Etiology and Clinical Presentation
Dilated cardiomyopathy (DCM) accounts for 60% of all cardiomyopathies and is defined as an intrinsic myocardial disease process characterized by progressive myocyte hypertrophy, dilation, and contractile dysfunction of one or both ventricles.1,3,4 Although ventricular wall thickness can be increased, the degree of hypertrophy is proportionally less compared to the amount of dilatation.5 The development of left ventricular (LV) hypertrophy is initially beneficial in reducing systolic wall stress, a major determinant of myocardial oxygen consumption. However, wall stress is never fully normalized and eventually stimulates LV remodeling, resulting in a reduced ejection fraction (EF) as the ventricle continues to dilate and assume a spherical shape.6 The combination of apoptotic and necrotic cell death, myocardial fibrosis, and cytoskeletal uncoupling contributes to eventual myocardial mechanical failure. In contrast to hypertrophic and restrictive cardiomyopathies, which often present with normal end-diastolic volumes and preserved or increased EF, DCM is defined by increased end-systolic and end-diastolic volumes and a reduced LV EF (<45%).7 Furthermore, mitral (MV) and tricuspid valve (TV) regurgitation may be present in association with increased ventricular volume and/or pressure load. Cardiac mural thrombi may also develop in the presence of stasis associated with reduced cardiac function and blood flow velocity, and are most commonly found in the LV apex or left atrial appendage (LAA).
A variety of distinctive pathological processes including viral myocarditis, autoimmune-mediated inflammation, cytoskeletal/contractile protein abnormalities, metabolic derangements, growth factor/cytokine signaling pathways, and cardiovascular disease may be responsible for initiating the myocyte injury, ventricular dilatation, and myocardial dysfunction associated with DCM.5,8 In addition, genetic factors, peripartum cardiomyopathy, and cytotoxic insults (alcohol, chemotherapeutic agents) have been implicated. Interestingly, many affected patients are classified as having idiopathic DCM since a specific etiology cannot be determined.
DCM may occur at any age including childhood; however, it most commonly affects those 18 to 50 years old. The incidence of DCM is reported to be five to eight cases per 100,000 per year, and is more prevalent in blacks and males than in Caucasians and females.5 Many patients with DCM may be asymptomatic. The typical presentation of patients with progressive deteriorating DCM include clinical signs (third and/or fourth heart sounds, systolic murmurs consistent with atrial-ventricular valve regurgitation, pulmonary congestion, atrial fibrillation, consequences of systemic embolization from intracardiac thrombi) and symptoms (fatigue, exertional intolerance, and angina often in the absence of coronary artery disease [CAD]), all of which are consistent with LV heart failure.9 The right ventricle (RV) may be independently involved in rare cases of a familial form of DCM; however, RV failure is usually a later and more ominous consequence of primary LV failure, and is usually associated with a particularly poor prognosis.10
Mortality associated with DCM can be significant. As much as 50% of patients die within 2 years. Five-year survival following the initial diagnosis has been reported in the 50% to 75% range depending upon the initiation of therapy,11 extent of cardiac remodeling and dysfunction, and advanced age.12,13 About 25% of patients with recent-onset DCM improve spontaneously.14 Patients with DCM and advanced CHF with LV end-diastolic diameters greater than 4 cm/m2 body surface area have twice the 1-year mortality rate compared to those patients with less significant ventricular dilatation.13
DCM can be identified using a number of diagnostic modalities including electrocardiography (sinus tachycardia, ventricular dysrhythmias, poor R-wave progression, intraventricular conduction delays, anterior Q waves even without evidence of CAD), radionucleotide ventriculography (biventricular dilatation, reduced EF, regional wall motion abnormalities [RWMA]), and cardiac catheterization (elevated LV filling pressures, ventricular dilatation, reduced EF, RWMA, mitral regurgitation [MR] and occasional mural thrombi).10 Two-dimensional (2D) and Doppler echocardiography are important noninvasive techniques for defining the degree of ventricular impairment, assessing valve function, and diagnosing intracardiac thrombi. In addition, echocardiography is essential for monitoring the response to pharmacological therapy and, when necessary, to assist in the optimal timing and planning of valve surgery, remodeling procedures, or cardiac transplantation.
Two-Dimensional Echocardiographic Evaluation of Anatomic Features
Classic 2D echocardiographic features of DCM include the presence of increased systolic and diastolic LV dimensions. The diameter of the LV in the transgastric midpapillary short-axis view is often larger than the diameter measured at the base because of the spherical configuration that develops with progressive remodeling. End-diastolic diameters may exceed 8 cm in severe DCM, and volumes can double.9 The LV wall can vary from normal to increased thickness; however, relative wall thickness (ie, the ratio of end-diastolic wall thickness to end-diastolic cavity radius) is severely diminished. In addition to increased cardiac mass and diminished contractile function, left atrial (LA) and right heart dilatation are common (Figure 14–1). RV dilatation may result from primary myocardial failure or can develop secondary to pulmonary hypertension associated with increased LV end-diastolic pressure (LVEDP). Although not pathognomonic, LV and/or RV wall motion tends to be symmetrically and globally reduced in patients with DCM compared to the typical segmental and focal wall motion abnormalities more commonly associated with ischemic heart disease and coronary artery narrowing.
Transesophageal echocardiographic views demonstrating two-dimensional anatomic features of idiopathic dilated cardiomyopathy. A: Severe dilatation and sphericity of the left ventricle (LV) is noted in this midesophageal four-chamber view. B: Midtransgastric short-axis view of the LV demonstrating severe dilatation (LV diameter = 6.5 cm). (RA, right atrium; LA, left atrium; RV, right ventricle.)
Dobutamine stress echocardiography may be helpful in demonstrating provocable differences in RWMA in patients with LV dysfunction associated with CAD, and thus differentiating them from those patients with idiopathic DCM.10,15 It is important to make this distinction since patients with ischemic cardiomyopathy may experience significant improvement in functional capacity with coronary revascularization. A central caveat of coronary revascularization is the recovery of myocardial function after resumption of flow to a chronically underperfused heart in a region known as ‘viable’ myocardium. The term hibernating myocardium refers to myocardium that is viable but exists in a state of contractile dysfunction due to hypoperfusion. Restoration of perfusion can reverse the hibernation and result in contractile recovery. Stunned myocardium is also viable and demonstrates decreased contractility, but has normal perfusion.
Evaluation of myocardial viability is based on the contractile response to inotropic stimulation, identification of perfusion, or assessment of myocardial cellular and metabolic integrity. All these techniques involve administration of an ‘uptake’ agent and an imaging modality. Contractility can be enhanced by an inotrope such as dobutamine, while imaging can be performed with echocardiography (dobutamine stress echocardiography, or DSE). Over the last 20 years, DSE has emerged as a popular, safe and cost-efficient technique for assessment of myocardial viability. While low dose dobutamine (5-10 mcg/kg/min) allows contractile reserve to be assessed, higher doses of dobutamine (up to 40 mcg/kg/min) are used to assess ischemia. At low dose, viable myocardium demonstrates an improvement in contractility. A higher dobutamine dose increases myocardial oxygen demand and if coronary flow is unable to meet the demand for increased perfusion, contractile function may worsen, indicating ischemia. Thus, low-dose dobutamine will improve function in hibernating myocardium but function will worsen with high-dose dobutamine. Both low-dose and high-dose dobutamine will improve function in stunned myocardium.
Four different patterns of response to high dose DSE are recognized: (1) monophasic (initial improvement and no deterioration) suggesting viable myocardium with no coronary stenoses; (2) biphasic (initial improvement with subsequent deterioration) indicating viability with ischemia; (3) ischemic (deterioration without initial improvement) indicating severe ischemia with critical coronary stenosis; and (4) no change throughout study, representing a transmural scar. When DSE indicates viable myocardium as well as ischemia, functional response to revascularization is more likely.
The presence of intra-atrial and intraventricular spontaneous echocardiographic contrast associated with a low cardiac output should raise concern for the presence of an intracavitary thrombus in patients with DCM and the potential need for anticoagulation to prevent systemic embolism (Figure 14–2). Thrombi tend to develop more commonly in the LV compared to the LA,16 perhaps due to the “protective” effect of blood flow turbulence associated with concurrent MR. Thrombi may be flat, laminated, and immobile, or protuberant and very mobile thus increasing the risk for systemic embolization (Figure 14–3). Echocardiography is the gold standard for diagnosing LV thrombus. Two-dimensional echocardiography combined with color-flow Doppler has a reported sensitivity of 100% and a specificity of 97% for diagnosing LV thrombus compared to angiography, which has only a 20% to 50% sensitivity and a 75% specificity.17 Diagnostic echocardiographic criteria for identifying an LV thrombus include a usual location adjacent to, but distinct from, abnormally contracting myocardium, visualization in at least two planes, demarcation by a clear thrombus-blood interface, and an abnormal LV Doppler flow pattern.18 Transesophageal echocardiography (TEE) may be superior to transthoracic echocardiography (TTE) for visualizing LV apical thrombi.19 However, the differential diagnosis of apical thrombi may be complicated by the presence of thickened false tendinae or trabeculae in the apical region. In addition, a smooth, laminated mural thrombus may be more difficult to visualize in the LV apex than a pedunculated, mobile thrombus. Further echocardiographic interrogation using contrast enhancement or an epicardial-placed transducer may be helpful in delineating the presence of a LV apical thrombus.20
Transesophageal echocardiographic midesophageal four-chamber (A) and midtransgastric short-axis (B) views demonstrating spontaneous contrast within the left ventricle (LV) of a patient with severe idiopathic dilated cardiomyopathy. (RA, right atrium; LA, left atrium; RV, right ventricle.)
Transesophageal echocardiographic views of left ventricular (LV) apical thrombus associated with dilated cardiomyopathy. A: Midesophageal four-chamber view of a laminated, LV apical thrombus (arrow). B: Midesophageal two-chamber view of a mobile, protuberant, LV apical thrombus (arrow). (LA, left atrium; RV, right ventricle.)
Evaluation of Ventricular Systolic Function
Reduced ventricular contractile function (EF <45%) is fundamental to the diagnosis of DCM. Global echocardiographic evaluation of myocardial contraction can be obtained by using 2D-echocardiography to measure the percentage of fractional shortening, EF-area, or ejection fraction using Simpson method of disks (see Chapter 6). Doppler findings may include a reduced aortic ejection velocity and time-velocity integral reflecting a diminished stroke volume. Indices of ventricular systolic function related to isovolumic contraction such as dP/dt are less influenced by loading conditions compared to ejection phase indices, and can be estimated from MR jet velocities using continuous-wave Doppler (CWD) echocardiography.21 All echocardiographic measurements of systolic performance are typically reduced in patients with DCM.
Evaluation of Ventricular Diastolic Function
Left Ventricle. Although DCM is defined by the presence of significant systolic dysfunction, concurrent diastolic dysfunction is common and may manifest anywhere within the full spectrum of severity from impaired relaxation to restriction. Symptoms of congestive heart failure (CHF) in patients with DCM appear to be related to the severity of diastolic dysfunction.22–25 Normal LV diastolic performance can be defined as sufficient LV filling to produce an adequate cardiac output at a pulmonary venous pressure of less than 12 mm Hg. In patients with DCM, elevation of pulmonary venous pressures compensates for decreased diastolic function.
The main determinants of LV diastolic filling include myocardial relaxation, passive filling characteristics (LV compliance), LA contractility and pressure, heart rate, and MV integrity. Doppler echocardiographic evaluation of the transmitral (TMDF) and pulmonary venous (PVDF) Doppler flow velocity profiles can provide information pertaining to LV diastolic function.26 In early diastolic dysfunction associated with DCM, the ratio of the early-to-late TMDF velocities (E/A ratio), which is normally greater than 1, decreases to less than 1 in response to impaired LV relaxation (E-to-A reversal) (Figure 14–4 and Table 14–2). In addition, the deceleration time (DT: time between the peak transmitral E wave and the return of the velocity to baseline) and isovolumic relaxation time (IVRT: time between the cessation of LV outflow and the beginning of LV inflow) are prolonged. Similarly, in the presence of impaired LV relaxation, the diastolic component of the PVDF becomes significantly diminished compared to the systolic component. In more severe cases of DCM, increased LV stiffness due to myocardial fibrosis contributes to progressive diastolic dysfunction and reduced LV compliance, resulting in an increased LVEDP and LA pressure (LAP). When the elevated LAP becomes the driving force for transmitral flow, a restrictive pattern develops characterized by a supranormal TMDF E/A ratio, and decreased DT and IVRT. Diminished LV compliance is also associated with a significantly blunted PVDF systolic velocity compared to the diastolic velocity. The PVDF atrial-reversal velocity (PVAR) and duration may be increased in the presence of an elevated LAP and preserved contractility, or decreased in later stages of diastolic dysfunction because of excessive afterload associated with an elevated LVEDP (see Figure 14–4).26 The transitional, pseudonormal phase of diastolic dysfunction that develops in between impaired relaxation and restriction, is characterized by a TMDF profile that appears identical to the normal profile since the gradual increasing LAP compensates for impaired LV relaxation to maintain the transmitral pressure gradient (see Figure 14–4). However, the systolic component of the PVDF profile tends to remain blunted relative to the diastolic component as long as the LAP is abnormally elevated.
The impact of progressive left ventricular (LV) diastolic dysfunction on transmitral (TMDF, top) and pulmonary venous (PVDF, bottom) Doppler flow velocity profiles. Note the change in TMDF early/late (E/A) ratio, which decreases when impaired relaxation develops, and gradually becomes supernormal as LV compliance is reduced with restriction. Changes in the PVDF compliment those in the TMDF profile over the spectrum of diastolic dysfunction. Progressive increases in LV stiffness is associated with blunting of the systolic (PVS1 and PVS2) component of the PVDF profile and increased early diastolic (PVD) velocities, while the left atrium serves as an open conduit between the pulmonary veins and left ventricle (see text for details). (PVAR, late diastolic, atrial reversal component of the PVDF profile.)
Table 14–2. Doppler Assessment of Left Ventricular Diastolic Function by Transmitral and Pulmonary Venous Doppler Flow Velocities |Favorite Table|Download (.pdf)
Table 14–2. Doppler Assessment of Left Ventricular Diastolic Function by Transmitral and Pulmonary Venous Doppler Flow Velocities
≤ or > 0.8
Conventional measures of diastolic function including TMDF and PVDF velocity profiles can be influenced by acute changes in loading conditions, tachycardia, dysrhythmias, tethering, stunning, and pacing. Recently, newer echocardiographic techniques for assessing LV diastolic function have been described including Doppler tissue imaging, color kinesis, color M-mode transmitral flow propagation velocity, myocardial strain, and strain rate.27 These echocardiographic modalities are reportedly less vulnerable to the effects of acute changes in loading conditions, and may therefore complement the use of conventional echocardiographic techniques for evaluating diastolic dysfunction in patients with DCM. It is also important to appreciate that MR, which is common among patients with DCM, can have a considerable impact on the LV diastolic filling pattern. Significant MR is often associated with an elevated LAP, which produces an increased TMDF E/A ratio and systolic blunting of the PVDF velocity profile, making the assessment of concurrent diastolic dysfunction even more challenging. Rossi et al have identified that the relationship between the increased duration of PVDF atrial-reversal relative to the TMDF A wave in patients with diminished LV compliance is preserved even in the presence of MR, and thus can be used to identify diastolic dysfunction while other measurements fail.28
Right Ventricle. Indirect evidence of RV diastolic function in patients with DCM can also be obtained from a comprehensive 2D echocardiographic examination by examining RV mass or volume. A thorough assessment of RV diastolic function, however, requires a Doppler echocardiographic evaluation of transtricuspid Doppler flow (TTDF) velocities.26 Transtricuspid Doppler flow velocities tend to be lower due to the larger TV annular size, but they are affected by the same physiologic variables that affect LV filling. Direct comparisons of RV and LV inflow velocities also reveal differences in timing and reciprocal respiratory variation. During spontaneous inspiration, negative intrapleural pressure results in an increase in right atrial (RA) volume and subsequent greater RV diastolic filling velocities up to 20% compared to end-expiratory values.29 LA and LV filling are actually reduced during spontaneous inspiration relative to end-expiration. These reciprocal patterns of respiratory variation become exaggerated in patients with diastolic dysfunction. Although not thoroughly investigated, positive pressure ventilation would presumably have an opposite effect on TTDF velocity patterns in comparison to spontaneous ventilation.
Echocardiographic evaluation of RV diastolic function in patients with DCM also includes an assessment of RA inflow velocities including the hepatic venous (HV), inferior vena cava (IVC), and superior vena cava (SVC) Doppler profiles, all of which have similar contours and components. The HVs join the intrahepatic IVC tangentially, and can be visualized by advancing and turning the TEE probe rightward from a midesophageal, bicaval acoustic window. The normal HV Doppler profile is characterized by (1) a small reversal of flow following atrial contraction (AR wave); (2) an antegrade systolic phase during atrial filling from the SVC and IVC (S wave) that is influenced by TV annular motion, RA relaxation, and tricuspid regurgitation (TR); (3) a second small flow reversal at end-systole (V wave) that is influenced by RV and RA compliance; and (4) a second antegrade filling phase while the RA acts as a passive conduit during RV filling (D wave).29
Diastolic RV dysfunction can manifest with the same relative changes in TTDF peak E- and A-wave velocities, E/A-wave ratios, and DT that occur with TMDF profiles associated with alterations in LV relaxation and compliance.30 The ratio of the total hepatic reverse flow integral/total forward flow integral (TVIA + TVIV/TVIS + TVID) increases with either RV diastolic dysfunction or significant TR, but appears to be more affected by the former.31 In addition, a marked shortening of the TTDF DT and diastolic predominance of HV flow with prominent V- and A-wave reversals during spontaneous inspiration indicates significant decreases in RV compliance and increased diastolic filling pressures. Changes in IVC diameter during spontaneous inspiration also reflect RA pressure (RAP). In general, low RAP (0 to 5 mm Hg) is associated with a small IVC (<1.5 cm diameter) and a spontaneous inspiratory collapse greater than 50% of the original diameter. In contrast, significant increases in RAP (>20 mm Hg) are associated with dilated IVC (>2.5 cm) and HVs with little respiratory variation (<50%). Diastolic RV dysfunction (lower TTDF peak E-wave velocity, lower E/A ratios, and prolonged RV IVRT) has also been demonstrated in patients with pulmonary hypertension (PHT) and in those with symptomatic CHF even in the absence of PHT, suggesting a potential role for ventricular interdependence in impaired RV filling.32
Evaluation of Mitral and Tricuspid Valve Lesions
Ventricular dilatation associated with DCM may produce functional atrioventricular valve incompetence. Incomplete closure of the MV and TV may develop due to annular dilatation; however, an independent role of mitral annular dilatation in the development of MR in patients with DCM remains controversial.33,34 Abnormal alignment of the papillary muscles related to the development of ventricular sphericity is more consistently responsible for atrioventricular valve incompetence due to apical displacement of the coaptation point, which increases tension on the leaflets (ie, “apical tenting”; Figure 14–5).35 Aikawa et al utilized three-dimensional (3D) echocardiography to demonstrate that functional MR associated with nonischemic DCM is related to annular dilatation.36 Furthermore, dilation of the anterior and anterolateral LV walls results in displacement of the anterior papillary muscle, narrowing of the angle of the anterior chordae to the mitral annulus, and widening of the central angle between the anterior and posterior chordae. Kwan et al also used 3D echocardiography to demonstrate that MV deformation from the medial to lateral side is asymmetrical in patients with ischemic cardiomyopathy, whereas it is symmetrical in those with DCM.37
Transesophageal echocardiographic midesophageal four-chamber views demonstrating a color-flow Doppler signal of significant mitral regurgitation associated with dilated cardiomyopathy. The mechanism of functional mitral regurgitation in dilated cardiomyopathy is related to annular dilatation and/or abnormal alignment of the papillary muscles causing apical tenting (arrow) of the anterior MV leaflet. (LA, left atrium; LV, left ventricle; RV, right ventricle; AscAO, acsending aorta.)
Mitral and tricuspid regurgitation should be semiquantified using color-flow, pulsed-wave, and continuous-wave Doppler to measure regurgitant jet length, jet area, vena contracta, proximal isovelocity surface area, effective regurgitant surface area, and regurgitant fraction, which may be helpful when corrective valve surgery is anticipated. Reductive annuloplasty of both MV and TV orifices in patients with DCM significantly changes LV morphology, reverses ventricular remodeling, decreases LV sphericity, and slows the progression of heart failure.38
Utility of Echocardiography in Determining Prognosis
A number of 2D echocardiographic findings have prognostic value in patients with DCM.22 In particular, marked chamber dilatation (LV, LA, RV)39 and depressed ventricular function (LV, RV)40 are associated with poor survival. In addition, decreased end-systolic and end-diastolic LV volumes following low-dose dobutamine infusion also indicate a more favorable prognosis. Furthermore, Doppler echocardiographic measurements including MR severity,41 significant pulmonary hypertension assessed from the TR Doppler flow velocity,42 and a restrictive TMDF velocity profile that does not respond to pharmacological intervention have been correlated with a worse outcome.43,44