Epidemiology

As already described, LVH is a compensatory mechanism aimed at adapting to higher demands for LV work, including pressure load. The threshold between adaptive (healthy) and maladaptive (pathologic) hypertrophy is not clearly defined; this makes the estimation of pathologic LVH on a population level difficult. In the Multi-Ethnic Study of Atherosclerosis (MESA), comprising middle-aged and older men and women without a diagnosis of cardiovascular disease but with HTN, 11% of the participants met criteria for LVH by cardiac magnetic resonance imaging (MRI). In the Dallas Heart Study, which included both hypertensive and normotensive persons ages 30 to 67 years, the overall prevalence of LVH by cardiac MRI was 9.4%, but it was higher in participants with elevated systolic BP. These prevalence rates are among the most reliable estimates for the general adult population because they stem from population-based samples subjected to cardiac MRI for the detection of LVH. In contrast, estimates of LVH prevalence among hypertensive individuals vary markedly between studies depending on the testing modality used (e.g., electrocardiography [ECG] vs. echocardiography vs. cardiac MRI), the LVH diagnostic criteria employed, and, importantly, the demographics and comorbidity profile of the study population. In a pooled analysis of studies using ECG as the diagnostic test, the reported prevalence of LVH ranged from 0.6% to 40% (average 24% in men and 16% in women). Another pooled analysis of studies utilizing echocardiography for the detection of LVH showed less variable prevalence estimates, ranging from 36% to 41% among patients with HTN.

Ethnic differences: In most population-based studies, non-Hispanic (NH) black individuals had a much greater prevalence of LVH than their NH white counterparts. Specifically, in the Hypertension Genetic Epidemiology Network Study (HyperGEN), middle-aged black adults with HTN had 2.5-fold greater odds for LVH by echocardiography even after adjustment for cardiovascular risk factors and body surface area (BSA). In the Dallas Heart Study, young and middle-aged black adults, including both normotensive and hypertensive individuals, had 1.8-fold greater odds of LVH by cardiac MRI after adjustment for systolic BP, body mass, age, gender, history of diabetes, and socioeconomic status. The cause of this much greater propensity for LVH in blacks is unknown but could be related to the earlier onset, less nocturnal dipping, and greater severity of HTN. However, the fact that the greater odds for LVH in blacks increased to 2.3-fold in the subgroup of hypertensive persons and that the prevalence of LVH was increased in blacks only if they were either in the prehypertensive or hypertensive range of systolic BP suggests a genetic predisposition of blacks to develop LVH in response to pressure overload, as discussed later (see section titled Genetic Factors in LVH ) . MESA compared left ventricular mass index (LVMI) with BSA between NH whites, NH blacks, and Hispanics of Mexican, Caribbean, and South/Central American origin. HTN was much more common in NH blacks than in all other groups. However, LVH (defined as >95th percentile of cumulative distribution separately for men and women) was more common in all Hispanic subgroups than in NH whites but was as frequently observed in Hispanics as in NH blacks. Similarly, an increased prevalence of LVH in Hispanics and NH blacks compared with NH whites has also been observed in individuals with chronic kidney disease (CKD). The Northern Manhattan Study—comprising a triethnic community cohort of NH white, NH black, and Hispanic participants—found that both Hispanics and blacks had worse echocardiography-derived LV diastolic indices than whites. However, these differences were not related to LV mass or HTN but rather to cardiovascular comorbidities and socioeconomic factors. A comparison of Asian and white cohorts demonstrated a higher prevalence of ECG-determined LVH and worse LVH-related cardiovascular events in the former group.

Gender differences: In general men have a greater LVMI as related to BSA than women. Therefore different threshold values have been established for the diagnosis of LVH in men and women. Using these different thresholds for the diagnosis of LVH, men tend to have a greater incidence of LVH even after adjustment for other characteristics thought of as risk factors for LVH.

Risk factors for LVH : Besides the aforementioned demographic determinants of LVH, many other clinical risk factors have been identified. Not surprisingly, BP tracks LV mass in a linear fashion. However, single office BP measurements are only weakly associated with LV mass ( Fig. 25.2 ) , whereas 24-hour ambulatory BP—a better measure of hemodynamic LV burden—is much more closely related to LV mass. Another explanation for the weak correlation of BP measurements and LV mass are nonhemodynamic (i.e., neurohumoral) stimuli to myocardial muscle growth; these are discussed in the next section of this chapter. Epidemiologic studies have identified the following risk factors for LVH: In the MESA study of adults without clinical cardiovascular disease, LV mass was independently associated with current smoking and diabetes. More recently, even impaired glucose tolerance in nondiabetics was found to be a risk factor for LVH after adjustment for obesity. Sleep-disordered breathing, even without symptoms of daytime sleepiness, has also been identified as a determinant of greater LV mass, which is likely related to a greater prevalence of nocturnal HTN and sympathetic nerve activation in these individuals. Closely linked with sleep apnea is body mass index and subscapular skin fold thickness, which were associated with greater LV mass in the Coronary Artery Risk Development in Young Adults (CARDIA) study and in MESA. CKD is closely linked with LVH, even when renal function is only mildly abnormal. Inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) are determinants of LVH in CKD and thus may hint at the involved mechanisms. The combination of black race and CKD is associated with a staggering LVH prevalence of 70% in this population.

The Hypertensive Myocardium.

Histologic findings in left ventricular hypertrophy: cardiomyocyte hypertrophy (A), apoptosis (B), which among other mechanisms leads to interstitial (C), and perivascular fibrosis (D), arteriole remodeling (E), and capillary rarefaction (F), all of which perpetuate myocardial fibrosis.

From Moreno MU, Eiros R, Gavira JJ, et al. The hypertensive myocardium: from microscopic lesions to clinical complications and outcomes. Med Clin North Am . 2017;101[1]:43–52.

Pathophysiologic Mechanisms

Macroscopically LVH is an increase in myocardial muscle mass. However, on a cellular level, this greater muscle mass consists not only of increases in myocyte protein and the recruitment of contractile elements; other cell types—such as fibroblasts, vascular smooth muscle cells, and endothelial cells—also undergo changes that contribute to an altered extracellular matrix (i.e., the connective tissue) ( see also Chapter 4 ). Fig. 25.3 depicts the complex interplay between mechanical (hemodynamic) and neurohumoral stress and key pathways for stimulating hypertrophic gene expression. The inability of the myocardial microvasculature to keep up with myocyte growth is a key aspect of the genesis hypertensive heart disease ( see also Fig. 25.2 ).Although our understanding of the underlying mechanisms remains incomplete, decades of research have identified several molecular mechanisms, as reviewed by Cacciapuoti, and genetic factors that influence the development of hypertensive heart disease.

Hemodynamic and Neurohumoral Stimuli and Pathways Leading to Myocyte Hypertrophy.

Both mechanical and neurohumoral stress in hypertension stimulates local release of paracrine substances, which signal hypertrophic gene expression and sarcomeric hypertrophy.

From Hill JA, Olson EN. Cardiac plasticity. N Engl J Med . 2008;358:1370–1380.

Importance of hemodynamic burden: As mentioned earlier, the correlation between office/clinic BP measurement and LV mass is less than perfect. There are several explanations for this finding: (1) Office BP is not a reliable surrogate for hemodynamic burden—24-hour ambulatory BP correlates much better. (2) Neither office nor 24-hour ambulatory BP monitoring provides information on lifetime hemodynamic burden—on the onset and progression of HTN. (3) Neurohumoral stimulation linked to the development of LVH may differ between hypertensive individuals. (4) A genetic propensity for LVH may exists in some and be absent in other hypertensive patients. Racial/ethnic differences in the probability of developing LVH strongly suggest (but do not prove) a genetic component and are discussed separately.

Clinical Presentation/Functional Classes

The onset of symptomatic heart failure and especially hospitalization for heart failure is an important indicator of poor outcomes and a high mortality rate, both in heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Therefore the following consideration of symptoms in the classification of hypertensive heart disease is extremely important.

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  Class I: Subclinical diastolic dysfunction without LVH: Asymptomatic patients with abnormal LV relaxation/stiffness by Doppler echocardiography, a common finding in individuals above 65 years of age.

  
  
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  Class II : LVH

  
  
  
  
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    IIA: With normal or mildly abnormal functional capacity (New York Heart Association class I)

    
    
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    IIB: With abnormal functional capacity (New York Heart Association class II or greater)

  
  
  
  
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  Class III: HFpEF—clinical signs and symptoms of cardiac decompensation (i.e., dyspnea, pulmonary edema) from increased left atrial pressure

  
  
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  Class IV: HFrEF

Anatomic Classification of Left Ventricular Hypertrophy

The anatomic classification proposed by Ganau and colleagues (1992) is based on echocardiographic measurements of LV geometry and muscle mass. LV geometry is determined by RWT calculated as doubling the width of the LV inferolateral wall and divided by the LV end-diastolic internal diameter in end-diastole. A RWT ≥0.44 is diagnostic of concentric LVH, whereas an RWT less than 0.44 with increased LV mass is indicative of eccentric remodeling. This category can be further distinguished from physiologic hypertrophy, which is characterized by mild increases of LV mass and an RWT between 0.32 and 0.44. LV mass is best calculated according to the modified Simpson rule and most commonly indexed to BSA. Fig. 25.4 depicts the four anatomic classes of LV mass and geometry.

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  Class I: Normal LV

  
  
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  Class II: Concentric remodeling without hypertrophy

  
  
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  Class III: Concentric LVH

  
  
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  Class IV: Eccentric LVH

Mechanisms by Which Aldosterone Excess Favors the Onset of Atrial Fibrillation.

Aldosterone is one known stimulant for left ventricular hypertrophy. In addition, stimulation of inflammatory cascades and fibroblasts leads to additional myocardial thickening via necrosis and reparative and direct fibrosis, all of which lead to the clinical phenotypes of hypertensive heart disease. LV , Left ventricle; LVH, left ventricular hypertrophy.

From Seccia TM, Caroccia B, Adler GK, et al. Arterial hypertension, atrial fibrillation, and hyperaldosteronism: the triple trouble. Hypertension . 2017;69:545–550.

Diagnostic Criteria for Left Ventricular Hypertrophy

LVH, the increase in LV myocardial mass beyond defined cutoffs, can be diagnosed by ECG, echocardiography, or cardiac MRI. Although cardiac MRI is the most accurate and precise method for determining LV mass, the preferred method is echocardiography because it is more widely available than cardiac MRI while also providing greater sensitivity than ECG. ECG is a reasonable cost-conscious alternative to the more expensive testing modalities, especially in the asymptomatic hypertensive patient with a low index of suspicion for hypertensive heart disease in whom echocardiography is not necessarily indicated. A clear limitation to the usefulness of screening for LVH irrespective of the testing modality is the fact that awareness of the presence or absence of LVH typically has little impact on physician behavior in the treatment of HTN.

Heart Failure With Preserved Ejection Fraction (see also Chapter 39 )

HTN is the most prevalent cause of heart failure. LV remodeling in response to pressure overload and neurohumoral stimulation causes structural geometric changes in the LV, and this process is initially adaptive. Later in the course of hypertensive heart disease, however, evidence of LV decompensation becomes evident. And diastolic dysfunction—abnormal LV relaxation and filling—typically occurs much earlier than systolic dysfunction.

Diastolic function is determined noninvasively by echocardiography. The diastolic phase of the cardiac cycle consists of four distinct components: (1) isovolumic relaxation —which starts at closure of the aortic valve and ends with opening of the mitral valve; (2) passive filling of the LV—after opening of the mitral valve, rapid filling of the LV propelled by the pressure gradient between left atrium and the LV (i.e., pulsed Doppler-derived E-wave); (3) diastasis —when the pressure gradient between the LV and the left atrium approaches zero, flow across the mitral valve is equal to pulmonary vein inflow, which is limited by LV pressure and compliance; and (4) atrial contraction —or pulsed Doppler-derived A-wave. Qualitative and quantitative evaluation of these four diastolic measures by Doppler echocardiography is essential to determine diastolic function and to estimate LV filling pressures noninvasively. Other echocardiographic surrogates of diastolic function are left atrial enlargement, a prevalent feature of hypertensive heart disease ; pulmonary vein flow pattern; and pulmonary arterial pressure. A detailed description of the evaluation of LV diastology is beyond the scope of this chapter. Fig. 25.5 summarizes echocardiography-derived grading of diastolic dysfunction utilizing Doppler-derived measurement of the early and late mitral inflow and pulmonary vein patterns, tissue Doppler-derived atrioventricular annulus velocities, and color Doppler–derived mitral inflow propagation velocity. Strain and strain rate can be assessed with echocardiography or MRI; these promise to be useful determinants of both the diastolic and systolic function of the LV. The association of some common measures of diastolic function with incident cardiovascular events, including heart failure, has been well established.

Anatomic Classification of Hypertensive Heart Disease.

Pressure overload of the left ventricle initiates concentric remodeling as a compensatory mechanism, followed by a frank increase in left ventricular mass above cutoff values for left ventricular hypertrophy. Left ventricular dilation with increased left ventricular mass occurs at a stage of decompensation. LV , Left ventricle; LVH , left ventricular hypertrophy.

Adapted from Ganau A, Devereux, Roman MJ, et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol . 1992;19[7]:1550–1558.

HFpEF is a major public health concern. Some 43% of patients admitted for heart failure have normal left ventricular ejection fraction (LVEF). HFpEF is linked to older age, female gender, diabetes, obesity, CKD, HTN, and coronary artery disease (CAD) ; thus, with an aging population, hospital admissions for heart failure, especially HFpEF, are increasing. Even after adjustment for other cardiovascular risk factors, which are common in patients with HFpEF, this common form of heart failure is associated with a marked increase in all-cause mortality. Although the clinical benefit of several medical and device-based therapies has been established in the treatment of systolic heart failure, HFpEF remains a therapeutic challenge. After several randomized trials, no specific therapy has been identified that definitively alters the course of this disease and provides a mortality benefit for these patients. Targeting the renin-angiotensin-aldosterone system has shown benefits in terms of LVH reduction and improvements in diastolic function. However, four large outcome trials studying the effects of the angiotensin blockers candesartan and irbesartan, the ACE-inhibitor perindopril, and the aldosterone antagonist spironolactone found that none of them showed a reduction in mortality rates in the active treatment arms. Nonetheless, spironolactone showed a reduction in heart failure hospitalizations, especially in North American study participants. An echocardiographic substudy of this trial showed that more than a third of study participants had both normal systolic and diastolic function ( Fig. 25.6 ) . This finding suggests that current indicators of LV systolic and diastolic function are inadequate to diagnose cardiac dysfunction in a large portion of patients admitted for heart failure.

Classification of diastolic function by Doppler/tissue Doppler echocardiography and correlating left ventricular and left atrial abnormalities. A , Late mitral inflow velocity during atrial contraction; AR , pulmonary vein flow reversal during atrial contraction; ARdur and Adur , duration of AR or A; D , diastolic component of pulmonary vein flow; DT , early mitral inflow deceleration time; E , early mitral inflow velocity; e ’, early annular velocity by tissue Doppler; S , systolic component of pulmonary vein flow.

From Redfield MM, Jacobson SJ, Burnett JC, et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA . 2003;289[2]:194–202.

Systolic Heart Failure

Although LVEF has been shown to be an insensitive measure of systolic function, it is the most commonly used parameter for describing cardiac function in clinical practice. It is most commonly assessed with measurements of end-diastolic and end-systolic volume from 2D echocardiography. 3D echocardiography or cardiac MRI are considered the gold standard in the estimation of LVEF. More sensitive indices of systolic function are global longitudinal strain, radial strain, circumferential strain, and LV torsion by speckle-tracking echocardiography, but these modalities are not yet widely used. Decreased LVEF is an important predictor of mortality in ischemic and nonischemic cardiomyopathy, with major implications for medical treatment and the prevention of sudden cardiac death. Although hospital admission for HFpEF is most common among white women, black males have the highest proportion of hospitalization for HFrEF.

A link between LVH and systolic function was found in the population-based Cardiovascular Health Study. Increased LVMI in relation to BSA was a strong predictor of depressed LV function after an average of 4.9 years of follow-up independent of age, baseline BP, diabetes, CAD, and Q-waves or atrial fibrillation on baseline ECG. This finding suggests that LVH is a direct or indirect—via ischemic events—predecessor of systolic deterioration in hypertensive heart disease. In patients with LVH, even minimal increases in natriuretic peptides and cardiac troponin may identify malignant subgroups with a high risk for progression to systolic heart failure and cardiovascular death. The treatment of systolic heart failure—including medical therapies, device-based therapies, and the prevention of sudden cardiac death—is beyond the scope of this chapter and is described in other pertinent chapters of this book. It should be noted here, however, that a reduction of LVH with medical therapy also improves systolic LV function.

Myocardial Ischemia

Convincing evidence exists that both HTN and LVH are potent risk factors for coronary heart disease. In the Framingham Heart Study, LVH was an important determinant of CAD in older participants. Similarly, in the CARDIA study, LV mass by echocardiography was independently associated with coronary calcium in young adults. Thus HTN, especially when accompanied by LVH, appears to cause progressive coronary plaque buildup to the point where the disease leads to cardiovascular events. Furthermore, LVH is associated not only with stable CAD from progressive arterial narrowing but also with increases in the risk of acute coronary plaque rupure. In addition to macrovascular ischemia from epicardial CAD, microvascular ischemia is a hallmark of LVH and leads to cardiac complications. As a consequence, in hypertrophied hearts suffering ST-elevation myocardial infractions, the resulting infarct size is larger, the postinfarction LVEF is lower, and the risk of death and heart failure is more than doubled. Therapeutic implications of microvascular blood flow disturbances are discussed in the last section of this chapter (Treatment Targets and the J-Curve Debate). Microvascular angina in the absence of obstructive epicardial CAD is now an established clinical entity and seems to be more common in women. From a mechanistic point of view, both microvascular and macrovascular ischemia are key factors in the development of hypertensive heart disease and both perpetuate its progression.

Atrial Fibrillation (see also Chapter 38 )

Atrial fibrillation is the most common supraventricular arrhythmia, with a prevalence ranging from 0.1% in individuals younger than 55 years to 10% in octogenarians; moreover, the prevalence estimates are higher in Europe than in the United States. As in the case of hypertensive heart disease and diastolic dysfunction, atrial fibrillation is closely linked to older age, HTN, obesity, and diabetes. HTN is the most prevalent modifiable risk factor for atrial fibrillation on a population level. The severity of diastolic dysfunction, as well as the degree of left atrial enlargement, both correlate with the rate of incident atrial fibrillation. Increased left atrial pressure load from chronic HTN and diastolic dysfunction causes similar changes in the atrial myocardium as previously described in the ventricular myocardium in the development of LVH (see section titled Pathophysiologic Mechanism). Myocyte hypertrophy, interstitial fibrosis, cell loss, and changes in structural and electrophysiologic properties can lead to zones of conduction slowing and microreentrant circuits (i.e., “rotors”) that perpetuate atrial fibrillation. In animal models, pressure overload from aortic banding, angiotensin II infusion, and 5/6 nephrectomy—a model of CKD—all caused left atrial fibrosis and increased atrial fibrillation inducibility. Oxidative stress and inflammation appear to be centrally involved, because pharmacologic antioxidants suppressed both left atrial fibrosis and atrial fibrillation inducibility in these animal models. Important clinical sequelae of atrial fibrillation are thromboembolism and worsening heart failure, both from loss of atrial systole in preload-dependent stiff LV and from deterioration of systolic function from persistently elevated heart rates (i.e., tachycardia-mediated cardiomyopathy). Higher BP was associated with an increased risk of stroke and thromboembolism in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Atrial fibrillation has also been associated with an increased risk of mortality independently of presence or absence of hypertensive heart disease. In addition, new-onset atrial fibrillation increases the risk of sudden cardiac death in patient with LVH. Therefore the prevention of atrial fibrillation could conceivably improve outcomes in hypertensive heart disease. This question has been asked in one large observational study and two post hoc analyses of randomized studies. In these studies, subjects who received an ARB had a significant (19%–37%) relative risk reduction for new-onset atrial fibrillation compared with control subjects. In contrast, in a large randomized trial for the prevention of recurrent (not new-onset) atrial fibrillation as the primary outcome, assignment to the ARB valsartan was ineffective.

Sudden Cardiac Death

Patients with LVH have a greater incidence of ventricular premature beats and ventricular tachycardia irrespective of the etiology of LVH. Sudden cardiac death, which is most frequently caused by sustained ventricular tachyarrhythmias, is among the leading causes of death worldwide and has been linked to LVH in large epidemiologic studies and registries. In the Framingham Heart Study there was a 1.45-fold increase in sudden cardiac death risk for every 50 g increase in LV mass. Although the mechanisms are not well understood, the arrhythmogenic substrate for sudden cardiac death may be subendocardial ischemia, interstitial fibrosis, increased sympathetic tone, increased tissue catecholamine levels, repolarization delay (i.e., prolongation of the QT interval), increased incidence of early afterdepolarizations, and a genetic predisposition of channelopathies in patients with LVH. Interestingly, in a population-based study of sudden cardiac death victims, LVH by ECG and LVH by echocardiography showed little overlap and were, in terms of risk prediction, nearly distinct entities. Because of the strong association between LVH and sudden cardiac death, the former may be a viable treatment target to prevent the latter. Indeed, regression of LVH decreased the incidence of sudden cardiac death in two large studies. In the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study, sudden cardiac death occurred at similar rates in both the atenolol and losartan treatment arms. However, absence of on-treatment LVH by Cornell voltage-duration product criteria on ECG was associated with a 66% risk reduction for incident sudden cardiac death even after adjustment for demographic and clinical characteristics. Given these and other encouraging results, it has been speculated that LVH could increase accuracy in the prediction of sudden cardiac death and thus make the implantation of implantable cardioverter defibrillators more cost-effective.

All-Cause Mortality

LVH is a potent cardiovascular risk factor independent of the degree of BP elevation or other comorbidities. In the Framingham Heart Study, adults above 40 years of age without apparent cardiovascular disease underwent echocardiography for the determination of LV mass. During a mean follow-up of 4 years, the relative risk for all-cause mortality for each 50 g increase in LV mass increased by 49% in men (adjusted relative risk [aRR] 1.49, confidence interval [CI] 1.14–1.94) and doubled in women (aRR 2.01, CI 1.44–2.81). In patients who are treated for HTN, LVH carries a much greater risk for cardiovascular death. In an observational study of 280 patients with essential HTN, after a mean follow-up period of over 10 years, cardiovascular death occurred in 14% of individuals with LVH compared with 0.5% of individuals without LVH ( P < .0001). Conversely, in the LIFE study, absence of in-treatment LVH was associated with a markedly reduced risk for all-cause mortality (multivariable adjusted hazard ratio 0.36, CI 0.23–0.59, P < .001) ( Fig. 25.7 ) . LV mass by echocardiography (not ECG) and age—not gender or BP—were the only independent predictors of cardiovascular events. Across the range of LV geometry, concentric LVH was associated with the greatest risk. Interestingly, an obesity paradox appears to exist for the association of LVH with all-cause mortality in women. In a large retrospective study of over 26,000 women with normal systolic LV function who underwent echocardiography in a major academic center, abnormal LV geometry was more common in obese than in nonobese individuals ( Fig. 25.8 ) . Although LVH—concentric more so than eccentric hypertrophy—was associated with increased all-cause mortality in both obese and nonobese individuals, this increase in mortality was much less dramatic in obese than in nonobese women .

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