to dilate and cell division share common mechanistic pathways. The increased baseline coronary flow of patients with hymyc proto-oncogene is activated in cells undergoing pertension and LV hypertrophy may shift the point of catecholamine-LV hypertrophy, and activation of the exhaustion of coronary vascular reserve to a higher sis proto-oncogene has been detected in at least one perfusion pressure, causing the myocardium to become ~ ~ findings suggest vulnerable to treatment-induced relative hypotenmodel of LV h y p e r t r ~ p h y .These that similar pathogenetic cellular mechanisms operate sion.” to cause myocardial h ertro h and vascular hyperPatients with hypertension and LV hypertrophy plasia and hypertrophy. All of p these y mechanisms may have a higher prevalence of clinical and silent coronary be applicable to increased LV mass that occurs in the artery disease than do atients with hypertension without LV hypertrophy.6d?Myocardial ischemia diagnosed elderly. Left Ventricular Function LV hypertrophy caused by thallium perfusion defects is associated with imby hypertension or other cardiovascular disease leads paired coronary vasodilator reserve in patients with to abnormal LV compliance, LV diastolic dysfunction hypertension and LV hypertrophy without coronary Silent myocardial ischemia detected with reduced LV diastolic filling, and abnormal LV artery di~ease.’~ systolic function with reduced LV ejection fraction. by 24-hour ambulatory electrocardiography was demUltimately, congestive heart failure results. Elderly pa- onstrated in 66 of 179 elderly patients (37%) with tients with isolated systolic hypertension tend to have hypertension or coronary artery disease and echocarLV hypertrophy, normal LV systolic function, and ab- diographic LV hypertrophy and in 29 of 176 elderly (16%) with hypertension or coronary arter normal LV diastolic function in contrast with age- patients disease and no echocardiographic LV hypertrophy. matched control subjects.” Patients with hypertension may have a normal LV ejection fraction at rest but an LV hypertrophy predisposes elderly patients with hyabnormal LV ejection fraction in response to exercise.” pertension or coronary artery disease to develop myoThe abnormal LV systolic function response to exercise cardial infarction, primary ventricular fibrillation, and in these patients may be due to LV hypertrophy with sudden cardiac death.” impaired LV diastolic filling leading to an insufficient PATTERNS OF LEFT VENTRICULAR increase of LV end-diastolic volume during exercise to HYPERTROPHY maintain LV systolic function. Abnormal LV systolic function during exercise in patients with hypertension There is a spectrum from normal LV mass to inmay also be due to increased afterload (that is, exag- creased LV mass, finally ending up as LV hypertrophy. gerated blood pressure response to exercise) or to an Savage et al’ described three different methods of intrinsic decrease in contractility in patients with long- determining LV echocardiographic mass. Echocardistanding hypertension. ographic mass was determined in the studies of elderly Myocardial Oxygen Demand and Supply An in- patients listed in Table 1 by measuring LV transverse crease in myocardial vascularity proportionate to the dimension, posterior wall thickness, and interventric-

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LEFT VENTRICULAR HYPERTROPHY

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TABLE 1. INCREASED INCIDENCE OF CARDIOVASCULAR EVENTS IN PROSPECTIVE STUDIES OF ELDERLY PATIENTS WITH ELECTROCARDIOGRAPHIC OR ECHOCARDIOGRAPHIC LEFT VENTRICULAR HYPERTROPHY Increased Incidence of Cardiovascular Events ECG LVH Study

Men age 65-94 in Framingham Study' (30 JT follow-up) Women age 65-94 in

Echo LVH

Cor Events

ABI

CHF

PAD

3.0

3.2

9.0

1.9

3.7

6.5

6.0

2.7

Framingham Study5(30 yr follow-up) 406 elderly men in Framingham Study' (4 yr fol-

Cor Events

ABI

CHF

V Fib orSCD

1.67*

low-up) 735 elderly women in

Framingham Study' (4 yr follow-up) 557 elderly patients4 (27 mo follow-up) 360 elderly patients with hypertension or CAD6 (37 mo follow-up) 468 elderly patients with heart disease' (27 mo follow-up) 110 elderly patients with chronic atrial fibrillation" 84 elderly blacks with hypertension7 (37 mo follow-up) 326 elderly whites with hypertension7 (43mo follow-up)

1.60*

1.4

1.7

2.7

3.7

2.0

2.8

3.3 2.4** 1.5

1.8

1.3

3.3

2.8

3.7

1.4

1.9

1.6

2.7

3.3

3.5

LVH = left ventricular hypertrophy; ECG = electrocardiographic; echo = echocardiographic; Cor = coronary; ABl = atherothrombotic brain infarction; CHF = congestive heart failure; PAD = peripheral arterial disease; V Fib = ventricular fibrillation; SCD = sudden cardiac death. * Relative risk for corona y events per 50 g/m increase in LV masslheight, ** Increased prevalence of thromboembolic stroke.

ular septal thickness at end-diastole using the Penn ventricle to normalize wall stress. Increased afterload convention.61,62 The formula26361 to determine LV mass causes an increase in LV systolic stress and the addition in these studies was LV mass (g) = 1.04 [(LV dimension of sarcomeres in parallel. This results in increased LV plus posterior wall thickness flus interventricular sep- wall thickness with a normal or reduced LV chamber tal thickness during diastole) minus (LV diastolic di- size and an increased relative wall thickness. This men~ion)~] minus 13.6. In the Framingham Heart pattern of LV hypertrophy is called concentric hyperStudy, using the Penn convention, the upper limits of trophy and is likely to develop in patients with LV normal for LV mass were 259 g in men and 166 g in pressure overload as in hypertension with increased women for LV mass, 131 g/m2 in men and 100 g/m2 systemic vascular resistance or in valvular aortic stein women for LV mass/body surface area, and 143 g/ nosis. m in men and 102 g/m in women for LV ma~s/height.~ Concentric LV hypertrophy is diagnosed by echoIn the prognostic studies of older ~ o h o r t s 7,9*10 ~ , ~ ,listed cardiography if the LV mass index is increased with a in Table 1, echocardiographic LV hypertrophy was relative wall thickness (relative wall thickness = 2X diagnosed if the LV mass index exceeded 134 g/m2 in diastolic LV posterior wall thickness/diastolic LV intermen and 110 g/m2 in women.26 nal dimension) 20.45.1,7r63Disproportionate septal LV LV hypertrophy represents remodeling of the left hypertrophy is diagnosed by echocardiography if the

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LV mass index is increased with the diastolic interventricular septa1 thickness/diastolic LV posterior wall thickness ratio rl .3.’,40Disproportionate hypertrophy of the septum of the left ventricle is associated with hypertrophic ~ardiomyopathy.~’ Hypertensive hypertrophic cardiomyopathy of the elderly is a syndrome which includes patients with severe concentric LV hypertrophy, a small LV cavity, and supernormal indexes of LV systolic function without concurrent medical illness or coronary artery disease.35 The prevalence of echocardiographic LV hypertrophy was 73% in elderly blacks with hypertension, 53% in elderly Hispanics with hypertension, and 60% in elderly whites with hypertension.’’ The prevalence of concentric LV hypertrophy was 60% in elderly blacks with hypertension, 40% in elderly Hispanics with hypertension, and 39% in elderly whites with hypertension.” Concentric LV hypertrophy was also present in 100% of elderly patients with severe valvular aortic stenosis, in 95 5% of elderly patients with moderate valvular aortic stenosis, and in 74% of elderly patients with mild valvular aortic s t e n ~ s i s . ~ ~ Increased preload causes an increase in LV diastolic stress and the addition of sarcomeres in series. This results in an increase in the ratio of LV chamber size to wall thickness. This pattern of LV hypertrophy is called eccentric LV hypertrophy and is likely to develop in patients with LV volume overload as with obesity, aortic regurgitation, or mitral regurgitation. Eccentric LV hypertrophy is diagnosed by echocardiography if the LV mass index is increased with a relative wall thickness