Heart Failure as a Consequence of Hypertension

Introduction: Definition and Impact

Hypertension (HTN) affects over 1 billion people worldwide and is the most prevalent risk factor for the development of heart failure. Despite some improvements in the treatment and control of HTN, the societal burden of hypertensive heart disease in an aging population has increased and heart failure—one major manifestation of hypertensive heart disease—continues to be the most frequent hospital admission diagnosis in the United States. The term “hypertensive heart disease” encompasses a spectrum ranging from clinically silent structural remodeling, such as left ventricular hypertrophy (LVH), to the development of clinical symptoms—often decades later—such as heart failure. Fig. 25.1 is a diagram of the progression and cardiovascular complications of hypertensive heart disease.

Fig. 25.1, Risk factors and the progression of hypertensive heart disease and its complications. AFIB , Atrial fibrillation; CHF , congestive heart failure; CKD , chronic kidney disease; LVH , left ventricular hypertrophy; MI , myocardial infarction; SCD , sudden cardiac death.

The human heart is a highly adaptive organ that responds to pressure overload by recruiting contractile elements in order to maintain normal left ventricular (LV) systolic wall stress; this includes myocyte hypertrophy with increased relative wall thickness (RWT), or concentric LVH. Although LVH can precede the clinical diagnosis of HTN, it is thought of as the inciting event in the development of hypertensive heart disease. Complex neurohumoral stimulation accompanies chronic HTN and eventually leads to cardiomyocyte dysfunction, pathologic increases in cardiac extracellular matrix (i.e., fibrosis), and disturbance of the intramyocardial microvasculature. LV diastolic dysfunction, left atrial enlargement, and atrial arrhythmias are early clinical signs of hypertensive heart disease. The development of ischemic events as a result of HTN is a common but not obligatory intermediate disease stage that can accelerate the progression of hypertensive heart disease. Finally, increases in LV dimensions, worsening of systolic performance, and ventricular arrhythmias indicate severe or end-stage disease.

LVH is a potent cardiovascular risk factor independent of the degree of blood pressure (BP) elevation or other comorbidities and correlates with biomarkers. Regression of LVH with medical treatment, even in advanced stages of hypertensive heart disease, improves prognosis and thus may be an important therapeutic target.

This chapter provides an overview of the diagnosis, epidemiology, molecular mechanisms, and treatment of hypertensive heart disease.

Left Ventricular Hypertrophy

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.

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.

Fig. 25.3, Hemodynamic and Neurohumoral Stimuli and Pathways Leading to Myocyte Hypertrophy.

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.

Molecular Mechanisms

a.
The Renin-Angiotensin-Aldosterone System ( see also Chapter 5 ) : Local release of angiotensin II causes the activation of G protein and rho protein, increasing protein synthesis in myocardial cells, and collagen synthesis in fibroblasts. Overexpression of angiotensin II in transgenic mice causes pressure-independent LVH. Angiotensin II may also stimulate the release of paracrine endothelin-1 from fibroblasts. Clinical evidence for the importance of renin stimulation and angiotensin II in the development of LVH comes from the fact that angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors are the most effective medical therapies used to reduce LVH in hypertensive individuals.
b.
Aldosterone: As described earlier, the renin-angiotensin-aldosterone system is important in the genesis of LVH. However, medical treatment with ACE inhibitors or ARBs does not protect against the effects of circulating aldosterone (i.e., aldosterone escape). Cardiomyocytes express mineralocorticoid receptors. Aldosterone itself has been shown to cause vascular and cardiac inflammation, myocardial fibrosis, and cardiac hypertrophy. In a hypertensive model of endothelial dysfunction, eplerenone prevented cardiac inflammation and fibrosis. The nonselective aldosterone antagonist spironolactone and the selective aldosterone antagonist eplerenone provide clear clinical benefit in patients with systolic heart failure and less clear benefit in patients with diastolic heart failure These agents decrease LVH as efficiently as an ACE-inhibitor and even more efficiently if given in combination with an ACE inhibitor. These data strongly suggest that aldosterone is directly involved in the development of hypertensive heart disease. The interplay between hyperaldosteronism, LVH, and atrial fibrillation has been comprehensively reviewed by Saccia and colleagues.
c.
Endothelin-1: Endothelin has been shown to induce hypertrophy in animal models, and this phenotype can be suppressed by a pharmacologic endothelin-1 receptor blocker. Direct evidence of endothelin-1 from human studies is lacking. As mentioned previously, there is an interplay between angiotensin II and endothelin-1.
d.
Heat-Shock Proteins: This is a group of intracellular proteins that become more abundant in cells exposed to thermal or other forms of stress; they regulate nuclear transcription factors. One of these is factor NF-κ-B, which was increased in a pressure-overload model in the rat and can be suppressed by either gene therapy with a viral vector or an antioxidant substance. As a result, the hypertrophic response to pressure overload was markedly attenuated in treated animals. Furthermore, in mice with cardiomyocyte-restricted expression of an NF-κ-B superrepressor gene, both angiotensin II and isoproterenol induced a hypertrophic response and the expression of hypertrophic markers, such as β-myosin heavy chain and natriuretic peptides, was reduced. The proteasome-inhibitor PS-519, which is known to suppress NF-κ-B, prevented isoproterenol-induced LVH when given before and during isoproterenol infusion and caused regression of LVH in those animals, which already had isoproterenol-induced LVH.
e.
G proteins: Many substances involved in the hypertrophic response to pressure and stress—including phenylephrine, angiotensin II, and endothelin-1—bind to myocyte membrane receptors that activate G protein and small subforms of G proteins (i.e., Rho proteins). These proteins regulate transcription and have been shown to be involved in phenylephrine-induced LVH. In addition, in transgenic mice that overexpress the carboxyl-terminal peptide of the G protein and thus inhibit normal G-protein activation, the slope of the hypertrophic response to increased LV pressure overload from transverse aortic banding was less steep.
f.
Calcineurin: Calcineurin is a calcium-dependent phosphatase; it dephosphorylates cytosolic factors, enabling them to translocate to the nucleus to activate transcription. Transgenic mice that overexpress calcineurin or its transcription factor targets develop cardiac hypertrophy and failure. This phenotype can be suppressed with pharmacologic calcineurin inhibition.

Genetic Determinants of Left Ventricular Hypertrophy

In the Framingham Heart Study it was estimated that heritability of LVMI was between 0.24 and 0.32 in patients without known cardiac disease and a low risk-factor profile. A much higher estimated heritability of 0.59 was found in a study of 182 monozygotic and 194 dizygotic twins. In addition, clinical observations have found a large variability of LV mass in patients with similar office BP and exceedingly high rates of LVH in certain race/ethnic populations. This suggest a genetic predisposition for the development of LVH in response to pressure overload. Indeed, some genes associated with LVH have been identified: (1) Corin is the enzyme responsible for processing the preforms of atrial and brain natriuretic peptide (ANP and BNP), which are protective against LVH. Corin knockout mice develop HTN and cardiac hypertrophy. Mutations of the corin I555(P568) gene were exclusive to African Americans in multiethnic samples with an allelic prevalence of 6% to 12%. The association of this mutation with an increased prevalence of HTN and LVH in African Americans has been demonstrated in three independent population-based samples. (2) Protein C overexpression causes progressive LVH and diastolic dysfunction in animals. (3) The bradykinin-2 receptor gene polymorphism, specifically the 9-bp receptor gene deletion, is associated with greater LV mass in subjects undergoing physical training. (4) ACE gene polymorphism is also associated with both greater tissue and plasma ACE levels and a greater probability for LVH.

Classification and Diagnosis of Hypertensive Heart Disease

Hypertensive heart disease is classified using a combination of structural and functional criteria. Two distinct entities are excluded from these classifications and therefore not discussed in this section: (1) physiologic hypertrophy, as seen in pregnant women or athletes, which leads to moderate adaptive increases of LV internal dimensions and LV muscle mass but with normal RWT (0.32–0.42) and normal Doppler-derived LV filling parameters, and (2) genetic or acquired hypertrophic cardiomyopathies in which pressure-independent LV wall thickening due to sarcomere-protein mutations occurs, as is seen in familial hypertrophic cardiomyopathy or with protein/glycolipid deposits as seen in amyloidosis or Fabry disease.

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.

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.
Class II : LVH
- IIA: With normal or mildly abnormal functional capacity (New York Heart Association class I)
- IIB: With abnormal functional capacity (New York Heart Association class II or greater)
Class III: HFpEF—clinical signs and symptoms of cardiac decompensation (i.e., dyspnea, pulmonary edema) from increased left atrial pressure
Class IV: HFrEF

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