Chapter 14. Echocardiographic Evaluation of Cardiomyopathies

Cardiomyopathy is generally defined as a “disease of the myocardium associated with cardiac dysfunction.”1 Primary cardiomyopathies are divided into four major classifications: (a) dilated cardiomyopathy (DCM), (b) hypertrophic cardiomyopathy (HCM), (c) restrictive (or infiltrative) cardiomyopathy (RICM), and (d) miscellaneous group including left ventricular non-compaction (LVNC), arrhythmogenic right ventricular dysplasia (AVRD), and Tako-tsubo cardiomyopathy. Each of the primary cardiomyopathies has distinctive morphological and functional characteristics even though they may present clinically in a similar fashion. The etiology of primary or idiopathic cardiomyopathies is not attributable to another systemic disease process. Alternatively, primary cardiomyopathies refer to primary diseases of the heart muscle (Table 14–1).

The incidence of cardiomyopathy is less than 1% in the general population, with DCM representing the vast majority of cases.2 Hypertrophic cardiomyopathy is less prevalent, while RICM, LVNC, and AVRD are the least common. The incidence of cardiomyopathy varies depending on a number of factors including diagnostic testing, the type of institution reporting the data, and the referral patterns. When all cardiomyopathies are considered, the incidence varies depending on the prevalence of cardiac pathology associated with coronary artery disease, valvular pathology, systemic hypertension, and a host of other systemic pathophysiologic conditions. Accurate diagnostic assessment of patients suspected of having a cardiomyopathy is important to establish prognosis and to institute appropriate treatment. This chapter focuses on salient echocardiographic features of primary cardiomyopathies, but also includes discussion and description of non-primary cardiomyopathies for completeness.

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

Echocardiographic Evaluation

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.

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

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.

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

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

Etiology and Pathophysiology

Hypertrophic cardiomyopathy has been described with a variety of terms including “idiopathic hypertrophic subaortic stenosis” (IHSS) and “asymmetric septal hypertrophy,” reflecting a narrowed LV outflow tract (LVOT) due to a focal pattern of hypertrophy. More recently, the classification has been simplified to reflect the pathophysiology and to accommodate the varied patterns of hypertrophy. While diastolic dysfunction occurs in almost all individuals with HCM, only 25% experience a dynamic, intermittent, or episodic obstruction to ventricular systolic outflow.45,46 Patients are therefore subdivided into two related but distinct groups: (1) hypertrophic cardiomyopathy (HCM) and (2) hypertrophic obstructive cardiomyopathy (HOCM), which includes those with obstruction to ventricular systolic outflow.

Hypertrophic cardiomyopathy (HCM/HOCM) is defined as an abnormal thickening of the myocardium without chamber dilation, in the absence of a demonstrable cause (eg, aortic stenosis [AS], systemic hypertension). The incidence is approximately 0.2% in the general population, but reporting may vary depending on the referral patterns of the institution, and the diagnostic criteria.45,46 Diagnosis may be based on presentation, family history, hemodynamic evaluation, and echocardiographic examination. A more definitive diagnosis may require myocardial biopsy and/or genetic testing.

Hypertrophic cardiomyopathy is inherited as an autosomal dominant trait with variable expression.45 Gene mutations involving the regulatory proteins of the sarcomere as well as the myofilaments have been reported. Defects of at least nine genes contributing to more than 130 mutations help to explain the heterogeneity of the disease. An anticipated increase in the frequency of genetic testing may have an impact on the currently reported incidence. In addition, improvement in the quality of genetic testing will help to pave the way for preventative and more targeted therapeutic intervention.

The histology of HCM/HOCM displays a range of abnormalities from simple hypertrophy of organized, longitudinally directed muscle fibers to a disarray of abnormal-appearing fibers.47 Over time, myocardial fibrosis may replace normal muscle, resulting in a less compliant ventricle. Abnormal concentric thickening can also be seen in the coronary arteries. These changes, when coupled with ventricular hypertrophy and elevated intracavitary pressures, increase the risk of myocardial ischemia.

The age of onset, morphology, and pathophysiology of HCM/HOCM vary greatly. More commonly, HCM/HOCM presents in young adulthood from the second to fifth decades, and is characterized by a diffuse or asymmetric ventricular hypertrophy. Presentation of HCM/HOCM in older patients (≥65 years old) is becoming increasingly recognized.48,49 Whether elderly patients have previously asymptomatic hypertrophy or develop hypertrophy later in life is not known. Although commonly ascribed to HCM/HOCM, asymmetric hypertrophy has also been reported as an adaptive response to AS, systemic hypertension, and in certain congenital cardiac anomalies.

Hypertrophic cardiomyopathy is classically defined by the presence of LV hypertrophy (>11mm thickness), which occurs disproportionately in the ventricular septum by a ratio of greater than 1.3:1.0 relative to the measured free-wall thickness (Figure 14–6).46 The inferolateral basal wall is infrequently involved. However, different patterns of hypertrophy have been reported including isolated proximal basal septal hypertrophy (“septal bulge”),48–50 inferlolateral wall hypertrophy,51 concentric or diffuse hypertrophy,52 and RV hypertrophy in a small number of cases. Four types of hypertrophic cardiomyopathy have been described: type I—hypertrophy limited to the anterior septum; type II—hypertrophy of anterior and posterior septum; type III—diffuse hypertrophy sparing only the basal inferlolateral wall; type IV—apical hypertrophy.53

The mechanism of LVOT obstruction (LVOTO) is complex, involving ventricular hypertrophy and abnormalities of the MV apparatus.54–56 The common pathway is represented by a narrower ventricular cavity with or without distortion of MV leaflet coaptation and subsequent MR. Scenarios more likely to result in LVOTO include asymmetric hypertrophy, a prominent basal septum, a narrowed outflow cavity (<25 mm), and structural abnormalities of the MV apparatus. The latter includes anteriorly positioned papillary muscles,57 abnormal insertion of the papillary muscles into the mitral leaflet,58 elongated mitral leaflets,59–61 and disturbances in MV annular function (eg, posterior annular calcification). LVOTO has also been reported with concentric hypertrophy. Delineation of the mechanism of LVOTO is important for planning therapeutic interventions, especially in regard to the requirement for and timing of surgery.

Presentation, Signs, and Symptoms

The annual mortality of patients with HCM/HOCM ranges from 2.5% to 4%. The 4-year mortality rate of asymptomatic patients is extremely low compared to severely compromised patients with New York Heart Association class III/IV symptoms. Patients with HCM/HOCM may be severely symptomatic early in life or remain asymptomatic for decades. Symptoms including decreased exercise capacity, angina, dyspnea, dizziness, syncope, and/or sudden death are due to ventricular diastolic dysfunction, myocardial ischemia, arrhythmias, LVOTO, and MR. Physical examination may be normal at rest. The cardiac apex may be displaced, reflecting the hypertrophy and overall increase in cardiac mass. Third or fourth cardiac sounds (S3 or S4) indicate decreased ventricular compliance and congestive heart failure (CHF). A harsh crescendo-decrescendo systolic murmur suggests LVOTO. Electrocardiography demonstrates a ventricular strain pattern including nonspecific ST- and T-wave changes. Prominent T waves have been noted in patients with apical hypertrophy.

Coronary ischemia may occur in the absence of coronary artery narrowing due to poor perfusion through the thickened myocardium and increased intracavitary pressures and/or a reduction in coronary artery vasodilatory reserve.62,63 Concentric hypertrophy of the coronary arteries increases the risk of myocardial ischemia. Dyspnea or CHF often occur despite normal or even supranormal systolic function. Myocardial ischemia, abnormal diastolic function, and/or systolic outflow obstruction with or without MR all contribute to development of CHF. These processes are dynamic and may not be present at rest, but may require provocative maneuvers such as a Valsalva or the administration of a systemic vasodilator such as amyl nitrate. Such interventions reduce ventricular preload resulting in a smaller or narrower cavity and LVOTO.

Atrial and ventricular arrhythmias are a primary cause of syncope, stroke, and sudden death. The electrical abnormalities of the hypertrophic heart are related to atrial chamber pressures and size, and abnormal myocardial architecture. Atrial fibrillation is the most common rhythm disturbance, while sudden death is the most significant cause of mortality. The risk of sudden death is highest for younger patients with severe LV hypertrophy (>20- to 30-mm thickness), LVOT gradient greater than 50 mm Hg, LA dilatation (>45 mm), a reduction in blood pressure during exercise, a history of syncope, and/or a family history of syncope. Interestingly, LVOTO has not been directly related to morbidity or sudden death.45,46 Risk assessment is important since placement of an implantable cardiac defibrillator is the recommended prophylaxis or treatment to prevent sudden death.

Echocardiographic Examination

Echocardiography is essential to assess and diagnose the etiology of hypertrophy as well as to assess ventricular function, diagnose LVOTO, and to quantify the severity of valve dysfunction. It is an important tool in formulating a prognosis and for initiating and planning treatment. For patients having surgery, intraoperative echocardiographic examination is important to re-evaluate cardiac function, help determine the surgical plan, and assess results immediately after cardiopulmonary bypass (CPB).64–66

Two-dimensional and M-mode echocardiography permit assessment of cardiac function, myocardial thickness, chamber size, valve function, and to locate the level of ventricular cavity narrowing. Two-dimensional imaging is complemented by Doppler evaluation. Color-flow Doppler examination permits the assessment of valve function and areas of high flows, and directs the pulsed-wave (PWD) and CWD Doppler exams, which are used to measure velocities and gradients within the ventricular cavity.

Ventricular Function and Morphology

In patients with HCM/HOCM, systolic function is usually preserved (LVEF ≥55%) or hyperdynamic (LVEF ≥65%) and the ventricular cavity is normal or reduced in size. A smaller percentage (<5% to 10%) of patients may have reductions in systolic function with or without chamber dilation, suggestive of late- or end-stage cardiomyopathy. Focal and global systolic dysfunction is due to disarray of the myocardial fibers with or without fibrosis. In addition, decreases in myocardial performance may be due to atheromatous CAD, hypertrophic involvement of the coronary arteries, reduction of coronary perfusion in a hypertrophied ventricle, or decreased coronary artery vasodilatory reserve.62,63

Echocardiographic assessment of ventricular wall thickness and intracavitary dimensions should be performed at the base, mid, and apical segments to delineate the pattern of hypertrophy and identify where systolic outflow obstruction may occur. Wall thickness in HCM/HOCM ranges from normal (≤11 mm) to greater than 30 mm. The absence of hypertrophy does not rule out HCM/HOCM since development of myocardial thickening may be delayed until the second or third decade, emphasizing the need for routine follow-up of patients with a family history of HCM/HCOM.

A number of patterns of myocardial hypertrophy have been reported including diffuse, asymmetric, concentric, or even isolated focal hypertrophy. While asymmetric septal hypertrophy is classically described, hypertrophy may be diffuse or concentrated elsewhere including the mid-, apical, or inferolateral ventricular segments (Figure 14–7). Narrowing of the ventricular cavity (<25 mm during systole) may be associated with abnormal systolic outflow velocities (>1.4 m/s). A variant of hypertrophy is isolated to the basal septum (septal bulge). The risk of LVOTO for these patients may be determined by the angle between LVOT outflow and ventricular (transmitral) inflow (Figure 14–8).49,50 A greater intrusion of septal tissue into the LVOT yields a larger angle and greater disturbance to outflow. Angles greater than 35° are predictive of LVOTO with provocation.50 Angles greater than 80° are associated with high velocity flows at rest.

Diastolic Function

Diastolic dysfunction associated with ventricular hypertrophy, myocardial disarray, fibrosis, and/or coronary artery insufficiency occurs in almost all patients. Reduced ventricular filling can also be due to inadequate systolic emptying caused by dynamic outflow obstruction. Relief of LVOTO and subsequent reduction in LV pressures also improves coronary blood flow, myocardial oxygen balance, and ventricular filling. The assessment of diastolic function can be achieved with a number of echocardiographic techniques including TMDF and PVDF velocity profiles (see Table 14–2). Doppler profiles of LV diastolic function in patients with HCM/HOCM range from normal to restrictive filling patterns, the latter reflecting greater degrees of hypertrophy and fibrosis. More commonly, abnormal ventricular relaxation is present. The severity of diastolic function correlates with reductions in exercise tolerance and CHF.

Mitral Valve Regurgitation and Systolic Outflow Obstruction

Mitral regurgitation and systolic outflow obstruction are not uniformly found in patients with HCM and may require provocation to identify. Both medical and/or surgical therapy may be indicated to treat MR and systolic outflow obstruction. Systolic outflow obstruction whether at the level of the LVOT or at the middle portion of the ventricular cavity results in high systolic flow velocities, incomplete systolic emptying, and increased ventricular cavity pressures. PWD sampling of the ventricular cavity from the apex to the subaortic valve (AV) area can be utilized to identify the location of abnormal systolic outflow. The Doppler profile is described as late peaking (>1.4 m/s) and “dagger shaped” in appearance (see Figure 14–7B; Figure 14–9). CWD may be necessary to quantify the outflow velocity when aliasing occurs during PWD examination. Although transesophageal windows allow Doppler sampling from the ventricular apex to the middle of the cavity, transgastric views allow better assessment of the LVOT and AV flows. LVOTO can also be demonstrated by using M-mode to interrogate the AV leaflets from the short- or long-axis AV views (see Figure 14–9). The AV leaflets will open normally but close prematurely in mid-systole due to dynamic obstruction of systolic outflow.

Two-dimensional echocardiographic assessment may display systolic anterior motion (SAM) of the mitral leaflets and chordae (Figure 14–10). Esophageal imaging demonstrates SAM more easily and clearly. A number of investigations describe how a narrowed LVOT creates a high-velocity flow, which subsequently creates a Venturi or vacuum effect on the MV leaflets causing them to move anteriorly, further narrowing the LVOT resulting in LVOTO.50,56 In these patients, SAM distorts MV leaflet coaptation causing MR. The Venturi effect, however, does not fully explain LVOTO and SAM, which may or may not occur with high-velocity systolic flows. Specific features of the MV associated with SAM and LVOTO include redundant or elongated mitral leaflets, lax chordae, abnormally positioned papillary muscles, and mitral annular dysfunction.

Color Doppler analysis of the LVOT and MV from the midesophageal three- or five-chamber and long-axis windows demonstrates aliasing of the CFD jet in LVOT at the level of narrowing consistent with high-velocity flow, and across the MV indicating significant MR. This “Y”-shaped CFD is consistent with LVOTO/SAM and MR (Figure 14–11). Quantitation of MR is discussed in detail in Chapter 7.

Clinical and experimental evidence suggests that manipulation of the MV annulus and/or subvalvular apparatus can either prevent or precipitate SAM and LVOTO.48,54,58,59 Normally, the MV annulus is dynamic in that it enlarges and contracts during the cardiac cycle.67 During systole,, all of the posterior and much of the anterior annular segments contract and move posteriorly. A small portion of the anterior annulus that abuts the LVOT lengthens in an anterior and superior direction. These movements result in a wider LVOT. Annular movement also moves the MV leaflets and coaptation more posteriorly during ventricular systole, resulting in a wider LVOT and making SAM/LVOTO less likely. Abnormalities of the MV annulus including calcification along the posterior annulus distorts normal annular posterior motion and increases the risk of SAM/LVOTO. Mitral annular calcification (MAC) alone does not contribute significantly to SAM/LVOTO as few patients with this single abnormality have this problem, and conversely, not all patients with SAM/LVOTO have MAC. However, posterior annular calcification hinders the normal posterior movement of the mitral apparatus, and the mitral leaflets are positioned closer to the outflow tract during systole thus increasing the risk of SAM (Figure 14–12). Conversely, normal posterior motion of the mitral apparatus decreases the likelihood of SAM/LVOTO as demonstrated after MV repair.

A large anterior mitral leaflet (AL >2.0 cm in length), measured in end-diastole from the midesophageal 5 chamber view, contributes to LVOTO.55,59–61 During ventricular systole, a relatively greater posterior leaflet (PL) contribution to MV coaptation also contributes to the development of SAM/LVOTO (Figure 14–13).55,60,61,68 More specifically, when the heights of the posterior leaflet (posterior annulus to coaptation point) and anterior leaflet (anterior annulus to coaptation point) are similar (AL:PL ≤1.3), the risk of SAM/LVOTO is increased.68 The larger PL coapts with the AL closer to its base, resulting in increased residual or “slack” leaflet portions that lie closer to the LVOT and are thus more susceptible to ventricular outflow exposure. The distance between the coaptation point and the ventricular septum (C-Sept) measured from the TEE midesophageal three- or five-chamber window reflects the position of the coaptation point and the thickness of the ventricular septum. A C-Sept distance of 2.5 cm or less is sufficiently narrowed to increase LVOT velocities for patients with HCM/HOCM, and also increase the risk of SAM/LVOTO/MR after MV repair.50,68,69

In vitro flow models demonstrate that anterior and inward displacement of the papillary muscle alters chordal tension resulting in excess leaflet mobility. Anterior displacement of the papillary muscles also shifts the mitral coaptation point toward the base of the leaflets and more anterior toward the LVOT.54,55 These alterations result in excess and lax mitral tissue in the LVOT, increasing the risk of SAM/LVOTO with or without LV hypertrophy (Figure 14–14). In contrast, when the papillary muscle(s) are positioned posteriorly along with the coaptation point, no SAM was seen despite severe septal hypertrophy and flow velocities of 3.3 m/s.

The angle at which the mitral leaflets open affects the direction of blood flow into the LV during diastole and subsequently the direction of ventricular systolic outflow (Figure 14–15).57 Normally, ventricular inflow is directed along the posterior wall, and outflow is directed along the septum exerting minimal forces on the mitral leaflets. However, anterior displacement of the papillary muscle(s) results in movement of the mitral coaptation point toward the LVOT, directing ventricular inflow toward the ventricular septum. Blood then moves from the septum toward the posterior wall during diastole, and during systole is subsequently directed toward the LVOT, thus pushing the MV leaflets toward the LVOT and causing SAM. Redirecting ventricular inflow toward the posterior wall will minimize mitral leaflet distortion during ventricular systolic outflow.

The mechanism of SAM/LVOTO and MR is likely to involve some combination of the Venturi effect and abnormalities of the mitral apparatus. These variables may contribute differently from one patient to another. Nevertheless, delineating the mechanisms of SAM/LVOTO/MR provides useful information when considering the best mode of therapy for patients who are symptomatic from outflow tract obstruction and MR. Reassessment of heart function after treatment is necessary to determine the need for adjustments and/or additional interventions. Nonsurgical goals and treatments include the use of β-receptor and calcium channel blockers, maintenance of preload and afterload (Figure 14–16), and avoidance of arrhythmias. Other treatments include ventricular pacing (to induce a left bundle branch block) and alcohol ablation of the ventricular septum. The goal of these therapies is to maintain ventricular function and enlarge the LVOT in order to reduce ventricular outflow gradients. Patients who remain refractory to these noninvasive therapies may be referred for surgical intervention.

Surgical procedures for SAM/LVOTO vary depending upon the mechanism of outflow obstruction and the presence and etiology of MR. The preoperative echocardiographic exam is particularly important to assess myocardial performance and valve integrity, and delineate the mechanisms of dysfunction. Routine intraoperative echocardiographic evaluation prior to and immediately after cardiopulmonary bypass (CPB) is performed to help guide surgical decisions and assess results. Surgical options include myomectomy/myotomy, which involves resecting a significant portion of the ventricular septum at the level of obstruction. In addition, MV surgery may be considered, especially if native valve abnormalities exist including prolapse, ruptured cordae, and redundant/elongated leaflets. Mitral valve replacement with a low-profile bileaflet mechanical valve should reliably eliminate MR and reduce LVOTO involving the mitral apparatus. Mitral valve repair has also been reported for patients with HOCM and MR70 and avoids complications associated with prosthetic valves. The feasibility of repair can be determined and guided by echocardiographic assessment. The primary goal of MV repair is to move the coaptation point posteriorly in order to (1) produce a posteriorly directed ventricular inflow while maintaining systolic flow along the septum, and (2) to keep the MV leaflets posterior and away from the LVOT, thereby minimizing or eliminating the effects of systolic “drag” forces on the leaflets. If the AL is considered excessively redundant, a triangular resection may also be necessary. Although MV repair eliminates complications of prosthetic valves, it is a more complex surgery.

The range of overall surgical mortality is 2% to 5%, and is higher for elderly patients (8% to 27%). Surgical resection of the myocardium can be complicated by a severed septal perforator artery,the creation of an iatrogenic ventricular septal defect and varying degrees of heart block.71 Furthermore, injury to the MV has been reported during myotomy-myectomy procedures.66 The importance of intraoperative echocardiography in diagnosing complications following surgical procedures for SAM/LVOTO/MR therefore cannot be overemphasized.

Systolic Outflow Tract Obstruction after Cardiac Procedures

LVOTO with SAM and MR may develop after cardiac surgical procedures including, but not limited to, AV replacement, especially for AS, and MV repair. Dynamic outflow tract obstruction or its potential has been recognized prior to and as long as 2 to 3 years after AVR.72 While it is not clear whether or not these patients have variants of HCM/ HOCM, the mechanisms of LVOTO/SAM/MR are similar and may include asymmetric hypertrophy of the ventricular septum, a prominent septal bulge, smaller ventricular cavity, hyperdynamic systolic function, excess or redundant MV leaflets, an increased incidence of posterior MAC, and/or a shorter C-Sept distance (ie, narrower LVOT). Recognition for the potential for SAM/LVOTO/MR allows for the opportunity to initiate medical therapy and/or surgical intervention.

Predictors of LVOTO/SAM/MR after MV surgery include a relatively greater contribution of the PL to mitral coaptation (AL [coaptation point to anterior annulus]:PL <1.3), and a shorter C-Sept distance (<2.5 cm).68,69 Resolution of LVOTO/SAM/MR was seen with a relative increase in AL contribution to coaptation (AL:PL >2.0) and an increase in C-Sept distance, both of which result in posterior movement of the mitral coaptation point. LVOTO has also been reported after MV replacement with a bioprosthetic valve. While imaging from esophageal windows may suggest LVOT narrowing due to the location of the bioprosthetic valve struts, assessment of the LVOT from TEE transgastric windows is necessary for confirmation. Three-dimensional TEE may also permit confirmation of MV bioprosthetic strut location within the vicinity of the LVOT, yet without obstructing blood flow, when 2D TEE imaging planes are not definitive (Figure 14–17). Aortic valve M-mode may also be useful in detecting early valve closure.

Etiology and Pathophysiology

Restrictive cardiomyopathy (RCM) is a pathologic process in which diastolic function of one or both ventricles is severely impaired in the absence of a definitive systemic disease. Although restrictive pathophysiology is implied, a range in severity of diastolic dysfunction occurs in relation to the extent of disease. While several diseases are associated with restrictive filling, only Loeffler hypereosinophilic endocarditis, endomyocardial fibrosis, and idiopathic restrictive cardiomyopathy qualify as primary restrictive cardiomyopathies.1,73 Secondary causes of RICM include infiltrative diseases such as amyloidosis, sarcoidosis, and storage diseases (eg, glycogen storage disease, hemochromotosis), certain drugs (anthracyclines, ergotamine, methysergide, serotonin), and a number of miscellaneous causes (transplant rejection, radiation, cancers, toxins). Collectively, these diseases have significant overlap and have been categorized as restrictive/constrictive, infiltrative, congestive, or obliterative cardiomyopathies reflecting the range of clinical and morphological presentations. Congestive cardiomyopathy more accurately reflects this group of disorders due to the presence of either pulmonary venous or vena caval congestion, which results in signs of left and right heart failure, respectively. However, since this term is vague and could include all cardiomyopathies, the diseases in this section will be referred to as “restrictive/infiltrative cardiomyopathies” [RICM]; Table 14–3).

RICM should be suspected when a patient presents with CHF, nondilated ventricles, dilated atria, diastolic dysfunction, and poor response to medical therapy. While chest x-ray reveals cardiomegaly and a thickened heart, electrocardiogram (ECG) demonstrates low QRS voltage consistent with replacement of the normal myocardium with non- or poorly conducting tissue. Tissue biopsy frequently confirms the diagnosis; however, it may also show nonspecific and nondiagnostic fibrotic changes of the endomyocardium and myocardium.74

Two-Dimensional Echocardiographic Evaluation

Establishing the diagnosis and determining the severity of ventricular dysfunction is important for treatment and prognosis. Differentiation from more treatable causes of heart dysfunction (eg, CAD, valvular heart disease, pericardial disease) is necessary to allow prompt performance of therapeutic procedures (eg, pericardiectomy for pericarditis) when indicated. There are a number of clinical and echocardiographic findings that are unique for each disease in this group of cardiomyopathies.

Amyloidosis is the most commonly reported etiology of RICM and is caused by an abnormal layering of protein within the myocardial tissues including all cardiac chambers as well as the coronary arteries, cardiac conduction system, and heart valves. Four types of amyloidosis have been described: (a) primary, (b) secondary, (c) familial, and (d) senile. The protein that is present in primary amyloidosis comes from plasma cells, possibly associated with multiple myeloma. Secondary amyloidosis is associated with chronic inflammatory diseases such as rheumatoid arthritis, and tuberculosis. Of the four types, primary and senile amyloidosis involve cardiac tissues, with the former involving other systemic organs and the latter occurring in older patients. Mortality for patients with cardiac amyloidosis is high, and survival beyond 2 to 3 years for patients presenting with CHF is less than 50%.75 Prognosis is related to the extent of infiltration, thickness of the ventricular walls, severity of diastolic dysfunction, presence of systolic dysfunction, and RV involvement.76,77

An autopsy study of 54 patients who died of cardiac amyloidosis highlights the extensive amyloid infiltration of the cardiac tissues.78 Amyloid deposition was found within the interstitium (53 of 54), endocardium, valves (46 of 54; 86%), and intramurally within the coronary arteries (54 of 54). No disease was found in the epicardial coronary arteries, distinguishing it from atheromatous disease. Forty-four of 54 (85%) patients with amyloidosis who died from cardiac causes had a history of CHF. Of the eight patients without CHF, three had sudden death, two had familial amyloidosis, two had multiple myeloma, and one had cirrhosis due to amyloid infiltration. Forty-five percent had varying degrees of heart block, and 18% had complete heart block. During autopsy, the heart was described as “rubbery” and noncompliant. Although all patients in this study had bi-atrial enlargement, only 20% had ventricular dilation, which was associated with other pathologies (eg, CAD, primary pulmonary disease). Intracardiac thrombi were found in 26% of patients, with a greater incidence in the atria. In 50 of 54 patients, the ventricular septum and free wall had equal or near equal thickness. Four (7%) of patients had asymmetric thickening with a septal/free-wall ratio greater than 1.3:1.

A number of echocardiographic features differentiate the amyloid heart from other causes of hypertrophy and/or diastolic dysfunction.77,79 The echocardiographic appearance of the amyloid heart is classically described as “speckled,” granular, or “starry skied” (Figure 14–18). Speckling may be due to the acoustic interface created by myocytes and amyloid protein. All cardiac tissues may be symmetrically or, infrequently, asymmetrically thickened and “speckled.” Similar to other etiologies of RICM, the atria are enlarged, while the ventricular cavity size is often normal or reduced. However, infiltration of the atrial walls, especially the interatrial septum, differentiates amyloidosis from other causes of CHF. In addition, RV thickening and speckling are more common with amyloidosis than other diseases. While speckling has been found in other diseases (eg, uremia), its presence is highly sensitive and specific for cardiac amyloidosis. Systolic dysfunction, when it occurs, is rarely associated with chamber enlargement or RWMA except in those patients with coronary artery involvement. Prognosis in patients with amyloidosis is based on myocardial wall thickness, severity of diastolic dysfunction, and systolic function.73,75 For patients with wall thickness 12 mm or less the median survival is about 2.5 years, while survival is reduced for those with wall thickness between 12 and 15 mm (1.3 years), and least for those with wall thickness 15 mm or greater (0.4 years). The incidence of systolic dysfunction is 0%, 35%, and 70% in these three groups, respectively. In patients with systolic dysfunction, only 5% have LV dilation and/or focal RWMA. These patients have significant amyloid involvement of the coronary arteries. Prognosis is also related to the severity of diastolic dysfunction, which in turn is correlated with ventricular wall thickening. For patients with milder cardiac involvement, wall thickness is less than 15 mm, and Doppler profiles suggest a pattern consistent with abnormal relaxation. In contrast, patients with wall thickness 15 mm or greater have flow profiles suggestive of a restrictive filling defect. Comparable profiles are found when assessing filling of the right heart of patients with amyloidosis.80 The TTDF, caval, or hepatic vein flow profiles for patients with RV free wall thickness less than 7 mm are usually consistent with abnormal relaxation. For patients with RV wall thickness 7 mm or greater the patterns suggest a restrictive filling defect.

Idiopathic restrictive cardiomyopathy is an autosomal dominant disease associated with heart block and skeletal myopathy, which presents in the third and fourth decades.73,75,81 Histologic examination reveals variable degrees of interstitial fibrosis throughout the heart, which cannot be explained by a specific etiology. For children under 10 years of age, the survival is less than 2 years, while more than 60% of adults survive beyond 4 years. Echocardiographic evaluation reveals diastolic dysfunction, relatively normal systolic function, variable myocardial thickening, atrial enlargement with or without thrombi, and pulmonary hypertension.

Endocardial fibroelastosis is found in children and characterized by a thick endocardium.35 Histology demonstrates infiltration of the endocardium with collagen and elastic tissue causing LV endocardial thickening with or without MV involvement. While the primary form is not associated with other congenital cardiac abnormalities, a secondary form may be found with LVOTO, aortic coarctation, coronary artery abnormalities, or hypoplastic left heart.

Hypereosinophilic syndrome (Loffler endocarditis) and endomyocardial fibrosis are a continuum of the same disease differing only by their presenting pathology.82 Although these diseases are uncommon, their occurrence is greater in parts of Africa and Asia, accounting for as much as 25% of cardiac deaths. While both are the result of cardiac eosinophilia, Loffler endocarditis presents with significant cardiac hypereosinophilia, while endomyocardial fibrosis represents a later stage characterized mainly by fibrosis. As both diseases progress, endocardial thickening and fibrosis develop with greater involvement of the MV and TV subvalvular apparatus producing valve insufficiency and/or stenosis. Involvement of the ventricular apex results in obliteration of the cavity, which may be further complicated by thrombus formation. Echocardiography demonstrates bi-atrial enlargement, endocardial thickening, or deposits along the MV and TV associated papillary muscles, and along the apices of both ventricles (Figure 14–19). The involved tissues appear bright and echo-dense, consistent with calcium deposition. While impairment to ventricular filling is present, systolic motion of the ventricular walls is usually preserved.

Hemochromatosis is an infiltrative process due to abnormal deposition of iron in a number of organs including the liver, heart, kidneys, pancreas, skin, and pituitary gland. Iron deposits within the cells cause degeneration and subsequent fibrosis. Cardiac involvement is the leading cause of death in these patients, occurring in as many as 40% of patients with primary hemochromatosis.83 Cardiac pathology is rarely seen without other organ system involvement. Echocardiographic features that are typical of this infiltrative disease include primary involvement of the LV associated with chamber enlargement and significant systolic dysfunction. In sharp contrast to primary RCM, a restrictive filling defect is rare. Wall thickening and RWMA are also uncommon; however, the latter may be present in infrequent cases of coronary artery involvement and microcirculatory insufficiency. Echocardiographic evaluation may be useful to monitor the beneficial effects of chelation.

Sarcoidosis is a systemic disease in which organs are infiltrated with non-caseating granulomas. Cardiac involvement is found in approximately 20% to 25% of cases, and is rarely seen without involvement of other organ systems.84 The LV free wall and papillary muscles are more commonly affected, causing ventricular dysfunction, conduction system abnormalities, and an increased risk of sudden death. Initially, patients have diastolic dysfunction, which gradually progresses to include systolic dysfunction. Echocardiographic features are less specific and include RWMA and chamber enlargement with ventricular thinning that may lead to aneurysm formation. Other less commonly found features include pericardial effusions, LV thrombi, and diastolic dysfunction. RV thickness and dysfunction usually develop from sarcoid involvement of the lung parenchyma producing pulmonary hypertension.

A number of miscellaneous etiologies of RICM have also been described. Carcinoid infiltration of the heart is associated with fibrous plaques within the TV, MV, and along the RV free wall. Radiation therapy results in both myocardial and endocardial fibrosis, especially of the RV, causing a restrictive pathophysiology. A number of pharmacologic agents also cause restrictive cardiac disease including anthracyclines (Doxorubicin), which are also known to cause a dilated cardiomyopathy and can aggravate the effects of radiation therapy on the heart. Glycogen, lipid, and mucopolysaccharide storage diseases are uncommon diseases, and therefore echocardiographic descriptions are not well established. These disorders share commonalties with both HCM/HOCM as well as with other RCM. For example, echocardiographic evaluation of Pompe disease (type II glycogen storage disease) may include asymmetric LV hypertrophy with SAM. Fabry disease (X-linked recessive, lysosomal storage disorder resulting from α-galactosidase deficiency) may share similar features with amyloidosis including biventricular abnormalities and reduced diastolic and systolic dysfunction.

Doppler Assessment of Diastolic Function: Restrictive Physiology

The demonstration of restrictive TMDF and PVDF profiles in patients with RICM is an inherent component of the diagnosis and has been shown to correlate with outcome. While distinct differences have been drawn between abnormal relaxation and restrictive physiology, it is likely that they are part of a continuum of diastolic dysfunction. For example, patients with cardiac amyloidosis progress over time from normal diastolic function to impaired relaxation, through pseudonormal pathophysiology, and then to a restrictive pattern (Figure 14–20; see Table 14–2). The Doppler flow profiles seen with mild diastolic dysfunction are primarily the result of reduced ventricular relaxation while atrial pressures and function are relatively normal. As diastolic function deteriorates, ventricular stiffness increases along with ventricular and atrial pressures. Atrial contractility and compliance subsequently decrease with further reductions in ventricular compliance.

Flow profiles suggesting a restrictive filling include an E/A ratio greater than 2.0, DT less than 150 milliseconds, IVRT less than 80 milliseconds, PVD less than 30 cm/s, a PVS/D much less than 1.0, an PVAR greater than 35 milliseconds, and a PVAR/TMDFA duration or peak velocity ratio of greater than 0.6 (see Figures 14–4 and 14–20).77 These filling patterns result from elevated LAP forcing early transmitral flow (decreased IVRT) into a stiff LV (decreased propagation velocity and DT), which subsequently limits transmitral flow during a diminished atrial contraction (ie, increased E/A ratio). A relatively larger LA volume is ejected backwards toward the pulmonary veins during atrial contraction, thus producing an increased PVAR/TMDFA ratio. Incomplete LA emptying during atrial contraction subsequently limits pulmonary venous inflow during ventricular systole, resulting in a decreased PVS/PVD. RV failure is associated with similar Doppler flow velocity profiles into the RA and across the tricuspid valve.

Restrictive filling patterns are associated with poor exercise tolerance, CHF, and mortality across a number of different populations including patients with RICM.43,77,85–87

Differential Diagnosis

Differentiation between RICM and from other causes of CHF is important to establish both prognosis and a treatment plan. While treatment for RICM is largely supportive and prognosis is comparatively poor, treatment for other causes of heart failure have greater success. The differential diagnosis includes CAD, hypertension, HCM/HOCM, DCM, valvular pathology, and pericardial disease. These etiologies are usually known or suspected based on the patient's history and examination, or are diagnosed with echocardiography and/or coronary angiography. The echocardiographic appearance of the myocardium is normal in these disease processes unless scarring is present (thin and bright echoes). Hypertrophic cardiomyopathies have been discussed in detail above. Although myocardial thickening is present with HCM/HOCM, hypertension, or aortic stenosis, the echocardiographic appearance does not typically appeared “speckled.” In addition, atrial infiltration and thickening are not likely. Furthermore, a restrictive pattern is less commonly reported with other causes of myocardial thickening. Valvular dysfunction may also occur with RICM; however, a pattern of valve apparatus infiltration is usually noted during 2D echocardiography. Valve surgery may improve functional capacity of patients with RICM.

Pericardial diseases including effusion/tamponade, tumor, and constrictive pericarditis are often included in the differential diagnosis of CHF. Differentiation from RICM is important since pericardial diseases can be treated with resection of the constrictive pericardium or pericardiocentesis.77,85 An accurate diagnosis of cardiomyopathy may prevent an unnecessary surgical procedure.

Since a range in the severity of diastolic dysfunction may be present in patients with RICM, similarities with constrictive pericarditis may be demonstrated in the resting TMDF and PVDF profiles. However, other differences allow distinction between the two pathological processes (Table 14–4). In patients with constrictive pericarditis, RAP and LAP waveforms demonstrate normal or reduced “a” and “v” waves along with a deep “y” descent. The “x” descent may also be normal or deep. RV pressure waveforms classically reveal a “dip” and “plateau” or “square root” appearance. There is equalization (within 5 mm Hg) of diastolic pressures in all four cardiac chambers, and pulmonary vascular pressures may be mildly elevated. In contrast, pressure waveforms in RICM reveal elevated RA and LA “a” and “v” waves along with a prominent “y” descent. Although a similar RV waveform may occur with RICM, equalization of diastolic pressures is unusual, and more severe pulmonary hypertension is often present.

A number of echocardiographic findings also help differentiate constrictive pericarditis from RICM (see Chapter 15). In constrictive pericarditis, 2D and M-mode echocardiography reveal a thickened and/or calcified (echo-dense) pericardium without apparent abnormalities elsewhere in the ventricular myocardium, valve tissues, or atrial walls (Figure 14–21). The inferlolateral ventricular wall may be flat due to the adherent pericardium, limiting its mobility. In addition, the ventricular septum may appear to “bounce” during diastole due to the near equal pressures in both ventricles, and limitation of filling during diastole.85 A dilated IVC is consistent with an elevated RAP or impaired filling.

Doppler echocardiography is also useful to distinguish constrictive pericarditis from RICM. By surrounding the heart, the abnormal pericardium attenuates the affects of intrathoracic pressure changes on the heart, while changes in intrathoracic pressures are transmitted to the central vessels (cavae and pulmonary veins that are not encased by the constricting pericardium). During spontaneous ventilation, inspiration lowers intrathoracic and also pulmonary venous pressures. This leads to reduction in LAP, which is reflected by reductions in TMDF peak velocities (E and A waves), an increase in IVRT, and a reduction in PVDF velocities into the LA. The opposite changes are seen during expiration. The corresponding right heart flows and velocities are opposite to the left side of the heart. Changes in right and left heart flows are opposite during positive pressure ventilation. Peak velocities change more than 15% from one respiratory phase to another. In contrast, for patients with RICM, there is little change (<15%) in Doppler measured flows across the TV and MV, since changes in intrathoracic pressure are transmitted to the heart and central venous tissues equally.

Left Ventricular Non-Compaction

Left ventricular non-compaction (LVNC) or hypertrabeculation results from an arrest of the normal fetal development of the myocardium. During its initial developmental stages, the heart muscle has a spongy texture and appearance, ie, non-compacted. At this time and through the 17th week of gestation, the developing myocardium receives its nutrition via diffusion across cell membranes, since the coronary arteries are not yet developed. This loose network of muscle trabeculations and bands maximizes the amount of surface area, thereby facilitating the diffusion of blood into the tissue beds. The coronary arteries develop around the 18th week of gestation as the spongy trabeculated myocardium becomes more compacted in preparation for contraction required for normal ventricular function. Beyond the 18th week, the prominent trabeculations further reduce in size and appear even closer to the surface, while the spongy myocardium becomes increasingly more compacted.

Approximately 0.015% to 0.05% of echocardiograms display images consistent with LVNC, although the actual incidence is difficult to ascertain.88 Among patients presenting with heart failure, this incidence may be greater.89 The timing of arrested development dictates the degree of myocardial dysfunction. In its most severe form, the pumping function of the myocardium is severely impaired. The genetic inheritance varies significantly, and mutations generally include genes coding for the myocardial filaments, cytoskeleton, and possibly coronary vasculature. Sponge-like interlacing smaller muscle bundles have been described during autopsy, along with non-compacted broad and coarse trabeculae; however, well-developed papillary muscles are usually absent.90

The clinical presentation of LVNC varies from asymptomatic to severe heart failure, the latter being characterized by a number of nonspecific signs and symptoms including peripheral edema, dyspnea, fatigue, and reduced functional capacity. A variety of atrial and ventricular arrhythmias, conduction delays, and blocks may develop; however, tachycardias are generally not well tolerated. There is also an increased incidence of intracavitary thrombi located within the trabecular mesh; however, they are not likely to develop in the absence of systolic dysfunction.

The diagnosis of LVNC is usually based on echocardiography and cardiac magnetic resonance imaging (CMRI). Jenni et al proposed the following echocardiographic criteria for the diagnosis of LVNC:

1. Thickened LV wall consisting of two layers: a thin, compacted epicardial layer and a markedly thickened endocardial layer with numerous prominent trabeculations and deep recesses with a maximum ratio of non-compacted to compacted myocardium greater than 2:1 at end-systole in a TTE parasternal short-axis view.91,92

2. Color Doppler highlighted flow within the recesses created by the deep trabeculations.

3. Involvement of the mid to apical inferior and lateral wall segments.

All three of these findings are required to make the diagnosis of LVNC. Apical and midventricular inferior and lateral walls may be affected most often. Hypokinesis of the affected walls, diastolic dysfunction, and thrombi may be observed; however, these are not required to establish the diagnosis.

Chin et al have also suggested that echocardiographic criteria for LVNC include a ratio of the distance from the epicardial surface to the trough of the trabecular recess and the distance from the epicardial surface to the peak of the trabeculations of 0.5 or less as viewed in a TTE apical four-chamber or sub-xiphoid view at end-diastole.93 Although both of these criteria highlight the presence of prominent trabeculations, the Jenni criteria have been shown to be more sensitive.94

Cardiac magnetic resonance imaging displays a maximum ratio during diastole, of non-compacted to compacted myocardial thickness of greater than 2.3 as assessed in three long-axis views (sensitivity 86%; specificity 99%). This finding distinguishes LVNC from other cardiovascular etiologies of prominent trabeculations including HCM associated with aortic stenosis and systemic hypertension.95

Treatment of LVNC is generally supportive, including standard therapies for heart failure and arrhythmia prevention. Oechslin et al described the outcome for 34 adults with LVNC over 44 ± 40 months.88 The mean age at diagnosis was 42 ± 17 years with 12 patients experiencing significant heart failure at the time of diagnosis. The mean LV end-diastolic diameter was 65 ± 12 mm and an LV ejection fraction of 33 ± 13%. Apical and midventricular segments of the inferior and lateral walls were involved in more than 80% of cases. Complications included heart failure (n = 18; 53%), thromboembolic events (n = 8; 24%), and ventricular tachycardias (n = 14; 41%). Sudden death occurred in 12 individuals, which was associated with heart failure in four patients, while two others died of noncardiac causes. Four patients underwent heart transplantation and four received automatic implantable cardioverter/defibrillators. Presentation in the neonatal period carries a 14% mortality at 3 years. For unclear reasons, there may be a period of recovery followed by significant deterioration.96

Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic right ventricular dysplasia (ARVD) is characterized histologically by fatty and/or fibrous infiltrate of the right ventricle. The severity varies from a functionally normal patient with mild structural changes to complete involvement of the RV myocardium with severe ventricular dysfunction and arrhythmias. The ventricular septum is typically spared. The left ventricle is also less commonly involved.

Patients with ARVC present between the ages of 10 and 50 years (mean age of 30 years). It is rarely diagnosed in infancy and uncommonly before age 10. The incidence is regionally different, although rare in the United States, with a maximum occurrence of approximately 1 in 1000. However, ARVC may account for 11% of sudden cardiac death in younger patients, and in 22% of athletes.97,98 The diagnosis is suspected for sudden cardiac death brought on by exercise.

The presentation of patients with ARVC varies depending on the extent of infiltration. Symptoms include palpitations, syncope, atypical chest pain, and dyspnea.99 Symptomatic atrial fibrillation and ventricular arrhythmias, the latter ranging from frequent premature ventricular contractions to ventricular tachycardia/ fibrillation, are typical.100 High-risk patients include those with symptoms including syncope, hemodynamic instability, and/or ventricular dysrhythmias, evidence of right ventricular failure, evidence of left ventricular involvement, and an increase in QRS duration of greater than 40 milliseconds.101

The diagnosis of ARVC is suspected for young patients with ventricular tachycardia and a left bundle branch block (LBBB) configuration or multiple morphologies. The QRS morphology usually resembles a LBBB configuration since the arrhythmia is more likely to originate from the right ventricle. The diagnosis, however, depends on histologic demonstration of fibrofatty replacement of the right ventricle. Nevertheless, since the sensitivity of tissue biopsy may be as low as 67%, other criteria have been established to determine the diagnosis of ARVC102:

1. Global and/or regional dysfunction and structural alterations

2. Repolarization or depolarization and conduction abnormalities on the ECG

3. Arrhythmias

4. Family history of ARVC

The evaluation of suspected patients includes ECG, echocardiography, radionucleotide ventriculography, and magnetic resonance imaging (MRI) studies. Forty to fifty percent of patients with ARVC have normal ECG at presentation; however, within 6 years, almost all patients present with of one of the following ECG findings103:

1. Prolonged QRS

2. Incomplete or complete bundle branch block

3. Epsilon wave (30%)

4. T-wave inversion that correlates with degree of RV enlargement

5. QT dispersion

6. Prolonged S-wave upstroke

Electrophysiologic testing often demonstrates inducible ventricular arrhythmias and typically localizes the foci to the right ventricle.

Echocardiographic evidence of ARVC includes right ventricular enlargement ± regional wall motion abnormalities.104 Right heart enlargement characteristically involves the right ventricular outflow tract (>30-mm diameter).105 Although right ventricular enlargement and dysfunction is common, RV failure is present in only 6% of patients. At a later stage, however, the right ventricle becomes increasing dilated and dysfunctional.

Disease severity can be classified echocardiographically as104:

1. Mild: Right ventricular end-diastolic volume (RVEDV) less than 75 mL/m2 with localized hypokinesis or akinesis

2. Moderate: RVEDV 75 to 120 mL/m2 with localized hypokinesis or akinesis

3. Severe: RVEDV 120 mL/m2 or greater with widespread akinesis/dyskinesis and diastolic bulging

Qualitative echocardiographic findings include trabecular derangement and a hyper-reflective moderator band.105

Treatment of ARVC is directed toward preventing sudden cardiac death. Although not well defined, placement of an implantable cardiac defibrillator may be indicated for both primary and secondary therapies.106 Sotalol may be the best pharmacologic therapy especially when an “electrical storm” occurs with an implantable cardiac defibrillator.106 Amiodarone can also be effective.106 Treatment of atrial fibrillation also follows similar protocols as for the general population including cardioversion, rate control, and anticoagulation. Since exercise is known to precipitate tachyarrhythmias, avoidance of exercise may be advised. More invasive therapies include radiofrequency ablation of a documented arrhythmogenic foci and surgical resection of the right ventricular free wall to decrease the ventricular mass responsible for initiating ventricular tachycardias, and to prevent the spread of ventricular arrhythmias to the left ventricle.

Tako-Tsubo Cardiomyopathy

Tako-Tsubo cardiomyopathy or Tako-Tsubo syndrome (TTS), also known as “stress cardiomyopathy” or “broken-heart syndrome” mimics an acute coronary syndrome and is accompanied by reversible left ventricular apical ballooning in the absence of angiographically significant coronary artery stenosis. In Japanese, “tako-tsubo” means “fishing pot for trapping octopus,” and the left ventricle of a patient diagnosed with this condition resembles that shape. About 70-80% of cases of TTS occur in post-menopausal women under some form of extreme, exceptional and prolonged mental stress. In the remaining 20%, the stress is physical such as massive trauma, surgery or severe pain. In very rare cases, no “cause” can be found.107,108

The etiology of TTS is not fully understood, but several mechanisms have been proposed. Dote and associates109 suggested coronary vasospasm as the pathogenic mechanism; however, induction of coronary vasospasm by acetylcholine or ergonovine has yielded mixed results. The possibility of myocardial injury due to microvascular spasm has also been suggested. Ako and coworkers,110 by using of an intracoronary Doppler wire technique, demonstrated microcirculation impairments in instances of transient LV hypocontraction. Another putative mechanism is neurogenic stunned myocardium. This condition is also observed during acute cerebrovascular accidents and during the catecholamine-induced cardiomyopathy in patients with pheochromocytoma. Enhanced sympathetic activity appears to play a very important role in the pathophysiology of TTS.

The electrocardiogram in patients with TTS often demonstrates non-specific ST-T abnormalities, ST elevation, and/or QT prolongation with large negative T waves while cardiac biomarkers (troponin, creatine kinase) are only very slightly elevated. Echocardiography typically shows significantly decreased left ventricular wall motion with hypokinesis or akinesis of the anterior wall and anterior septum from the mid-papillary level to the apex. A hallmark of this syndrome is apical ballooning with sparing of the base of the heart. The apex is thought to be structurally vulnerable because it does not have a 3-layered myocardial configuration, has a limited elasticity reserve, can easily become ischemic as a consequence of its relatively limited coronary circulation, and is more responsive to adrenergic stimulation.111,112

An inverted Tako-Tsubo syndrome has also been recently described in patients with severe intracranial processes or with pheochromocytoma crisis. In those rare cases, instead of the tip of the left ventricle becoming stunned and “paralyzed”, the tip of the left ventricle is hyperdynamic while the base of the heart appears stunned and “paralyzed”.113,114

Treatment of TTS relies largely on support measures as short-term outcomes are excellent, with complete resolution in a few weeks in most but not all patients. Data on long-term outcome is limited but TTS recurs in approximately 5% and appears to be a marker for increased noncardiac mortality.115