Abstract
The primary abnormality in restrictive cardiomyopathy (RCM) is diastolic dysfunction in the presence of preserved left ventricular ejection fraction, with gradually increasing left ventricular end diastolic and left atrial filling pressures. Restrictive cardiomyopathies may be either primary or secondary to other infiltrative or storage disorders. Diastolic functional assessment of myocardium using Doppler echocardiography plays an important role in its diagnosis. In addition, there is accumulating evidence of the diagnostic and prognostic role of speckle tracking in various conditions with RCM, even prior to the development of overt cardiomyopathy. Cardiac amyloidosis is characterized by increased symmetric left and right ventricular wall thickness with reduced ventricular cavities, a granular, sparkling texture of the myocardium, valvular, and interatrial septal thickening, and low voltage on electrocardiography. Cardiac amyloidosis demonstrates the characteristic “bull’s eye” pattern on speckle tracking, with preserved motion at the left ventricular apex and reduced motion at the ventricular base. Endomyocardial fibrosis, which is probably the most common cause of RCM worldwide, demonstrates endomyocardial fibrosis with apical obliteration of ventricular cavities, and formation of biventricular thrombi. Carcinoid syndrome is characterized by mural plaques and valvulitis with regurgitation and stenosis of the affected valves, especially the tricuspid and pulmonic valves. In addition, RCM should also be considered in patients post-chest radiation, or with the chemotherapy patient who presents with heart failure of unknown etiology.
Keywords
carcinoid syndrome, cardiac amyloidosis, endomyocardial fibrosis, Löffler (eosinophilic) endocarditis, restrictive cardiomyopathy
Introduction
Restrictive cardiomyopathy (RCM) refers to either an idiopathic or a systemic myocardial disorder in the absence of underlying atherosclerotic coronary artery disease, valvular disease, congenital heart disease, or systemic hypertension, which is characterized by abnormal left ventricular filling, and is associated with normal or reduced left ventricle (LV) and right ventricle (RV) volumes and function. The term is not precise, but it incorporates infiltrative and fibrotic cardiac pathology, which are dealt with in this chapter. While the majority of patients with infiltrative and fibrotic cardiomyopathies develop a restrictive filling pattern, especially in the later stages of the disease, it is important to differentiate the pathology from a restrictive filling pattern, which can be associated with other types of heart disease, such as dilated cardiomyopathy. In patients with dilated cardiomyopathy the restrictive filling pattern is often a reversible phenomenon, related to worsening heart failure, and morphologically the ventricle is dilated, usually with severe reduction in ejection fraction. Although the clinical presentation of RCM may be similar to dilated cardiomyopathy, the nondilated, stiff ventricles often result in highly sodium-sensitive heart failure symptoms, associated in the late stage of the disease with a low cardiac output due to the small stroke volume. Because of the restriction to diastolic filling and an associated impaired ability to augment cardiac output at higher heart rates, these patients may also present with symptoms of exercise intolerance.
Diastolic dysfunction in the presence of preserved left ventricular ejection fraction (LVEF) is the key component of pathophysiology of RCM. Initial stages of RCM demonstrate preserved LVEF with noncompliant walls that impair the normal diastolic filling of the ventricle. This restriction can be isolated to either ventricle, or show biventricular involvement. Biventricular volumes are either normal or reduced. Over a period of time, the chronically elevated LV diastolic pressure leads to increased atrial size, which may be considerable. Although severe biatrial enlargement without valve disease is a classic finding of RCM, this is a nonspecific feature, as it may occur in other conditions, particularly if associated with long-standing atrial fibrillation. In later stages of the disease, as the compliance of the LV decreases, a small change in LV volume is associated with a steep rise in LV pressure. A reduced ejection fraction may occur in the very late stages of the disease. It is important to recognize that, although the left ventricle may show diastolic dysfunction with a normal ejection fraction, longitudinal systolic function may be significantly impaired, and thus a normal ejection fraction should not be considered synonymous with normal systolic function ( 
).
Spectrum of Restrictive Cardiomyopathy
RCM can be considered as either “primary” RCM or RCM secondary to other conditions such as infiltrative disorders and storage disorders. Infiltrative disorders primarily affect the interstitial space of the myocardium, whereas storage diseases are associated with deposits within the cardiac myocytes. In addition, endomyocardial involvement, leading to restriction, may occur in a variety of uncommon conditions ( Box 24.1 ).
Primary RCM
- •
Idiopathic and familial RCM
- •
Mitochondrial cardiomyopathy
Infiltrative Diseases
- •
Amyloidosis
- •
Mucopolysaccharoidoses (Hurler syndrome, Gaucher disease)
Storage Diseases
- •
Anderson-Fabry disease
- •
Glycogen storage disorders
- •
Hemochromatosis (may present with restrictive or, more commonly, dilated phenotype)
Endomyocardial Involvement
- •
Endomyocardial fibrosis and Löffler endocarditis
- •
Carcinoid syndrome
- •
Postradiation
- •
Postchemotherapy
- •
Lymphoma
- •
Scleroderma
- •
Churg-Strauss syndrome
- •
Pseudoxanthoma elasticum
RCM , Restrictive cardiomyopathy.
Diagnosis of Restrictive Cardiomyopathy
Due to the varied pathophysiology and clinical manifestations of the underlying systemic process, a systematic approach, beginning with a comprehensive history and detailed systemic evaluation, can help guide further management. Among patients with suspected idiopathic and familial RCM, a comprehensive family history should be obtained, as the condition is increasingly being recognized as familial. Clinical screening of first-degree relatives should be considered, and abnormalities, if present, may include hypertrophic and dilated cardiomyopathy. Comprehensive genetic screening should also be considered, particularly if family members with suspicious cardiac abnormalities are identified.
Echocardiography in Restrictive Cardiomyopathy
Cardiac imaging plays a pivotal role in establishing the diagnosis of RCM. Despite the availability of multiple cardiac imaging options, including cardiac magnetic resonance (CMR) imaging and nuclear cardiology, echocardiography remains the initial imaging method of choice among patients with suspicion of RCM. Echocardiography not only assesses the anatomy and function of the cardiac chambers, but it can also provide vital clues to the diagnosis of the underlying etiology. The first step in cardiac assessment when interpreting an echocardiogram in suspected restrictive heart disease involves a thorough evaluation of the overall and regional anatomy of the left ventricle with regard to underlying wall thickness, altered myocardial texture, and wall motion abnormality. LV mass assessed by using three-dimensional (3D) echocardiogram is more reproducible, and mirrors the mass obtained by cardiac MR more closely. Similarly, while the quantitative assessment of overall left ventricular volumes and systolic function assessment are usually performed using the biplane method of disks (modified Simpson’s rule), the use of 3D-based volumes and ejection fraction, when feasible and available, is encouraged since it does not rely on underlying geometric assumptions leading to superior accuracy and reproducibility. Nevertheless, two-dimensional (2D) echocardiography can give extremely useful diagnostic information, and the use of contrast for better delineation of the endocardium when two or more contiguous LV endocardial segments are poorly visualized in apical views improves accuracy and reduces interreader variability of LV functional analyses. In “primary” RCM, ventricular wall thickness is usually normal, whereas the myocardium in patients with cardiac amyloidosis is usually thickened, and may show increased echogenicity. It is also important to evaluate the right ventricular wall thickness and function, as involvement of right ventricle may have prognostic significance in a number of diseases.
Doppler Features
Diastolic functional assessment of myocardium plays an important role in the diagnosis of RCM. In the early stages of restrictive heart diseases, the myocardial relaxation (e′) is reduced, resulting in septal e′ less than 7 cm/s and lateral e′ less than 10 cm/s ( Fig. 21.1 A and B). In early stages of the disease, the mitral inflow pulse-wave Doppler shows an abnormal relaxation pattern, is characterized by an E/A ratio of ≤0.8, an increased mitral inflow E-wave deceleration time (≥240 ms), and an increased isovolumic relaxation time (>90 ms). At this stage of the disease, the left atrium is usually normal or mildly dilated in size, and the patient is rarely symptomatic. As this pattern is common in older patients in the general population, it is nondiagnostic even in a gene-positive patient. With progression of disease, the mitral inflow pulse wave Doppler pattern shows pseudonormal filling pattern, where the E/A ratio is 0.8–2, and this ratio reverses with Valsalva maneuver. Due to the elevated left ventricular filling pressures, there is an increase of the E/e′ ratio (≥10) and the left atrial volume index is elevated, ≥34 mL/m 2 . There is also a reversal in the pulmonary vein Doppler velocity pattern, with gradual blunting of the systolic wave and dominance of the diastolic wave (S/D <1, while normal S/D is >1; see Fig. 24.1C and D ). With further deterioration of ventricular compliance, advanced diastolic dysfunction develops, characterized by a restrictive filling pattern, namely an E/A ratio greater than 2, and a short (<160 ms) transmitral E wave deceleration time due to rapid equalization of atrioventricular pressures (<160 ms). As the left ventricular compliance decreases further, the diastolic filling pattern becomes irreversible, which can be demonstrated by the lack of reversibility of E/A ratio with Valsalva maneuver.
A major limitation of using these traditional Doppler echocardiographic features is their lack of specificity. In addition, there are significant limitations to acquisition and interpretation of these measurements in patients with underlying atrial fibrillation and in patients with significant mitral valvular disease (including ≥ moderate mitral regurgitation and stenosis, or mitral valve repair or mitral valve replacement).
Speckle Tracking
Speckle tracking tissue Doppler echocardiography can assess cardiac mechanics, including global and regional myocardial deformation, which can differentiate active wall thickening from passive motion. It allows detection and quantification of subclinical LV and RV systolic dysfunction, even when the global and segmental LV ejection fraction appears preserved. An important strength of this technique is that myocardial deformation or strain can be assessed in different spatial directions, including radial, circumferential, longitudinal, and transverse directions, as the technique is angle-independent. Reduction in echocardiographic measures of myocardial deformation parameters may be a sign of early myocardial dysfunction, and these measures have now been well validated for several clinical conditions, including cardiac amyloidosis (see 
) and postchemotherapy. Speckle tracking has also been shown to provide greater accuracy than LV ejection fraction in predicting adverse cardiac events in patients with heart failure.
Speckle tracking also possesses the ability to identify different patterns of changes in cardiac mechanics produced by various diseases, and can thus help to facilitate the diagnosis. For example, apical sparing is a pattern of regional differences in deformation seen in cardiac amyloidosis, where the longitudinal strain in the basal and middle segments of the left ventricle is more severely impaired compared with strain values in apical segments. This can help distinguish cardiac amyloidosis from other conditions that cause true left-ventricular hypertrophy, such as hypertensive heart disease and Fabry disease.
Cardiac Amyloidosis
Cardiac amyloidosis is an infiltrative cardiomyopathy, which in some forms has a toxic component. It is the most commonly encountered cause of restrictive cardiac disease. The term “amyloid” refers to proteinaceous material derived from misfolded products of a variety of precursor proteins. This abnormal protein is deposited in the extracellular space of all chambers of the heart, including the coronary vasculature, and alters the tissue structure and function. Cardiac dysfunction in the form of diastolic and systolic dysfunction, conduction system disturbances, and ischemia are a result of not only direct tissue infiltration, but also due to the toxic effect of the circulating precursor proteins, especially the immunoglobulin light chain amyloidosis (AL). Several different forms of amyloidosis are recognized, with the type of amyloidosis being defined by the precursor protein. The four most common precursor proteins associated with cardiac amyloidosis are abnormal light chains produced by a plasma cell dyscrasia (AL amyloidosis), amyloid derived from wild-type transthyretin (ATTRwt) or mutant TTR (familial ATTR amyloidosis, ATTRm), and localized atrial amyloid deposits derived from atrial natriuretic peptide. In secondary amyloidosis the deposits are derived from the inflammatory protein serum amyloid A, but the heart is rarely involved. Of these different types of cardiac amyloidosis, the AL and transthyretin (TTR) form of amyloidosis are the most common forms to involve the heart.
Cardiac amyloidosis should be suspected in a patient with a thick left ventricular wall with nondilated ventricle, normal or near-normal ejection fraction, and a normal LV cavity size in the absence of a history of poorly controlled hypertension ( Fig. 24.2 ). In AL amyloidosis low QRS voltage pattern and pseudoinfarction pattern may be present on the electrocardiogram (ECG), but voltage is often normal in TTR amyloidosis. Especially in ATTR, wall thickness may approach or exceed 20 mm—this is very rarely seen in hypertensive heart disease. Once the diagnosis of cardiac amyloidosis is entertained, advanced echocardiographic techniques, including speckle strain imaging, can be used, as can several other imaging modalities. However, since the therapy and prognosis of cardiac amyloidosis differs among the different types, the diagnosis has to be eventually confirmed histologically, which often requires endomyocardial biopsy and special staining.
On 2D echocardiography, other features of infiltrative cardiomyopathy can be appreciated: symmetric increased LV and RV wall thickness, sometimes with increased echogenicity; speckled or granular sparkling appearance; normal or small ventricular cavity size; and diffuse valvular and interatrial septum thickening, with biatrial enlargement (see Fig. 24.2 and 
). A small pericardial effusion is often present, but hemodynamically significant effusion is rare. It is important to recognize that the increased ventricular wall thickness in patients with cardiac amyloidosis is due to infiltration with amyloid, and not true hypertrophy as in patients with systemic hypertension or aortic stenosis. Hence the use of “left ventricular hypertrophy” to describe the increased left ventricular wall thickness is inappropriate. Although the left ventricle almost never dilates in cardiac amyloidosis, the right ventricle may demonstrate dilation late in the disease, most likely due to an underlying combination of increased afterload from pulmonary hypertension and intrinsic right ventricular systolic dysfunction due to infiltration. Atrial function may be severely impaired, due to the infiltration of atrial wall with amyloid protein ( Fig. 24.3 ), and thromboembolism may occur even in the presence of underlying sinus rhythm ( Fig. 24.4 ). LV 3 and RV tissue Doppler imaging, and strain imaging of the right and left ventricles (longitudinal 2D strain) are very sensitive for the early identification of cardiac amyloidosis, even with a near-normal LV ejection fraction. Cardiac amyloidosis demonstrates a specific pattern of longitudinal strain characterized by worse longitudinal strain in the mid and basal ventricle with relative sparing of the apex. This pattern can help distinguish cardiac amyloid from true ventricular hypertrophy of hypertensive heart disease and hypertrophic cardiomyopathy. When the strain pattern is color coded, a typical “bulls eye” appearance pattern is noted (see 
).
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