INTRODUCTION
Dilated cardiomyopathy (DCM) is a heterogeneous disease of the myocardium that is characterized by left ventricular (LV) or biventricular dilatation and systolic dysfunction. In the classification of the World Health Organization/International Society and Federation of Cardiology Task Force, DCM in its primary (e.g., idiopathic, familial) and secondary forms (most commonly ischemic, hypertensive, valvular, alcohol-related, or viral or autoimmune in origin) is the most common cause of the clinical syndrome of heart failure (HF). Familial DCM accounts for approximately 20% to 35% of DCM cases and has been linked to a diverse group of loci and genes.
The reported annual incidence of the primary form of DCM varies between five and eight cases per 100,000 population ; true incidence is likely underestimated, since many asymptomatic cases remain unrecognized. Primary DCM can occur at any age but is first seen mostly between the ages of 20 and 50 years. Blacks and males have a 2.5-fold increase in risk compared with Caucasians and females. The natural history of DCM is often progressive, and the clinical picture at the time of diagnosis can vary widely, with the most common initial manifestation being HF in 75% to 85% of patients. Echocardiography plays an essential role in the diagnosis and the follow-up of DCM. A portion of patients fortunately experience recovery of function and “reverse remodeling,” which can be documented with serial echocardiographic examinations.
PATHOPHYSIOLOGY
Diastolic Dysfunction in Dilated Cardiomyopathy
In patients with DCM, there are abnormalities in the LV systolic pressure-volume (P-V) relationship, which are almost always associated with changes in the diastolic portion of that relationship. Indeed, nearly all patients with systolic dysfunction have impaired relaxation and variable decreases in ventricular compliances. LV diastolic dysfunction may lead to an increase in LV diastolic pressure and greatly influence the symptomatic status and outcome of patients. Despite improved treatment, the mortality rate in DCM remains high, accounting for 10,000 deaths annually in the United States.
Diastolic function has traditionally been evaluated by cardiac catheterization with direct measurement of filling pressures and relaxation. This invasive approach, describing LV filling pressures, compliance, and relaxation as major determinants of LV diastolic function, is neither feasible nor suitable for routine evaluation. The development and validation of several noninvasive Doppler echocardiographic techniques that are relatively load independent have made echocardiography the clinical standard for the assessment of LV diastolic function.
Pathomorphology and Pathogenesis of Dilated Cardiomyopathy
DCM is heterogeneous in its morphology. Common to the whole group is a poorly contracting dilated LV with a normal or reduced LV wall thickness. The lack of an increase in LV wall thickness often masks a significant increase in LV mass. The histological changes are variable and nonspecific, including (a) increased myocyte diameter and nuclear size, (b) myofibrillary loss, (c) focal myocyte apoptosis and death, (d) increase in interstitial T-lymphocytes/macrophages, and (e) interstitial fibrosis.
The pathogenesis of DCM remains uncertain despite intense research. Four basic mechanisms have been hypothesized, including familial and genetic factors, chronic viral infection of the myocardium and other cytotoxic insults, immune abnormalities leading to cellular and humorally mediated myocyte damage, and metabolic, energetic, and contractile abnormalities. With the onset of failure of the heart’s intrinsic mechanisms for sustaining a reasonable ejection fraction (EF) (e.g., contractile protein and excitation-contraction coupling mechanisms, cellular remodeling, bioenergetics), the cardiac remodeling process gradually becomes maladaptive. This is compounded by the effects of endogenous bioactive chemicals (e.g., hormones, neurotransmitters, cytokines) and cell loss via myocyte apoptosis or necrosis compounds, which alter the expression of genes regulating contractility, contributing to the progressive myocardial dysfunction in DCM.
Diastolic Dysfunction and the Pressure-Volume Relationship
In patients with DCM and systolic HF, the abnormalities in the P-V relationship occur during systole, including decreased LV EF, stroke volume, and stroke work. As diastolic function is critically important to systolic function and is linked to it symbiotically, virtually all patients with symptomatic HF have abnormalities in diastolic function. Conversely, as diastolic function worsens and filling pressures increase, systolic function is affected by the Frank-Starling mechanism. This is often called the “yin and yang” of cardiac function. Ventricular diastole involves the complex interplay of numerous components, including LV relaxation, diastolic suction, stiffness or compliance of the myocardium, pericardial restraint, ventricular interaction, and atrial contribution. LV relaxation is related to the time constant of intracavitary pressure decay during isovolumic relaxation, whereas LV compliance and stiffness are related more to the local slope of the diastolic P-V curve. LV relaxation remains relatively intact until LV EF falls below approximately 30%. To maintain cardiac output, relaxation begins to prolong, becomes more afterload dependent, and eventually leads to elevation in LV end diastolic pressure (LVEDP). Thus, while the diastolic P-V relationship may reflect a more compliant chamber, the other abnormal diastolic indices support the conclusion that all patients with systolic HF and elevated diastolic pressures in fact have combined systolic and diastolic HF ( Fig. 20-1 ). Alternatively, some patients may have only a modest decrease in LV EF and a modest increase in end diastolic volume, but a marked increase in LVEDP and a diastolic P-V relationship, reflecting decreased chamber compliance. Conversely, improvement in systolic function following treatment often leads to concomitant improvement in relaxation, especially if these changes are mediated through the β-adrenergic pathways.
Echocardiographic Indices of Left Ventricular Diastolic Dysfunction
Abnormal ventricular contractility and dilatation are the hallmarks of DCM. Although DCM is usually a diffuse process, LV dysfunction can exist independently of concomitant right ventricular (RV) involvement in some patients. The early opening of mitral valve leaflets on M-mode echocardiography (the so-called C-hump) may reflect a high LVEDP. A large body of literature has accrued describing the various Doppler echocardiographic techniques in assessment of diastolic function. These techniques can be used alone or in combination, but most of them are dependent on heart rate, preload, and afterload. The LV filling or transmitral flow pattern remains the starting point. The pulmonary venous flow signal should always be sought as an adjunct to the mitral inflow pattern. These have been described in great detail in Chapters 2 , 10 , and 18 . Briefly, most patients can be categorized into one of the three patterns based on the following Doppler indices and timing ( Fig. 20-2 ):
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Impaired relaxation (IR) pattern. Intracardiac pressures are unaffected, but less effective suction from LV relaxation results in a delayed and diminished left atrial (LA)-to-LV early diastolic pressure gradient. This is characterized by long isovolumic relaxation time (IVRT), prolonged deceleration time (DT) of the early diastolic E wave, a high late diastolic A-wave velocity, and a decreased E/A ratio.
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Pseudonormal (PN) pattern. Increased LA pressure offsets the reduced flow related to impaired relaxation. Trans-mitral flow pattern appears normal in terms of E/A ratio and DT.
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Restrictive filling (RF) pattern. LV distensibility is reduced because of increased intrinsic stiffness or decreased operating compliance, and LA pressure is increased. The elevated LA pressure results in an increased E velocity. The decrease in mid-to-late diastolic distensibility produces a more rapid transmitral pressure equilibration, creating a “dip-and-plateau” effect. This is characterized by short IVRT, high E velocity and short DT, and reduced A velocity. This pattern can be further stratified into “reversible” and “irreversible” subgroups with loading manipulations, resulting in incremental prognostic value.
Because the majority of patients with DCM are studied while on medications, drug effects must also be considered. A study by Makhoul et al. demonstrated a direct relationship between changes in pulmonary capillary wedge pressure (PCWP) induced by intravenous isosorbide dinitrate and the transmitral E/A ratio. The initial high E/A ratio, typical of the RF pattern, was reduced by more than 50% after administration of nitrates in nearly all patients with New York Heart Association class IV HF. In addition to analysis of filling pattern, the mean LA pressure (MLAP) may be accurately predicted from the DT of the pulmonary venous diastolic (DTD) flow slope, using the following regression equation :
MLAP = 53.236 – [ 0.302 DTD ] + [ 0.000484 ( DTD 2 ) ] .
Other echocardiographic indices of diastolic function pertaining to DCM include rate of LV pressure decline, the Tei index, color kinesis, and flow propagation velocity (Vp).
Rate of LV Pressure Decline
This can be obtained by tracing the deceleration phase of the mitral regurgitation Doppler spectral signal and applying the Bernoulli equation to obtain the instantaneous pressure gradient between the left ventricle and the left atrium. This derivative of Tau (τ) from the velocity curve, validated in human studies as a standard for assessment of active relaxation, is not applicable to those cases of DCM without a complete mitral regurgitant envelope.
The Tei Index
This is a combined myocardial performance index (isovolumic contraction time plus IVRT divided by ejection time) that may be more effective for analysis of global cardiac dysfunction than for systolic and diastolic measures alone. Although it may be a sensitive indicator of overall cardiac dysfunction in patients with mild to moderate HF, it has variable prognostic significance in both adults and children with DCM (see Chapter 16 ).
Color Kinesis
Color kinesis is an echocardiographic technique based on acoustic quantification that allows color encoding of endocardial motion in real time. The regional LV filling properties can be derived from segmental analysis of diastolic color kinesis images. Increased diastolic asynchrony has been found in patients with DCM and severe mitral regurgitation, which are known to adversely affect global diastolic function. However, this technique is dependent on the quality of two-dimensional images and may be affected by significant cardiac translation and/or rotation.
Flow Propagation Velocity
This method offers a glance at different intrinsic LV properties that determine LV filling, such as geometry and LV synchrony. The color M-mode velocity propagation of early diastolic flow correlates with intraventricular pressure gradients and has been proposed as a load-independent indicator of LV diastolic function. Brun et al. were the first to show that Vp is related to LV relaxation. The progressive decrease of Vp runs in parallel with the increase of τ, irrespective of rising filling pressure. It is therefore free of pseudonormalization, unlike transmitral flow. Compared with the brisk Vp in normal patients, there is often significantly delayed propagation and prolongation of the duration of inflow in patients with DCM. In fact, continuous apical flow can be visualized in 25% of DCM. The ratio of E/Vp is a widely used index in the estimation of filling pressure. Coelho et al. found that in patients with severe LV dysfunction, Vp correlated closely with E/A ratio, IVRT, DT, and the Tei index. In a heterogeneous group comprising normal, ischemic, and dilated hearts, PCWP was calculated as:
PCWP = [ 5.27 × E / Vp ] + 4.6 ( mmHg ) .
Reported positive and negative predictive values for E/Vp greater than 1.5 to predict PCWP greater than 12 mmHg were 93% and 70%, respectively. Correlation between E/Vp and PCWP outperformed correlations with maximal E and E/A, independent of LV EF (see Chapter 11 ).
Tissue Doppler Imaging
Early diastolic LV longitudinal expansion, as represented by mitral annular velocity (Ea), and late diastolic mitral annular velocity (Aa) correspond fairly to the E and A waves on mitral inflow. Although Ea has been suggested as being less load sensitive than mitral inflow variables, this remains debatable. Ea is often reduced to less than 8 cm/sec in the RF pattern. Blunting of the magnitude of Ea correlates closely with diastolic dysfunction established invasively. Tissue Doppler imaging (TDI) may even be of value in the presence of atrial fibrillation, where there is no A wave.
The ratio of transmitral peak inflow E velocity to Ea has also been shown to correlate significantly with invasively derived mean PCWP using a regression equation,
Mean PCWP = 1.24 ( E / Ea ) + 1.9 ( mmHg ) ,
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