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Restrictive Cardiomyopathy
Definition and Pathophysiology
Restrictive cardiomyopathies (RCMs) are a heterogeneous group of heart muscle disorders that, in their advanced stages, are characterized by a marked increase in left ventricular (LV) myocardial stiffness. Clinically, this manifests as congestive heart failure, often in the setting of a normal left ventricular ejection fraction (LVEF). The reduction in LV compliance results in hemodynamic abnormalities and associated cardiac structural changes, both of which have characteristics that are detected and characterized by echocardiography. Classically, the increase in left atrial (LA) pressure required to fill a noncompliant LV results in LA enlargement, pulmonary venous congestion, pulmonary edema, and secondary pulmonary hypertension. Reduced LV filling manifests as low cardiac output, which often is very difficult to augment by modulating afterload, preload, or contractility. Later-stage disease is associated with right ventricular (RV) dysfunction, a harbinger of very poor outcome.
The underlying etiopathology of reduced myocardial compliance is varied and includes all aspects of the myocardium, spanning cardiomyocytes, the interstitium, genes, and the proteome. Specifically, increased interstitial or endocardial fibrosis is seen in response to both sarcomeric gene mutations (e.g., MYBPC3, MYH7, troponin, titin) and infiltration or deposition of material from systemic disorders such as amyloidosis, hemochromatosis, and glycogen storage diseases. Table 14.1 shows the classification of the RCMs. The most common type in the developed world is infiltrative cardiomyopathy secondary to amyloidosis.
TABLE 14.1
Classification of Restrictive Cardiomyopathy.
| Noninfiltrative | Idiopathic |
|---|---|
| Scleroderma | |
| Infiltrative | Immunoglobulin amyloidosis |
| Hereditary transthyretin amyloidosis (hATTR) | |
| Wild-type transthyretin amyloidosis (wtATTR) | |
| Light-chain amyloidosis (AL) | |
| Sarcoid | |
| Storage disease | Gaucher disease |
| Hurler–Hunter syndrome | |
| Hemochromatosis | |
| Pompe disease | |
| Fabry disease | |
| Endomyocardial | Endomyocardial fibrosis |
| Hypereosinophilic syndrome | |
| Carcinoid | |
| Scleroderma | |
| Ehlers–Danlos syndrome | |
| Systemic lupus erythematosus | |
| Metastatic malignancy | |
| Radiation | |
| Anthracycline toxicity | |
| Drugs causing fibrous endocarditis (serotonin, methysergide, ergotamine, mercury-containing agents, busulfan, chloroquine) |
In almost all RCMs there is a progressive decrease in myocardial compliance over time that is well described and is easily followed using echo-Doppler variables. In the early stages of disease, LV size and LVEF are normal, and only mild abnormalities of diastolic function, such as impaired LV relaxation, are present. With disease progression, LVEF typically remains normal but myocardial compliance decreases, which raises LV and LA filling pressures and leads to atrial enlargement. The increase in LA pressure “normalizes” early diastolic filling at the expense of pulmonary venous congestion, and LA hypertension becomes an important compensatory mechanism to maintain a normal LV end-diastolic volume and cardiac output.
In advanced stages of disease, restrictive physiology is present, with its typical dip-and-plateau hemodynamic waveform seen in invasive hemodynamic assessment. At this stage, very high filling pressures are needed to fill an extremely noncompliant LV, but the rapid rate of early diastolic filling terminates abruptly due to a rapid rise in LV pressure. Filling at atrial contraction becomes greatly reduced because of LA systolic failure. Heart failure symptoms and functional limitation are common because of pulmonary venous congestion and, in many cases, a reduced stroke volume and cardiac output. The stages of progression of diastolic dysfunction resulting in advanced RCM are summarized in Chapter 5 .
Fig. 14.1 shows the Doppler echocardiographic characteristics of advanced RCM. At this stage, LV size and LVEF vary depending on the underlying etiology, but in general the diastolic abnormalities tend to be more severe than the systolic dysfunction. Restrictive physiology is characterized by a high spectral early Doppler mitral inflow (E) velocity, together with a high ratio of E to the late-diastolic atrial (A) transmitral velocity (E/A ratio), a rapid mitral deceleration time, a short pulmonary vein diastolic (D) wave deceleration time (<160 ms), a short isovolumic relaxation time (<50 ms), decreased early diastolic mitral septal and lateral e ′ velocities (3–4 cm/s), and a markedly increased LA volume index (>50 mL/m 2 ). When present, these features portend a very poor prognosis.
Introduction to Imaging in Restrictive Cardiomyopathy
Although it is convenient to envision systole and diastole as separate hemodynamic events, in reality they are intricately intertwined. Good diastolic function depends on good myocardial contraction. This is now evident from recently developed echocardiographic (and other imaging) techniques. Myocardial deformation imaging (strain) using two-dimensional (2D) speckle tracking clearly demonstrates abnormal systolic mechanics in patients traditionally classified as having diastolic heart failure or heart failure with preserved ejection fraction (HFpEF). Currently there is a groundswell of evidence based on the use of this technique to diagnose, prognosticate, and guide treatment of patients with amyloid cardiomyopathy. In particular, incorporation of the evaluation of longitudinal strain analysis into clinical practice is resulting in the earlier diagnosis of amyloid cardiomyopathies. This is a direct result of the unique distribution of segmental strain abnormalities in these disorders (i.e., relative apical sparing with predominant basal segmental involvement) ( Fig. 14.2 ).
Complimentary imaging with cardiac magnetic resonance imaging (MRI), using gadolinium to augment tissue characteristics (late gadolinium enhancement [LGE]), enables evaluation for the presence and distribution of myocardial fibrosis (replacement and interstitial), as well as quantification of myocardial extracellular volume (ECV). Similar to characteristic patterns observed with strain echocardiography, there are clues in the degree, distribution, and nature of abnormalities seen with LGE and ECV that are associated with specific pathologies. Additionally, bone scintigraphy, mainly using technetium pyrophosphate or technetium 99m–labeled 3,3-diphosphono-1,2-propanodicarboxylicacid ( 99m Tc-DPD), has re-emerged as a highly sensitive and specific imaging technique for transthyretin amyloidosis (ATTR) deposition in the myocardium, and in combination with targeted genotyping, it has enabled the diagnosis of ATTR cardiomyopathy without the need for myocardial biopsy.
Reducing the technical limitations of three-dimensional (3D) echocardiography for single-beat 3D strain will likely enable better quantification of global LV contractility and compliance and link the benefits of echocardiography for functional assessment with the advantages of 3D structural evaluation (LV geometry). Additionally, strain imaging is proving to be a promising technology for the evaluation of atrial function. ,
2D Echocardiographic and Doppler Features
Echocardiographic assessment for RCM includes a comprehensive evaluation using multiple echocardiographic modalities that evaluate cardiac structure and function. These include M-mode, 2D imaging, color Doppler, spectral Doppler (CW and pulsed wave [PW]), and strain imaging ( Tables 14.2 and 14.3 ).
TABLE 14.2
Echocardiographic Features of Restrictive Cardiomyopathy.
| M-mode and color M-mode | Square root sign in the interventricular septum and the inferolateral wall motion |
|---|---|
| LV hypertrophy | |
| Small LV dimensions | |
| Decreased velocity of flow propagation (Vp) | |
| Prolonged IVRT in early stages, short IVRT in late stages | |
| 2D findings | Decreased LV volumes |
| Preserved LV systolic function (early stages) | |
| Biatrial enlargement | |
| Unexplained myocardial hypertrophy | |
| Myocardial speckling | |
| Atrial septal thickening | |
| Homogenous AV valve thickening | |
| Small pericardial effusion | |
| Ventricular thrombi or apical mass despite normal underlying wall motion | |
| Mitral PW Doppler | Large E wave, small A wave; E/A ratio >2 |
| Short DT <150 ms; short IVRT <60 ms | |
| No significant change in mitral E wave, deceleration time, or IVRT with Valsalva maneuver | |
| Abnormal relaxation pattern with E/A ratio <1 and DT in early stages | |
| Pseudonormal and reversible restrictive patterns in intermediate stages | |
| Tricuspid PW Doppler | Restrictive filling; increased E/A ratio and short DT; with inspiration, further shortening of the DT and minimal change in E/A ratio |
| Pulmonary veins | Dilated pulmonary veins, diastolic dominant pattern, and S/D ratio <0.5 |
| Prominent atrial reversal velocity with pulmonary vein atrial A duration > mitral inflow A duration | |
| Rapid D wave deceleration time in late stages | |
| No change in D wave with respiration | |
| Mitral regurgitation | Increased dP/dt in early stages, reduced dP/dt in late stages, and elevated LA filling pressure [SBP − 4(MR velocity) 2 ] |
| Tricuspid regurgitation | Pulmonary artery systolic pressure [4 × (tricuspid insufficiency jet 2 ] |
| Pulmonary regurgitation | Pulmonary artery diastolic pressure [4 × (pulmonary insufficiency jet 2 ] plus RA pressure |
| Color Doppler findings | MR and TR due to leaflet or papillary muscle involvement (as in endomyocardial fibrosis) |
| TR secondary to pulmonary hypertension | |
| Diastolic MR due to increased LV end-diastolic pressure | |
| Diastolic TR and MR due to first-degree AV block or complete heart block | |
| Mitral annulus TDI | E/E′ ratio to assess LV filling pressure; in RCM, E′ usually <8 cm/s and E/E′ >15 due to elevated filling pressure |
| Tricuspid annulus TDI | Decreased RV function s <1 cm/s |
| RA pressure E/E′ >6 | |
| Color M-mode examination | Vp <45 cm/s in RCM; E/Vp >1.5 can be used to assess LV filling pressure |
| Hepatic vein/flow | Dilated hepatic veins, S/D ratio <0.5 |
| Prominent atrial reversals that increase with inspiration | |
| Inferior vena cava | Dilated (>2.1 cm) with reduced respiratory variation (<50%) |
AV, Atrioventricular; BP, blood pressure; DT, deceleration time; IVRT, isovolumic relaxation time; MR, mitral regurgitation; PW , pulsed-wave; RCM , restrictive cardiomyopathy; S/D ratio , ratio of pulmonary vein systolic to diastolic flow; SBP , systolic blood pressure; TDI , tissue Doppler imaging; TR , tricuspid regurgitation; Vp, propagation velocity.
TABLE 14.3
Other Approaches in the Diagnosis of Restrictive Cardiomyopathies.
| Diagnostic Modality | Key Findings | Limitations |
|---|---|---|
| 2D/Doppler echocardiography | LV hypertrophy | Comorbidities of advanced age and coexisting hypertension renders LVH nonspecific and commonly a late finding with limited impact on guiding treatment or affecting prognosis. Nonreproducible measurements make regression difficult to follow. |
| Restrictive filling | Does not provide etiologic information in amyloidosis. | |
| Systemic markers | Light chains, serum amyloid P component, troponin, and pro-BNP in primary amyloidosis | |
| Biopsy (tongue, subcutaneous fat pads, kidneys, bone marrow, gastric mucosa, rectal mucosa, and EMB) | May reveal specific cause of restrictive cardiomyopathy. Eosinophilic interstitial deposits on H&E, apple-green birefringence on Congo red staining, and fibrillar protein on EM in cardiac amyloid. | Procedural risk and uncertainty about sampling error limits use in monitoring disease. |
| Cardiac catheterization | Systolic area index | Procedural risk Radiation exposure |
| Dip and plateau | ||
| RV systolic pressure usually >50 mmHg | ||
| Often, LVEDP > 5 mmHg > RVEDP | ||
| RVEDP <⅓ of RV systolic pressure. | ||
| CT imaging | Pericardium of normal thickness. No pericardial calcification | Radiation exposure Contrast agent side effects |
| MRI | Amyloidosis: global subendocardial LGE, increased native T1 relaxation time, and increased extracellular volume | Use in early stages of the disease has not been evaluated. |
| Significantly decreased T1 relaxation time in Fabry and hemochromatosis; decreased T2∗ in hemochromatosis. | ||
| Nuclear scintigraphy with 99Tc pyrophosphate or indium-labeled systemic amyloid protein scan | Tc pyrophosphate scan (semiquantitative visual grade II and III) differentiates between AL and ATTR. | Radiation exposure |
AL , Immunoglobulin light-chain amyloidosis; ATTR, transthyretin amyloidosis; BNP , brain natriuretic peptide; EM , electron microscopy; EMB , endoscopic muscle biopsy; H&E , hematoxylin and eosin stain; LGE , late gadolinium enhancement; LVEDP, LV end-diastolic pressure; LVH, LV hypertrophy; MRI, magnetic resonance imaging; RVEDP, RV end-diastolic pressure; Tc, technetium.
M-Mode Imaging
Parasternal views in the long and short axes are used to measure LV chamber dimension and interventricular septum and posterior wall thickness and to calculate LV mass (see Chapter 8 ). Color M-mode in the apical 4-chamber view is used to assess the velocity of flow propagation (Vp) and to measure isovolumic relaxation time by placing the M-mode cursor in the center of the LV. Vp values are expressed in centimeters per second, and normal values are greater than 50 cm/s.
2D Imaging
Parasternal views (2D parasternal long- and short-axis views) are now the most commonly used and recommended views to measure LV dimensions, wall thickness, and LV mass. The mid-short-axis view is also used to assess LV radial and circumferential strain and the strain rate of all myocardial segments by speckle tracking and the strain rate of the anterior interventricular septum and inferolateral wall by tissue Doppler imaging (TDI) (see Chapter 4, Chapter 8 ).
Apical views allow assessment of the biplane LVEF by the Simpson method. Inherent variability in the LVEF measurement (±5%) and lack of endocardial border visualization occur in up to 31% of patients undergoing stress echocardiography. Use of contrast imaging improves the accuracy of LV volume measurements and LVEF. LV volume measurements by contrast-enhanced 2D imaging and by 3D echocardiography have superior reproducibility and closer approximation to results of the cardiac MRI technique than does non–contrast-enhanced 2D echocardiography (see Chapter 3 ). Longitudinal LV strain and strain rate are assessed in the apical 4-, 3-, and 2-chamber focused LV views, and right ventricular (RV) strain and strain rate are assessed in the RV focused view (see Chapter 2 ). Calculation of global longitudinal strain (GLS) and segmental strain analysis are possible from high-quality apical views with sufficiently high frame rates (50–80 fps). Additionally, the apical views are used for evaluation of atrial strain, giving insight into LA pump and LA reservoir function.
Spectral Doppler Imaging
Parasternal and apical views allow assessment of LV and RV diastolic function and filling pressures. The technique and specific information for data acquisition using both PW and CW are detailed in Chapter 8 . We provide here a summary of spectral Doppler findings that are used to characterize various stages of RCM.
Mitral inflow PW Doppler is used to measure the peak mitral inflow E-wave and A-wave velocities, the E/A ratio, E-wave deceleration time, and mitral A-wave duration.
Pulmonary vein PW Doppler is used to measure peak pulmonary vein systolic (S) and diastolic (D) velocities, D-wave deceleration time, and atrial reversal velocity and duration (see Fig. 14.1). Use of contrast improves the pulmonary vein PW Doppler signal in technically difficult studies.
Mitral annular PW TDI in the apical 4-chamber view is used to measure mitral annular systolic and early and late diastolic velocities (S′, E′, and A′, respectively) from the medial and lateral mitral annuli (see Chapter 5 ).
Findings
Specific echocardiographic features of various types of RCMs are summarized in Table 14.2 . RCMs are characterized by concentric hypertrophy (elevated LV mass) or remodeling (elevated wall thickness with normal LV mass), with marked increase in wall thickness relative to cavity size, and normal or small LV end-diastolic volume. Atrial enlargement is associated with the grade of diastolic dysfunction: mild, moderate, and severe diastolic dysfunction are reflected by progressively increasing LV stiffness and resultant filling pressures. Mild, moderate, and severe LA enlargement are defined by the American Society of Echocardiography guidelines as an LA volume index of more than 34 mL/m 2 , 40 to 47 mL/m 2 , and more than 48 mL/m 2 , respectively, as measured by the Simpson method.
Mitral Inflow Pulsed-Wave Doppler Imaging
Diastolic variables in RCM usually progress through a spectrum of increasing severity, beginning with abnormal relaxation, followed by a pseudonormal pattern, and ultimately restrictive filling. In the early stages, the mitral inflow filling pattern shows an E/A ratio lower than 1, a prolonged mitral inflow E-wave deceleration time, and a prolonged isovolumic relaxation time. As the disease progresses and LV stiffness increases, the compensatory increase in LA pressure results in a return to an apparently normal E/A ratio (>1), known as pseudonormalization; however, the increase in E-wave velocity results solely from increased LA pressure. This pattern is recognized by LA enlargement and reduced mitral annular e ′ velocity. Temporary reduction of preload (and LA filling pressure) by Valsalva maneuver, nitroglycerine administration, or diuresis unmasks the underlying disordered relaxation and reveals the abnormal E/A (<1). With severe abnormalities of ventricular compliance, advanced diastolic dysfunction develops, characterized by an increased E velocity and a reduced atrial contribution due to LA systolic failure. The E wave decelerates rapidly as pressure between the LA and LV quickly equilibrates earlier in diastole (see Fig. 14.1 ). Because of poor LA function and a limited late-diastolic left atrioventricular pressure gradient due to elevated LV diastolic pressure, the atrial amplitude becomes small, and a restrictive pattern develops that is irreversible (unresponsive to preload-reducing maneuvers). Because of a marked increase in LV end-diastolic pressure, diastolic mitral regurgitation may be seen, especially in the presence of first-degree heart block.
Pulmonary Vein Pulsed-Wave Doppler Imaging
In early stages of the disease, pulmonary venous flow may show a systolic-dominant pattern with an S/D ratio greater than 1 and normal atrial reversal. As LA pressures rise, the A-wave velocity and duration progressively increase. This is followed by a blunting of the S-wave velocity and an increased D-wave velocity, with resultant reversal of the normal S/D ratio (see Fig. 14.1 ). In the presence of atrial fibrillation, there is further absence of the early systolic component (S 1 ) of pulmonary vein filling, which is related to atrial relaxation after atrial contraction, and resultant marked blunting of the totality of the S wave. The pulmonary vein D wave is a result of the pulmonary vein–LA pressure gradient created during atrioventricular filling in early LV diastole (LA conduit), and it is dependent on the same factors that influence the early mitral velocity and its deceleration time. In advanced stages of the disease, there is a tall D wave with a shortened deceleration time, truncated atrioventricular filling with atrial contraction, and prominent regurgitation into the pulmonary vein (A-wave reversal > mitral E-wave duration). Finally, impairment of LA contraction due to mechanical atrial failure leads to a decrease in the amplitude and duration of the pulmonary vein atrial wave.
Tissue Doppler Imaging of the Mitral Annulus
TDI of the septal and lateral mitral annulus interrogates myocardial tissue motion directly; it is a key modality for the assessment of myocardial relaxation and is less load-dependent than mitral inflow Doppler imaging. As one would expect, progressive decline in LV compliance is mirrored by a decline in early tissue velocities. Relating the early velocities of mitral inflow to the tissue velocities enables one to ascertain whether the myocardium is sufficiently compliant to accept mitral inflow normally, or whether the tissue is too stiff to do so. This ratio (E/ E ′) has been associated with the mean pulmonary capillary wedge pressure. Decreased RV systolic and diastolic velocities reflect a global impairment in myocardial relaxation.
Additionally, this metric (E/ E ′ ratio) is critical for the echocardiographic differentiation of restrictive from constrictive cardiomyopathy. Diminished tissue velocities are observed in patients with RCM, whereas patients with constrictive pericarditis have normal or even increased velocities. Furthermore, as opposed to the positive correlation between E/ E ′ and pulmonary capillary wedge pressure in patients with myocardial disease, there is an inverse relationship between these values in patients with constrictive pericarditis (annulus paradoxus).
Color M-Mode
Impaired LV relaxation causes a reduction in the Vp of blood from the mitral annulus deep into the LV cavity. Using color M-mode, this can be calculated as the slope of a linear approximation of an isovelocity contour of the color-flow jet; it is obtained from the apical views. Unlike PW TDI, color M-mode provides spatial information along with velocity and time data and is relatively load-independent; however, it is more difficult to perform. A slope greater than 100 cm/s has 74% sensitivity and 91% specificity in identifying constrictive pericardial disease.
Tissue Doppler Imaging and Longitudinal Strain
Longitudinal systolic strain echocardiography is an accurate technique for the detection of systolic dysfunction in amyloidosis. TDI can be used to detect impaired LV systolic function even when no evidence of cardiac involvement exists on standard 2D and Doppler echocardiography. Doppler-based strain imaging is confounded by a relatively low signal-to-noise ratio, is subject to the usual technical limitations of Doppler signals (discussed later), and as such has largely been replaced by speckle tracking strain imaging.
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