Dilated Cardiomyopathy

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CHAPTER 62 Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy and is responsible for significant morbidity and mortality. The etiology of DCM is quite heterogeneous, and the DCM phenotype likely represents a common final outcome in response to many different myocardial insults; however, it has been recognized more recently that genetic factors probably account for 35% to 50% of all cases of DCM.¹^,² Advances in imaging have provided insight into mechanisms of pathology in DCM, and have allowed more confident noninvasive separation of patients with ischemic DCM from patients with nonischemic DCM.

DEFINITION

DCM is a disease of the myocardium that is characterized by dilation and impaired systolic function of the left ventricle or both ventricles.³

PREVALENCE AND EPIDEMIOLOGY

DCM is the most common of the cardiomyopathies, accounting for approximately 55% of cases, and responsible for greater than 90% of cases referred to specialty centers.³ Idiopathic DCM is the most common cause of congestive heart failure in young patients with an estimated prevalence of 36.5 per 100,000 individuals in the United States, and is responsible for more than 10,000 deaths per year.⁴ Depending on the diagnostic criteria applied, the annual incidence in adults is 5 to 8 cases per 100,000 population.⁵ The true incidence is likely underestimated because many asymptomatic cases are unrecognized. DCM is responsible for a high proportion of cases of heart failure and sudden cardiac death, and is a leading cause of cardiac transplantation. The mortality rate in the United States owing to cardiomyopathy is greater than 10,000 deaths per year, with DCM the major contributor to this mortality.⁶

ETIOLOGY AND PATHOPHYSIOLOGY

DCM has been linked to many different etiologies, including infection, hypertension, pregnancy, alcohol, autoimmune disease, nutritional deficiency, cardiotoxins (e.g., anthracycline, heavy metals, cocaine, methamphetamines), genetic inheritance (e.g., mitochondrial disorders), or any cardiovascular disease in which the degree of myocardial dysfunction is not explained by the abnormal load conditions (e.g., valvular dysfunction) or the extent of ischemic damage.³ The World Health Organization definition of DCM excludes patients with enlarged and dysfunctional ventricles secondary to ischemic or valvular dysfunction, which are categorized as their own specific cardiomyopathy (i.e., ischemic cardiomyopathy and valvular cardiomyopathy).³ Viral myocarditis may be an important etiology in childhood, but in adults the relationship between myocarditis and DCM is less clear, and inconsistent results have been achieved in the attempt to isolate specific disease pathogens.

Family screening has emphasized the importance of inheritance in the etiology of DCM. Genetic transmission is most often autosomal dominant, with a lesser number of autosomal recessive, or X-linked, cases. Echocardiography family screening studies have shown abnormalities in approximately 25% of relatives of patients with DCM, including DCM and isolated left ventricular enlargement. Of individuals with left ventricular enlargement, 10% to 25% develop clinical DCM with symptomatic heart failure, arrhythmias, or thromboembolism within 5 years.⁷ These observations suggest that familial DCM is a slowly progressive disorder, and that screening of first-degree relatives of patients with DCM should assume a similar role to that of screening in hypertrophic cardiomyopathy patients, with more well-established genetic linkages.

The autosomal forms of familial DCM can be grouped into forms with a pure DCM phenotype or DCM with cardiac conduction system disease. Genetic heterogeneity is the hallmark of autosomal dominant DCM with 15 loci mapped for pure DCM and 5 for DCM with cardiac conduction system disease. These mutations include genes encoding cardiac actin, desmin, δ-sarcoglycan, β-sarcoglycan, cardiac troponin T, and α-tropomyosin. Most genes identified to date encode either cytoskeletal or sarcomeric proteins. These proteins are important for structural integrity and for force transmission.²

X-linked DCM occurs in adolescent boys and young men with rapid progression from congestive heart failure to death or transplantation, and is characterized by mutations in the gene for cardiac dystrophin, a cytoskeletal protein providing structural support to the myocyte and linking it to the sarcolemma. The dystrophin gene is also responsible for Duchenne and Becker muscular dystrophies, which also have DCM as a prominent feature.⁸

Histologic changes associated with DCM are frequently nonspecific, and not all features may be present. DCM is characterized by progressive interstitial fibrosis with a reduced number of functional myocytes and, in advanced stages, relative wall thinning. Although atrophic changes predominate histologically, there is also myocyte elongation with an addition of newly formed sarcomeres, which is the major factor responsible for increased chamber size. Myocyte diameter increases, but is inadequate to preserve a normal ratio of wall thickness to chamber diameter. Myocyte nuclear hypertrophy and pleomorphism may also be seen. There is often an increase in interstitial T lymphocytes and focal accumulation of macrophages associated with individual myocyte death.⁸

MANIFESTATIONS OF DISEASE

Clinical Presentation

The clinical presentation of DCM varies, but typically includes signs and symptoms of left heart failure, including fatigue; dyspnea on exertion; shortness of breath; orthopnea; paroxysmal nocturnal dyspnea; and increasing edema, weight, or abdominal girth. On physical examination, patients may exhibit tachypnea, tachycardia, hypertension, jugular venous distention, and peripheral edema. Many patients have minimal symptoms. Right-sided heart failure is less common and is generally seen in severe cases.

Imaging Indications and Algorithm

Indications for imaging in patients with known or suspected DCM can be grouped into a few broad categories. For initial diagnosis, echocardiography, MRI, or ECG gated contrast-enhanced CT all show dilated ventricular cavities and reduced function characteristic of DCM.

When the diagnosis of DCM is established, the distinction between ischemic and nonischemic DCM needs to be made because treatment options differ. Traditionally, conventional coronary angiography was performed to determine whether or not significant coronary atherosclerosis was present, and this is still a common alternative. More recently, noninvasive alternatives to coronary angiography have become widely available, including stress and rest nuclear perfusion imaging using technetium or thallium agents, positron emission tomography (PET) viability imaging, stress echocardiography, coronary CT angiography (or noncontrast CT for coronary calcium assessment), and contrast-enhanced MRI with myocardial delayed enhancement (MDE) images.

A third set of indications for imaging involves assessing for prognostic factors, such as the presence of significant nonischemic fibrosis on MRI MDE images, and the presence or absence of significant coronary flow reserve or inotropic reserve or both on nuclear medicine stress/rest perfusion images or stress echocardiography. Finally, imaging may be performed to assess for changes in ventricular function after therapeutic intervention.

The optimal imaging technique should be safe, should be noninvasive, should have relatively few contraindications, should be widely available, should be easily interpretable, should be reproducible, and should be able to confirm the diagnosis and provide prognostic information in a single examination. Currently, there is no widely accepted single modality that fulfills these criteria in most patients.

Imaging Technique and Findings

Radiography

Findings on chest x-ray are nonspecific and include cardiomegaly and signs of congestive heart failure, such as pleural effusions, pulmonary vascular congestion, and interstitial edema.

Ultrasonography

Echocardiography reveals a dilated left ventricular cavity with reduced global function. End-systolic and end-diastolic diameter are increased, and ejection fraction, fractional shortening, stroke volume, and cardiac output are decreased (Figs. 62-1 and 62-2).

FIGURE 62-1 DCM shown by echocardiography. A and B, Short-axis end-diastolic (A) and end-systolic (B) frames reveal a dilated left ventricle with poor function. C, Three-chamber view shows left ventricular enlargement with end-diastolic dimension of 73 mm.

FIGURE 62-2 DCM on transesophageal echocardiography. A and B, End-diastolic (A) and end-systolic (B) two-chamber frames reveal dilated left ventricle and atrium with poor ejection fraction.

The left ventricle becomes more spherical, with the sphericity index (long-axis/short-axis dimension) nearing 1 (normal value >1.5). Left ventricular wall thickness varies, but is usually normal; however, left ventricular mass is generally increased.

Secondary features of DCM include dilation of the mitral annulus and incomplete coaptation of mitral valve leaflets with mitral regurgitation and enlarged left atrium. As ventricular size increases and function declines, thrombi may develop, with the ventricular apex a common location. Interventricular conduction delay (left or right bundle branch block) is common and contributes to ventricular dysfunction.

Doppler echocardiography is an important tool for evaluation of patients with DCM and can be used to assess cardiac output, pulmonary artery pressure, mitral inflow patterns, left ventricular filling pressure, and mechanical dyssynchrony. Mitral regurgitation is common in DCM and is related to left ventricular enlargement and remodeling. The mitral leaflets become tented because of apical displacement of papillary muscles with reduced coaptation.

There is a wide range in severity of systolic and diastolic dysfunction. Persistence of restrictive filling after therapy is associated with high mortality; whereas patients with reversible restrictive filling have high probability of clinical improvement and excellent survival. Pulmonary artery pressure can be estimated from the tricuspid valve regurgitant (TR) velocity. Patients with TR velocity greater than 3 m/s have higher mortality and higher incidence of heart failure and more frequent hospitalizations.

Proper timing of diastolic filling is important in optimizing cardiac output. If the P-R interval is prolonged, atrial contraction may occur before early diastolic filling is completed. If the P-R interval is too short, the atrium may contract at the same time as the ventricle. Optimizing the P-R interval with guidance of Doppler echocardiography may improve cardiac output and reduce the severity of symptoms.

Evaluation of right ventricular function is also important. Patients with biventricular dysfunction have a lower New York Heart Association functional class, tend to have more severe left ventricular dysfunction, and have a worse long-term prognosis.⁹^,¹⁰

Stress echocardiography may also play a role in assessment of patients with DCM. Patients with improvement in ejection fraction greater than 20% during stress echocardiography have a better prognosis. Drozd and colleagues ¹¹ showed that the incidence of cardiac death or transplantation is lower in patients with preserved contractile reserve. Another study assessed the prognostic significance of high-dose dobutamine stress echocardiography, and concluded that the change in wall motion score index is able to identify patients at greater risk for cardiac death during follow-up, and that change in wall motion score index had superior prognostic information to change in ejection fraction.¹²

Stress echocardiography with dipyridamole has also been used to assess coronary flow reserve in patients with DCM. Rigo and colleagues ¹³ evaluated 129 patients with DCM and found that coronary flow reserve, assessed via Doppler velocity interrogation of the mid left anterior descending coronary artery, was often impaired, and that reduced coronary flow reserve was an independent marker of poor prognosis. Pratali and coworkers¹⁴ performed dobutamine and dipyridamole stress echocardiography in 87 patients with DCM and found that both tests have similar feasibility and prognostic accuracy.

Computed Tomography

Traditional nongated thoracic CT can provide useful but nonspecific information in assessment of patients with DCM. Signs of congestive heart failure, including enlargement of pulmonary vessels, thickening of interlobular septa, pleural effusions, and cardiomegaly, are easily appreciated on CT. CT also allows assessment for alternative or confounding pathologies, such as pulmonary embolus, infectious or inflammatory pulmonary infiltrates, emphysema, and pulmonary fibrosis. Assessment of the cardiac chambers is limited without cardiac gating; however, large ventricular or atrial thrombi can often be seen on contrast-enhanced CT, and significant chamber enlargement can be appreciated.

ECG gated CT, particularly with the advent of 64-row multidetector systems, offers many additional possibilities in the assessment of patients with known or suspected DCM. CT can provide excellent spatial resolution, with isotropic submillimeter voxels and rapid acquisitions (10 to 20 seconds) and short total examination times. A typical contrast-enhanced ECG gated CT acquisition consists of spiral overlapping data from each detector row obtained over several heartbeats. These data are retrospectively sorted into different spatial and temporal locations, and can generate axial images in an optimal motion-free diastolic time frame and short-axis and long-axis cine images, which can be used to evaluate and quantify ventricular size, function, and mass.

Although MRI is generally considered the gold standard for assessment of ventricular mass and function, preliminary results indicate that CT has similar accuracy and reproducibility. Limitations of CT include temporal resolution, which is typically on the order of 150 ms for single source 64-row MDCT. Dual source CT improves temporal resolution to 70 to 80 ms, which approaches that of MRI. Functional ventricular assessment with CT also requires the use of iodinated contrast material, limiting the application of this technique in patients with renal insufficiency or allergy to iodinated contrast agents. Finally, radiation dose in cardiac CT is significant, even considering the dose reduction algorithms currently employed by most vendors. Ionizing radiation exposure is particularly problematic in pediatric patients, women (with the high radiation dose to the breast), and patients requiring multiple follow-up imaging evaluations.

In addition to assessing ventricular function, myocardial mass, and chamber size, CT can be used to screen for coronary artery disease. A few more recent investigations have compared the accuracy of coronary CT angiography with conventional angiography in assessing patients with ischemic or nonischemic DCM (Fig. 62-3). Andreini and associates¹⁵ studied 61 patients with idiopathic DCM and 139 patients with normal cardiac function and indications for coronary angiography. Using 16-row MDCT, the authors found excellent agreement with angiography, with sensitivity, specificity, and positive and negative predictive values for identification of greater than 50% stenosis of 99%, 96%, 81%, and 99%. Cornily and colleagues¹⁶ achieved similar results with a smaller group of 36 patients with DCM, also using a 16-row system and comparing results with conventional angiography.

FIGURE 62-3 DCM. A, Four-chamber reformatted view from coronary CT angiogram shows dilated left ventricle. B and C, Subvolume maximum intensity projection images from coronary CT angiography reveals only minimal disease in the left anterior descending and circumflex coronary arteries (B) and normal right coronary artery (C).

It has also been suggested that coronary calcification scoring alone may be adequate for distinguishing ischemic from nonischemic DCM (Fig. 62-4). Budoff and associates¹⁷ assessed 56 patients with cardiomyopathy using coronary angiography, nuclear exercise stress testing (Tc 99m sestamibi), and coronary calcification electron-beam CT. Nuclear stress testing had a sensitivity of 97% using the criteria of a reversible or fixed defect, but a low specificity of 18%. Using receiver operating curve analysis, the authors determined that a cutoff coronary calcification score of 100 yielded a sensitivity and specificity of 82%. CT has the potential to reduce or eliminate the use of conventional coronary angiography in distinguishing ischemic from nonischemic DCM. CT also effectively detects complications of DCM, such as atrial or ventricular thrombus.

FIGURE 62-4 DCM. A, Image from coronary calcification scan reveals single small focus of calcification in the proximal left anterior descending coronary artery. Coronary angiography was also performed and showed no significant coronary artery lesions. B and C, Axial end-diastolic (B) and end-systolic (C) images show mildly dilated left ventricle with reduced function.

A major limitation of CT with respect to MRI is in the area of tissue characterization. MDE acquisitions have proved valuable in distinguishing ischemic versus nonischemic DCM, and the presence of mid-wall hyperenhancement on MDE imaging seems to have prognostic implications as well. More recently, delayed contrast enhancement has been described in CT; however, its role in routine clinical practice is uncertain, and the potential diagnostic benefit of this acquisition must be balanced against the additional radiation exposure.

Magnetic Resonance Imaging

MRI is the gold standard for quantification of myocardial size and function. The diagnosis of DCM can be confirmed by obtaining standard gated cine steady-state free precession (SSFP) bright blood images in long-axis and short-axis orientations. End-diastolic and end-systolic frames are traced to obtain end-diastolic and end-systolic volumes, stroke volume, and myocardial mass. Typical findings include left ventricular and atrial enlargement, increased left ventricular mass, reduced stroke volume and ejection fraction, increased end-diastolic and end-systolic volumes, and frequently right-sided chamber enlargement and reduced function.

Much interest in MRI evaluation of patients with DCM more recently has focused on the diagnostic and prognostic implications of hyperenhancement on MDE imaging. MDE images are typically obtained 10 to 20 minutes after an intravenous injection of 0.1 to 0.2 mM/kg of a standard gadolinium-chelate contrast agent. MDE pulse sequences are usually T1-weighted inversion recovery sequences in which the inversion time (TI) is selected to null the signal from normal myocardium. Damaged, scarred, or infarcted myocardium has a larger extravascular volume by virtue of its acellularity or damaged cell membranes, leading to longer wash-in and washout times for standard gadolinium-chelate contrast agents, and retention of contrast agent in these regions (i.e. “hyperenhancement”) relative to normal myocardium.

Infarcts on MDE images have a characteristic appearance, showing subendocardial or transmural enhancement in a distribution corresponding to the territory of the affected coronary artery. MDE imaging has a high sensitivity for detection of infarcts, and it has been shown that small infarcts seen using this technique are often missed with nuclear medicine perfusion imaging. MDE imaging is an excellent method for distinguishing nonischemic DCM from ischemic cardiomyopathy (Figs. 62-5 and 62-6). Soriano and colleagues¹⁸ evaluated 71 patients with heart failure and left ventricular systolic dysfunction without a prior history of myocardial infarction with coronary angiography and MDE imaging. Subendocardial or transmural hyperenhancement on MDE imaging characteristic of previous infarction was present in 81% of the angiography-positive group, whereas only 9% of the angiography-negative patients had an ischemic MDE pattern. McCrohon and coworkers¹⁹ evaluated 90 patients with heart failure with MRI and MDE imaging, and compared the results with coronary angiography. All angiography-positive patients showed an ischemic subendocardial or transmural MDE pattern. In the angiography-negative patients, 59% showed no hyperenhancement on MDE imaging, 13% had an ischemic hyperenhancement pattern (i.e., subendocardial or transmural), and 28% had a longitudinal or patchy mid-wall hyperenhancement pattern with subendocardial sparing on MDE imaging that was not restricted to distinct coronary territories.

FIGURE 62-5 MRI demonstration of DCM. A and B, End-diastolic (A) and end-systolic (B) four-chamber SSFP images reveal dilated left ventricle with mildly reduced function. C and D, Four-chamber (C) and two-chamber (D) MDE images show no late hyperenhancement, indicating nonischemic etiology.

FIGURE 62-6 Ischemic cardiomyopathy. A, Four-chamber SSFP image reveals dilated left ventricle with subtle apical thrombus. B and C, Four-chamber (B) and two-chamber (C) MDE images reveal extensive transmural hyperenhancement in the apex and anterior wall, consistent with a large infarct. Note better visualization of nonenhancing apical thrombus (arrows).

Although most patients with nonischemic DCM show no late gadolinium enhancement, there is more recent evidence that some patients have nonischemic enhancement patterns, in particular enhancement in the middle of the ventricular myocardium (Fig. 62-7), and that the presence of this late enhancement is an indicator of poor prognosis compared with patients without MDE. Assomull and colleagues²⁰ evaluated 101 patients with DCM and found a mid-wall fibrosis pattern in 35% of patients. Mid-wall fibrosis was associated with a higher mortality and hospitalization for cardiovascular events and sudden cardiac death and ventricular tachycardia. Park and associates²¹ also evaluated 46 patients with nonischemic left ventricular systolic dysfunction with late enhancement MRI and showed that the absence of delayed hyperenhancement had excellent sensitivity and negative predictive value in predicting functional recovery of left ventricular systolic dysfunction.

FIGURE 62-7 Mid-wall delayed hyperenhancement in DCM. A, Mid-ventricular short-axis SSFP image reveals concentric dilation of the left ventricle. B, Corresponding MDE image reveals curvilinear mid-myocardial hyperenhancement of the inferoseptal, anteroseptal, anterior, and anterolateral walls of the left ventricle.

The mid-wall late myocardial hyperenhancement described in approximately one third of patients is probably not specific for idiopathic nonischemic DCM. Myocarditis and myocardial sarcoid can also exhibit similar hyperenhancement patterns. The distinction between ischemic and nonischemic hyperenhancement is not always obvious, particularly in patients with thin ventricular walls. The prognostic value of mid-wall hyperenhancement on MDE has been described in only a few patients.

MRI has yet unrealized potential with regard to evaluation of patients with DCM. Nuclear and echocardiographic stress testing provides useful prognostic information from estimation of perfusion and inotropic reserve. Pharmacologic MRI stress testing can be performed using first-pass perfusion imaging and vasodilators (typically adenosine) or inotropic agents (dobutamine), and some protocols employ both methods. These techniques are employed routinely in some centers as an alternative to nuclear and echocardiographic stress tests, but little investigation has been performed regarding the use of these techniques in patients with DCM. MRI is also unparalleled in assessment of the right ventricle, and echocardiographic data indicate that assessment of right ventricular function may have an important role in determining prognosis of these patients. MRI tissue tagging pulse sequences can be used to investigate intrinsic contractile properties of myocardium. The relationship between asynchronous electrical excitation and the onset of mechanical contraction has been investigated with MRI tagging, and these techniques may be useful in understanding the nature of mechanical asynchrony found in some patients with DCM, particularly patients who are candidates for cardiac resynchronization therapy (CRT).

MRI has several general and specific limitations for the investigation of DCM. Patients with pacemakers and defibrillators and other internal electrical devices are currently excluded. Claustrophobia is a relative contraindication. More recent concern regarding nephrogenic systemic fibrosis and gadolinium contrast agents may limit the availability of this technique in patients with severe renal insufficiency. MRI is expensive and is less widely available than most other noninvasive imaging techniques.

Nuclear Medicine

Nuclear medicine techniques have an important role in evaluation of patients with DCM. More recent development of ECG gated single photon emission computed tomography (SPECT) techniques allows assessment of myocardial perfusion and ventricular function, and SPECT would seem to be an ideal tool for distinguishing ischemic and nonischemic DCM (Fig. 62-8). Danias and colleagues²² assessed 37 patients with severely reduced left ventricular function with exercise Tc 99m sestamibi gated SPECT and found that the summed stress and rest perfusion defect scores were widely separated between the two groups, and completely distinguished ischemic from nonischemic patients. A larger trial from the same group using the same technique assessed 164 patients with ejection fraction less than 40% and without known coronary artery disease. Using a combined analysis of stress perfusion, reversibility, and regional wall motion deficits, Danias and colleagues²³ achieved a high sensitivity (94%) but relatively low specificity (45%) for detection of ischemic cardiomyopathy. Generally, patients with ischemic cardiomyopathy have more severe perfusion defects than patients with nonischemic cardiomyopathy. Fixed defects are occasionally encountered in nonischemic cardiomyopathy, and may be related to attenuation associated with the severely dilated left ventricular cavity and supine imaging.

FIGURE 62-8 Nonischemic DCM. A, Four-chamber SSFP image reveals moderately dilated left ventricle. B, Short-axis SPECT stress-rest sestamibi scan reveals normal resting and stress perfusion images, and no evidence of ischemic etiology.

Dobutamine stress myocardial perfusion imaging has been used to predict patient response to β blocker therapy in DCM. Kasama and coworkers ²⁴ found that the change in ejection fraction measured by Tc 99m tetrofosmin gated SPECT was significantly higher in patients who responded to therapy than in nonresponders.

PET can also be used to assess DCM patients. O’Neill and colleagues ²⁵ examined 44 patients with PET, echocardiography, and radionuclide ventriculography, and found that myocardial scarring (defined as a matched perfusion and metabolic defect) was very common, occurring in 91% of patients, and that the extent of scar correlated with the QRS duration.

Another group has used PET to assess global and regional myocardial oxygen consumption () and blood flow in patients with DCM and left bundle branch block.²⁶ Complete left bundle branch block is a common finding in severe DCM and is a strong predictor of mortality. Global and regional and myocardial blood flow were assessed using acetate C 11 PET. Patients with severe DCM and left bundle branch block exhibited a significantly lower (impaired) global and reduced myocardial blood flow at rest than patients with mild or moderate disease without left bundle branch block. Analysis of regional differences in and blood flow revealed more heterogeneous distribution of and myocardial blood flow in DCM patients with left bundle branch block.

CRT has been advocated in patients with poor left ventricular function and conduction delays for symptomatic improvement and prolonging survival. Lindner and colleagues ²⁷ studied patients with nonischemic cardiomyopathy before and 4 months after CRT using acetate C 11 PET, and showed that CRT induces changes of and myocardial blood flow leading to a more uniform distribution with less regional heterogeneity. More novel applications of nuclear medicine include the use of Tc 99m–labeled annexin A5 to identify focal, regional, or global uptake of annexin A5, a marker of cellular apoptosis.²⁸