INTRODUCTION
Hypertension and valve disease are key risk factors for heart failure. Uncontrolled hypertension results in left ventricular (LV) remodeling, often with an increase in LV mass. Valve disease is associated with pressure or volume overload of the left ventricle, depending on its etiology. Significant valve disease is associated with LV remodeling, usually with LV hypertrophy (LVH). The pattern of LV remodeling and its severity vary depending on the nature, severity, and chronicity of valve disease. LV remodeling is a fundamental substrate for overt heart failure. Thus, an overlap exists between the pathophysiology of LV remodeling in hypertensive heart disease and severe valve disease. The hypertrophic response in patients with valve disease results from the activation of biological pathways that also play a key role in the evolution of hypertensive heart disease. LV diastolic impairment occurs in patients with hypertension or valve disease, even in those without evidence of LVH or systolic dysfunction. Cases of heart failure due to hypertension and valve disease both frequently manifest with a preserved LV ejection fraction.
When heart failure occurs in association with a normal LV ejection fraction but with concomitant LV diastolic filling abnormalities, the term diastolic heart failure (DHF) has been used. In cases of heart failure on the basis of hypertension, blood pressure control may lead to amelioration or resolution of abnormal LV diastolic function, and therefore may change the natural progression to hypertension-associated DHF. In the case of valve disease, medical management and/or surgical correction of the condition is associated with resolution of heart failure and LV diastolic dysfunction.
In this chapter, we discuss pathophysiologic and clinical considerations in DHF due to hypertension or valvular heart disease. Although valvular heart disease constitutes an exclusion in some definitions of DHF, we employ a broader view by examining these conditions in the context of the syndrome of heart failure with preserved LV systolic function.
PATHOPHYSIOLOGY AND CLINICAL RELEVANCE OF DIASTOLIC DYSFUNCTION IN HYPERTENSION
Mechanical Considerations
Hypertension increases the load on the left ventricle, with a resultant increase in LV mass (referred to as hypertrophy ). The LV response to increased load is to normalize wall tension. According to Laplace’s law, wall stress is defined by its relationship with pressure ( p ), chamber radius ( r ), and wall thickness ( h ), thus:
Laplace’s law: Wall stress = p × r / 2 × b
To normalize wall stress in the presence of pressure overload, LV wall thickness increases, and this concept is applicable to both hypertension and valvular disease. Initially, this response to increased wall tension occurs with thickening of the LV walls within the “normal” range. However, progression toward an abnormal increase in LV wall thickness occurs with prolonged exposure.
The development of LVH is not only load dependent but multifactorial and may be influenced by endocrine, autocrine, paracrine, and genetic factors. It is of interest that both blood pressure and LV mass exhibit familial aggregation and are heritable quantitative traits. Additionally, familial aggregation of LV diastolic measures and left atrial (LA) size (a marker of diastolic dysfunction) has also been reported, suggesting that LV diastolic dysfunction in response to stressors such as pressure overload may be modulated in part by genetic influences and shared environmental factors.
Hypertension and Left Ventricular Mass
Systolic blood pressure is an important determinant of LV mass in hypertension. LV mass (LVM), in grams, is calculated by echocardiography using the following equation :
LVM(g) = 1.04 × [ ( IVS + LVEDD + PWT ) 3 – LVEDD 3 ] – 13.6 ,
In hypertensive individuals, observed LV mass may be significantly greater than that which is predicted based on demographic, clinical, and hemodynamic factors (e.g., systolic blood pressure, stroke volume, sex, height). For instance, de Simone et al. calculated predicted LV mass as :
LVM = 39.95 + 14.61 × height ( m 2.7 ) + 0.65 × SW ( grams-meters / bear ) – 17.17 × sex ,
Regression of increased LV mass is correlated with reduction particularly in systolic blood pressure and parallels similar changes in the electrocardiogram (ECG). In patients with regression of LVH on ECG with treatment, there is regression of LV mass.
Hypertension and Left Ventricular Geometry
The effect of hypertension on LV diastolic dysfunction is also partly dependent on LV geometry (see the section “Echocardiographic Features of Hypertensive Left Ventricular Hypertrophy”), a phenotype defined on the basis of presence versus absence of LVH, and the relative wall thickness (RWT). The RWT has been calculated as:
RWT = 2 × PWT / LVEDD .
The RWT is considered to be increased if greater than 0.42. Alternatively, RWT has also been calculated as:
RWT = ( IVS + PWT ) / LVEDD
In those without LVH, normal LV geometry is represented by normal LV mass and normal RWT, whereas concentric LV remodeling is defined by normal LV mass and increased relative wall thickness. Concentric remodeling represents the early adaptive changes to decrease LV wall tension in response to an increase in pressure overload. In the presence of LVH, LV geometry may be concentric or eccentric. Concentric hypertrophy occurs when RWT is increased and LVH is present, often in the presence of reduced ventricular internal dimensions. Eccentric hypertrophy is characterized by ventricular enlargement and an increase in LV mass, where wall tension is increased by virtue of an increase in radius so that RWT is normal.
Hypertensive Overload and Left Ventricular Diastolic Dysfunction
In hypertension, ventricular hypertrophy occurs to compensate for elevated wall stress and increased ventricular stiffness, and impaired LV relaxation may ensue. Impairment in LV relaxation decreases early LV filling, and the atrial contribution to ventricular filling increases. In hypertensive states, due to increased afterload from vascular or valvular etiologies, increased LV chamber stiffness may result from an increase in myocyte hypertrophy and/or alterations in the cardiac interstitium. An increase in LV stiffness or reduction in ventricular compliance results in increased LV diastolic pressure for any degree of ventricular preload, and subsequent pulmonary venous congestion with symptoms of dyspnea.
In adult patients with diastolic, isolated systolic, borderline isolated systolic, and combined systolic and diastolic hypertension, as well as in children with hypertension, an abnormal diastolic filling pattern characterized by impaired early diastolic ventricular filling with an enhancement in late diastolic filling (due to atrial systole) has been reported, indicating sub-normal LV relaxation with normal ventricular compliance. A prolonged IVRT has also been demonstrated in hypertensive persons.
Possible contributing factors for the LV diastolic dysfunction observed in hypertensive patients include myocardial fibrosis and increased LV mass (see the sections “Cellular and Molecular Basis of Left Ventricular Diastolic Dysfunction in Hypertension” and “Clinical Epidemiology of Hypertensive Heart Disease”) although they do not always accompany hypertension. An indication that diastolic dysfunction may be present in the context of the pressure-overloaded ventricle is the identification of LVH or an abnormal increase in LV mass. Although diastolic filling abnormalities often occur when LV mass is increased, ventricular hypertrophy is not a requisite for LV diastolic dysfunction, which may also occur at an earlier stage in hypertensive patients without overt LVH. Early diastolic filling abnormalities in hypertension correlate with increased LV mass. As noted previously, LVH is one of the most common causes of isolated LV diastolic dysfunction and is an important independent risk factor for heart failure.
Myocardial fibrosis with increased interstitial collagen deposition is another mechanism underlying LV diastolic dysfunction in hypertensive subjects. There is a strong relation between LV stiffness and myocardial collagen content and plasma levels of fibrosis markers in hypertensive persons. Improvement of LV diastolic function during antihypertensive treatment is related to regression in myocardial collagen content. This may indicate that LV mass is determined mainly by loading conditions, whereas myocardial fibrosis and LV diastolic dysfunction may be the consequence of the detrimental effects of neurohormonal activation. The hypothesis that LVH and myocardial fibrosis are regulated independently of each other, and to some extent of blood pressure, is supported by limited experimental evidence.
Left Atrial Function in Hypertension
Compensatory changes in the left atrium reflect functional changes due to LVH that occur as a result of hypertensive load. Because the impairment in LV relaxation decreases early LV filling, the contribution of the left atrium to ventricular filling in later diastole increases. These changes may operate under the Frank-Starling principle, to prevent marked changes in mean LA pressure that can occur with elevated LV diastolic pressure or with an increase in LA preload. Increases in LA size and systolic force have been associated with aging, and both have been suggested as a compensatory response to age-related reduction of ventricular relaxation. LA systolic force (LASF), can be calculated echocardiographically as:
LASF = 0.53 × MOA × ( peak A velocity ) 2 ,
A change in LA size over time is not a feature of “normal aging.” The left atrium enlarges in response to changes in LV filling patterns that characterize abnormal LV relaxation, with a reduction in the emptying volume from the left atrium to the left ventricle and a reduced flow from the pulmonary veins into the left ventricle in early diastole. The left atrium may compensate by an increase in its size, an augmentation of active contraction, and an increase in late diastolic emptying. Therefore, LA size or volume is an indicator of LV diastolic dysfunction in patients without valve disease or atrial fibrillation. In one study, patients with an LA volume index of less than 27 ml/m 2 had a similar future risk of atrial fibrillation or heart failure as those with normal LV diastolic filling.
Impaired LA contractility arising from a loss of LA systolic force or atrial arrhythmia will result in a further reduction in LV preload, a decrease in cardiac output, and increased LA pressure. Hypertension is associated with LA enlargement, depression of LA contractile function, and an increased risk for atrial fibrillation, all of which can precipitate overt heart failure in patients with underlying LV diastolic dysfunction.
Effect of Associated Metabolic Risk Factors on Left Ventricular Diastolic Function in Hypertension
The concomitant presence of other cardiovascular disease risk factors can worsen the impairment of LV diastolic function in hypertension. Metabolic factors such as dyslipidemia and dysglycemia may be important in this regard. Indices of LV mass and diastolic function have been correlated with lipid profile. Additionally, elevated glucose levels, insulin resistance, and hyperinsulinemia have been associated with LV diastolic dysfunction in hypertensive patients. The development of LV diastolic dysfunction with elevated glucose levels in persons with and without diabetes has been reported in hypertensive patients, and even slight elevations in fasting glucose levels have been reported to affect LV diastolic function.
Experimental treatment interventions with thiazolidinediones and insulin-sensitizing agents have been found to inhibit cardiac hypertrophy and improve LV diastolic function. These effects are thought to be mediated in part by activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ). Additionally, these treatments may decrease cardiac fibrosis by inhibiting collagen synthesis, mediated by a decrease in the ratio of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).
Effect of Obesity on Left Ventricular Diastolic Function in Hypertension
Obesity may also modulate the development of LV diastolic filling abnormalities in hypertensive patients. In a study of lean (body mass index [BMI] <25 kg/m 2 ), overweight (BMI 26–29 kg/m 2 ), and obese (BMI >30 kg/m 2 ) persons with hypertension, LV mass itself and LV mass indexed to height increased progressively with higher BMI. The LA diameter, which reflects LA diastolic filling abnormalities, is also significantly increased in obese individuals. An increasing trend of E-wave deceleration time and IVRT with increasing BMI has been observed, and the E/A ratio was significantly lower in overweight and obese versus lean hypertensive individuals. When those with normal and abnormal LV diastolic function were compared, the major differences were older age and higher LV mass in the latter group.
Aortic Stiffness and Left Ventricular Diastolic Dysfunction in Hypertension
Among hypertensive patients, aortic stiffness has been identified as a predictor of cardiovascular mortality and all-cause death. Aortic stiffness has been closely linked with DHF in hypertension and may contribute to the pathophysiology and progression of diastolic dysfunction: Patients with DHF have stiff, large arteries and increased blood pressure lability. Mechanisms of increased aortic stiffness in hypertension include hemodynamic stress caused by high pressure in the arterial walls, structural alterations in the vasculature, and atherosclerotic disease. However, hypertension may increase aortic stiffness even in the absence of coronary artery disease. LV diastolic function in hypertension is associated with indices of aortic stiffness and may be even further increased by the coexistence of other conditions, such as diabetes. Given the associations demonstrated in early studies, evaluation of aortic stiffness may take on greater importance in future studies of DHF.
Evaluation of aortic stiffness includes assessment of aortic strain and distensibility, which are aortic elasticity parameters and can be calculated as:
Aortic strain ( % ) = ( AoSD – AoDD ) × 100 / AoDD Distensibility ( cm 2 / dyne ) = 2 × aortic strain / ( SBP – DBP ) ,
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