INTRODUCTION
Heart failure is a clinical syndrome of signs and symptoms resulting from cessation of normal heart function whereby the heart is not able to pump enough blood to meet the body’s energy demands. Hence, heart failure is not a specific disease entity; instead, the development of heart failure represents the final common pathway of any and all forms of cardiovascular disease. The diagnosis of heart failure is incomplete without assignment of a specific etiology. The components of the cardiac cycle provide an intellectual framework for the appropriation of the breakdown in heart function. As a result, terms such as “diastolic heart failure” or heart failure in the setting of “normal systolic function” have crept into the medical nomenclature.
Although it is practical to classify heart failure patients as those with either normal or abnormal systolic function, such a classification is based on physiologic principles destitute of virtue. Each component of the cardiac cycle is functionally dependent on the other. Unlike two-dimensional (2D) echocardiography, where crude parameters of cardiac performance such as ejection fraction are used, Doppler echocardiography is able to detect and quantitatively display minor amplitude and temporal subtleties that may occur in ventricular mechanical function. Traditionally, parameters of diastolic function have been derived from Doppler, and those of systolic function from 2D variables. This may create the illusion that individuals with heart failure have “normal systolic function.” The interrogation of cardiac function with derived parameters of deformation such as strain and strain rate confirm the illusion despite frequent pronouncements and mutual citation. Despite its incipient limitations, for the purpose of further discussion the term diastolic heart failure (DHF) will be used in this chapter to refer to the syndrome of heart failure in the setting of normal ejection fraction.
Individuals with heart failure, whether associated with a normal or a reduced ejection fraction, may be equally disabled and have a similarly poor prognosis. In individuals with heart failure, independent of etiology, the New York Heart Association (NYHA) functional classification is useful in defining prognosis and monitoring response to treatment. Similarly, a comprehensive evaluation and staging of diastolic function, independent of disease, is useful in defining prognosis, monitoring response to treatment, and developing new treatment strategies.
Diagnosis and staging of diastolic dysfunction provide a framework for the approach to management of individuals with DHF (see Chapter 10 ). The echocardiogram is a powerful tool enabling the clinician to noninvasively obtain parameters of flow, pressure, and resistance and thus evaluate intracardiac hemodynamics influenced by ailments in the diastolic phase of the cardiac cycle.
PATHOPHYSIOLOGY
The mitral valve is the door that when opened exposes the left atrium to the hemodynamic elements of the left ventricle. Prolonged exposure to elevated filling pressure results in structural remodeling of the left atrium. Therefore, the comprehensive evaluation of diastolic function should begin with a measure of left atrial (LA) size. The anteroposterior dimension of the left atrium obtained by M-mode echocardiography was initially the only available method to determine LA size. However, for this unidimensional measurement to accurately represent the true LA size, it must be assumed that it bears a consistent relation to other LA dimensions. This assumption is not accurate, and thus LA size should be represented by a volume-based method of evaluation. As diastolic function is staged from mild to moderate to severe, so will there be mild, moderate, and severe increases in LA volume in the absence of atrial arrhythmias or valvular heart disease. LA volume may therefore be considered the “morphophysiologic” expression of left ventricular (LV) diastolic function. LA volume reflects the cumulative effect of exposure to increased LV filling pressure over time. An increase in LA volume has profound clinical implications. LA volume has been found to be a robust predictor of cardiovascular outcomes, not the least of which is an increased risk for the development of heart failure.
CLINICAL RELEVANCE
Primary Prevention of Diastolic Dysfunction
Identification of risk and intervention prior to overt disease is essentially the first therapeutic target for all disease and no less our first strategy in the management of DHF. The age distribution of DHF incidence is skewed toward the elderly, and in individuals over 70 years of age the incidence of DHF exceeds that of heart failure with reduced ejection fraction. A primary prevention strategy becomes even more germane as society is faced with a burgeoning elderly population creating a social and health care economic crisis. Echocardiography, with its ability to reliably and reproducibly measure LA volume, provides a window of opportunity to identify individuals at risk for DHF and potentially provide therapeutic intervention. The intervention for prevention is based on little clinical trial data and requires the art of medicine to intervene.
DHF is a pathophysiologic manifestation of a heterogeneous group of diseases. Common underlying etiologies of DHF include hypertension, ischemic and diabetic heart disease, metabolic syndrome, and obesity. Less common but important considerations are diagnoses of valvular heart disease, infiltrative and storage diseases, hypertrophic cardiomyopathy, pericardial disease, and other restrictive cardiomyopathies. Another very important but underappreciated etiology for DHF is sleep apnea. Ventricular-arterial stiffening contributes importantly to the development of DHF. Precipitating factors (acute decompensation) of DHF may include sudden elevation in blood pressure, tachycardia (commonly atrial fibrillation with an uncontrolled ventricular response), acute ischemia, renal failure, anemia, the institution of nonsteroidal antiinflammatory medication, and other factors, such as excessive salt load that may increase intravascular volume. Early identification and aggressive targeted treatment of underlying etiologies and potential precipitating conditions, as mentioned above, must be the goal of short- and long-term management strategies. Neurohormonal modulation of the renin-angiotensin-aldosterone system (RAAS) has a proven salutary effect on each of the above-mentioned conditions.
Angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin I receptor antagonists (ARBs), and aldosterone receptor antagonists (ARAs), independently of their hemodynamic effect, mediate potentially favorable effects of reduced smooth muscle cell growth, prevention of collagen deposition, and reduced growth factor expression. Statins have touted similar pleiotropic effects. Intellectually intriguing is the low threshold to the use of statins and consideration of therapy targeting the RAAS in individuals with an increased LA volume and/or a subclinical history of coronary disease (positive coronary artery calcification score by computed tomography or increased carotid intima-media thickness) or prediabetes in an effort to prevent eventual development of DHF. Limited data in patients with hypertension suggest that favorable remodeling of the left atrium can be influenced. ACEIs may also result in favorable remodeling of the left atrium (the morphophysiologic expression of diastolic function) independently of their influence on blood pressure. Opportunities exist for these hypotheses to be tested in clinical trials (see Chapters 32 and 34 ). Until furnished with data, definitive therapeutic recommendations are null, and potential therapeutic approaches are based on prophecy.
Secondary Prevention and Treatment of Diastolic Heart Failure
In individuals with DHF, the question is generally not what the cumulative effect of filling pressure over time has been, but rather what the filling pressures at the instant in time of the evaluation are. The echocardiogram reliably provides us with this information through the integration of data obtained from blood flow velocities with those of wall motion analysis. This integrative evaluation also allows for staging of disease severity ( Fig. 33-1 ) (see Chapter 10 ). Here the evaluation often begins with measures of the mitral inflow velocity profile ( Fig. 33-2 ). Annular excursion interrogated generally with Doppler tissue imaging techniques provides an evaluation of wall motion ( Fig. 33-3 ). Notwithstanding constrictive pericarditis, ubiquitous to individuals with diastolic dysfunction is a relaxation abnormality of the left ventricle. This is characterized by a low early mitral inflow velocity (E) and E/A ratio (A = the atrial component of mitral inflow), with a prolonged deceleration time and a low early mitral annular velocity (E′). With progression to more severe diastolic dysfunction, the association of reduced LV compliance with increased LA pressure will result in an increase in the E velocity and E/A ratio and a reduction in deceleration time. The mitral blood flow velocity profile may now appear normal. However, the E′ velocity will remain reduced, identifying the underlying LV relaxation abnormality. The E/E′ ratio can therefore be used to discriminate an individual with normal versus grade II diastolic dysfunction.
Similarly, individuals with a restrictive mitral inflow pattern, E/A greater than 2, and deceleration time less than 150 msec who are able to favorably influence the mitral inflow velocity profile with hemodynamic manipulation (often the Valsalva maneuver) declare themselves of less severe diastolic dysfunction than those with an irreversible restrictive pattern. The former are designated with grade III diastolic dysfunction and the latter are designated with grade IV. Beyond the scope of this chapter but worthy of note is that the evaluation of the pulmonary venous blood flow velocity profile, the mitral inflow flow propagation velocity, and a measure of the isovolumic relaxation time may also be helpful in the evaluation and staging of diastolic dysfunction.
The absence of clinical trial data makes treatment of DHF largely empirical and generally based on therapeutic strategies thought to favorably target the underlying causative etiologies and precipitating factors. As the etiologic classification of individuals with DHF is varied, so are recommended treatment strategies. For example, the need to individualize the therapeutic approach to DHF is highlighted by judicious blood pressure control in hypertensive patients, anti-ischemic therapy (pharmacologic and/or revascularization) in patients with ischemic heart disease, treatment of sleep apnea, definitive management of valvular heart disease, gradient reduction therapy in individuals with hypertrophic cardiomyopathy, surgical treatment of constrictive pericarditis, control of ventricular rate, restoration and maintenance of sinus rhythm in individuals with atrial fibrillation, and appropriate targeted therapies for disorders such as hemachromatosis, Fabry’s disease, and amyloidosis.
As one cannot categorize individuals with DHF into a homogeneous etiologic classification, should one create a simple unifying treatment strategy? This is a consideration often overlooked in the design of heart failure trials. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Preserved) trial, a prospective outcome trial evaluating a treatment strategy (candesartan) solely for individuals with DHF, included a heterogeneous etiologic classification of DHF. The findings, however, were promising, showing a significant reduction in hospitalization for heart failure and a strong trend toward significance in the primary outcome of death or hospital admission for heart failure. We await the results of the Irbesartan in Heart Failure with Preserved Systolic Function (I-Preserve) trial, in which inclusion defined a more discriminate patient population.
A number of small studies have evaluated the efficacy of ACEIs, ARBs, beta blockers, digoxin, and calcium channel blockers in the management of patients with DHF. These studies have yielded dichotomous outcomes and little conclusive insight into definitive treatment strategies. The echocardiographic staging of diastolic dysfunction (see Fig. 33-1 ) may provide a useful guide for therapeutic intervention. Congestive symptoms can often be ameliorated with the judicious use of venodilators and diuretics. Medications that modify atrioventricular (AV) nodes can be used to slow heart rate and increase the diastolic filling time. Additional neurohormonal modulation is intellectually intriguing. Treatment may be tailored to a defined success of a reduction in diastolic dysfunction grade and NYHA functional class.
Individuals with grade 1 diastolic dysfunction are generally asymptomatic at rest but may complain of dyspnea on mild exertion. In the normal heart, as heart rate increases, there is an increase in contractility and faster relaxation. In myocardial disease, there is incomplete restitution, less LV pressure decline, reduced coronary flow reserve, and thus higher LV diastolic pressure ( Fig. 33-4 ). For these individuals, the duration of diastole is critical, and beta blockers or rate-slowing calcium channel blockers often provide a favorable symptomatic response. In Figure 33-5 , intracardiac hemodynamics are favorably influenced with diuresis, and better blood pressure control is characterized echocardiographically by a change to a grade I mitral inflow velocity profile and reduced E/E′ ratio. The persistent and unchanged reduced E′ velocity suggests that myocardial mechanical properties are in fact unaltered, but with hemodynamic manipulation a more favorable position of the end diastolic pressure-volume relationship has been achieved. In patients with grade 3 or 4 diastolic dysfunction, LV filling may be complete in middiastole. Such patients have a fixed stroke volume, and empirically slowing the heart rate to between 50 and 70 bpm may result in a further reduction in cardiac output and a worsening of the clinical symptom complex. Therefore, in these patients, the initiation of beta blocker therapy should be monitored closely and done with small doses.
