Spectrum of Restrictive and Infiltrative Cardiomyopathies: Part 1

Pereira NL, Grogan M, Dec GW.
Spectrum of Restrictive and Infiltrative Cardiomyopathies: Part 1 of a 2-Part Series. J Am Coll Cardiol 2018;71:1130-1148.

The following are summary points from part 1 of a 2-part series on the spectrum of restrictive and infiltrative cardiomyopathies:

  1. Restrictive cardiomyopathies (RCMs), the least common form of heart muscle disease, are characterized as infiltrative and non-infiltrative, storage diseases, and endomyocardial diseases. RCM should be classified according to its etiology as either primary or secondary. Both hypertensive heart disease and hypertrophic cardiomyopathy (HCM) must be excluded. Primary restrictive cardiomyopathy includes idiopathic RCM and endomyocardial fibrosis. Common secondary forms include infiltrative cardiomyopathies, particularly amyloidosis as well as sarcoidosis, primary and secondary forms of hemochromatosis, storage disorders such as Fabry disease, metastatic cancer, and radiation-induced forms of disease.
  2. RCM in younger adults (<30 years of age) is largely due to genetic abnormalities that lead to increased fibrosis, abnormal deposition of iron, proteins, or glycogen), whereas RCM in older adults (patients >65 years) is confined to a smaller number of distinct etiologies. Idiopathic RCM is rare, but may occur in patients in this age group. More common causes are cardiac amyloidosis, iron overload conditions, and radiation-induced heart disease. Sarcoidosis may also occur, but is distinctly uncommon in this age group.
  3. Wall thickness is generally normal, but may be increased with infiltrative processes. Systolic function measured by left ventricular ejection fraction (LVEF) is typically normal until advanced stages of disease ensue. The ventricular myocardium has increased stiffness that results in severe diastolic dysfunction, restrictive filling pattern with elevated filling pressures, normal left ventricular cavity size, and dilated atria. The noncompliant LV demonstrates rapid elevation in filling pressures with only small increases in volume. Most conditions affect both right and left ventricles and may cause signs and symptoms of right, left, or biventricular failure. Progressive atrial enlargement can lead to atrial arrhythmias and the development of secondary atrioventricular (AV) regurgitation. Thromboembolic complications, with or without concomitant atrial fibrillation, are not uncommon due to marked biatrial enlargement and poor atrial contractility. Renal dysfunction commonly ensues as the disease progresses, likely due to elevated systemic filling pressures and reduced stroke volume.
  4. Clinical features: Heart failure (HF) is the most common initial manifestation, with shortness of breath on exertion a typical feature. Fatigue and lower extremity edema are also prominent features. Chest pain is infrequent. Physical examination typically reveals prominent right-sided findings including jugular venous distention and prominent x and y descents without respiratory variation (negative Kussmaul’s sign). The apical impulse may be mildly displaced, but is usually palpable. S1 and S2 are normal; there is typically a loud S4 gallop and an S3 gallop is not infrequently audible. Hepatomegaly, ascites, and marked pedal edema may occur as the disease progresses. Mitral and tricuspid regurgitation are frequently present.
  5. Investigation:
    • Chest x-ray and electrocardiogram (ECG): The chest x-ray usually shows a normal-size ventricular silhouette with enlarged atria and varying degrees of pulmonary congestion. The ECG exhibits sinus rhythm with large P waves indicative of biatrial enlargement accompanied by nonspecific repolarization abnormalities. Atrial fibrillation, however, is not uncommon. Low voltage, a pseudo-infarction pattern, bundle branch block, and AV block should suggest an infiltrative process or sarcoidosis.
    • Transthoracic echocardiography is a critical initial step in diagnosing HF with preserved EF (HFpEF). Echocardiography in RCM typically demonstrates normal right ventricular (RV) and LV EF, normal chamber volumes with biatrial enlargement, and restrictive diastolic filling parameters. Increased LV wall thickness after excluding causes such as hypertensive heart disease and HCM is seen with infiltrative processes. Abnormal diastolic compliance is characterized by the following Doppler echocardiographic findings—increased early diastolic filling velocity (E waves) reflecting elevated left atrial pressure, decreased atrial filling velocity (A wave) due to elevated ventricular diastolic pressures, E/A ratios >1.5, decreased mitral deceleration time (DT <120 ms), and decreased isovolumetric relaxation time. A markedly decreased systolic/diastolic pulmonary venous flow ratio is typically seen due to high atrial filling pressures and augmented atrial reversal velocity consequent to decreased ventricular compliance. Doppler tissue imaging (DTI) reveals reduced early diastolic longitudinal axis or mitral annular velocities (e’), a measurement that is relatively independent of preload and an increased E/e’ ratio. In constrictive pericarditis, echocardiography may detect the presence of a thickened (>4 mm) pericardium, but is less useful than computed tomography or cardiac magnetic resonance imaging (MRI). Unlike constrictive pericarditis, there is no discordance of intracavitary and intrathoracic pressures. The most specific sign on echocardiography of constrictive pericarditis is shifting of the septum during the respiratory cycle, caused by the variability in venous return in exaggerated interventricular dependence. Of all echocardiographic parameters, the most useful to distinguish the two conditions is TDI. A normal tissue Doppler e’ velocity (>8 cm/s) indicates normal LV relaxation and virtually excludes RCM.
    • Cardiac MRI is a powerful diagnostic tool for assessing patients with suspected pericardial or myocardial disease. Delayed gadolinium enhancement often provides incremental prognostic information above serum biomarkers such as immunoglobulin light chains in cardiac AL amyloidosis. T1-weighted imaging may prove to be more sensitive than gadolinium for detecting early amyloid deposits. Cardiac MRI has excellent accuracy (93%) for detecting pericardial thickening >4 mm.
    • Cardiac catheterization: Hemodynamic findings on cardiac catheterization include elevation of right- and left-sided filling pressures with reduction in cardiac index. Right atrial pressure is elevated with prominent x and y descents. The classic square root sign (i.e., a prominent early decrease in ventricular diastolic pressure followed by a rapid rise to a plateau phase) characterizes restrictive physiology. RV systolic pressure is often >50 mm Hg while RV diastolic pressures are usually less than one third of systolic pressure. LV diastolic pressure is typically ≥5 mm Hg higher than RV end-diastolic pressure; however, it is not uncommon for both pressures to be nearly identical. This difference may be accentuated by the Valsalva maneuver, exercise, or an acute fluid challenge.
    • Endomyocardial biopsy plays an important role in the diagnostic evaluation of patients with restrictive disease (American Heart Association/American College of Cardiology Class IIa recommendation). Cardiac involvement in systemic diseases such as amyloidosis and hemochromatosis can be definitively established by RV biopsy. Biopsy is occasionally useful in differentiating restrictive disease from constrictive pericardium.
    • Therapy: Therapy should be aimed at relieving congestive symptoms. Judicious use of loop diuretics is essential to control pulmonary congestion, peripheral edema, and ascites. However, even mild hypovolemia due to overdiuresis in the presence of a nondilated, nondistensible ventricle can lead to further decline in stroke volume and cause hypotension, worsening prerenal azotemia, and low-output state. A 2-4 g sodium restriction and 2 L fluid restriction is recommended. Supraventricular arrhythmias, particularly atrial fibrillation, occur commonly and are poorly tolerated. Rhythm control with the use of antiarrhythmic agents rather than rate control is therefore preferred.
    • Genetics of RCM: A key observation was the coexistence of a RCM phenotype with mutations in the HCM-associated genes. Clinicians must be mindful that not all forms of familial RCM have an identified genetic basis and not all RCM patients with an identified mutation will have an affected family member due to variable penetrance.
  6. Cardiac amyloidosis: All forms of cardiac amyloidosis are likely underdiagnosed and often cardiologists fail to understand that the differences between different types of amyloid and consider cardiac amyloidosis to be “one disease.” Therapy depends entirely on the type of amyloid, and incorrect typing may lead to life-threatening mistakes in treatment. Patients continue to present with end-stage cardiac disease, despite commonly seeing multiple providers over months to years before the correct diagnosis is established. Patient survey data demonstrate that although cardiologists are the most common subspecialists to whom amyloid patients are referred, the correct diagnosis is made in only approximately 20% of patients. The failure to establish the diagnosis of cardiac amyloidosis is multifactorial and related to heterogeneity in presentation, failure to consider the diagnosis in a busy clinical setting, confusion about the types of amyloidosis, and the lack of knowledge of a proper diagnostic strategy. Despite the fact that cardiac amyloid types share common clinical manifestations and cardiac imaging findings, the diseases are very different in clinical presentation, diagnostic strategy, and prognosis, depending on the source and nature of the precursor protein. Treatment depends entirely on the type of amyloid. There are two main types of amyloid that commonly affect the heart: immunoglobulin light chain associated amyloid (AL, previously called “primary systemic amyloidosis) and transthyretin amyloid (ATTR). ATTR is further divided into a hereditary form due to a pathogenic transthyretin DNA mutation (ATTR-m) and the “wild-type” (ATTR-wt) in which a mutation is not identified. There are other more rare forms of cardiac amyloid that can be identified with use of a proper diagnostic strategy. Treatment of all types of amyloidosis is directed at the underlying precursor protein. The mainstay of therapy is to stop production of the protein and to reduce the burden of amyloid infiltration. Although overall survival in AL is improving due to more effective treatment strategies, 12-month mortality remains high at approximately 24% in recent years. ATTR is generally much more slowly progressive than AL. Consideration needs to be given to referring patients with cardiac amyloidosis to centers dedicated to treating the disease due to the complexity involved in diagnosing the various types of amyloid and the advanced, often experimental therapy options available for patients.

Note: Most of the text in this summary is verbatim from the original manuscript.

Keywords: Amyloid, Amyloidosis, Atrial Fibrillation, Atrioventricular Block, Biomarkers, Blood Pressure, Bundle-Branch Block, Cardiac Catheterization, Cardiomyopathy, Hypertrophic, Cardiomyopathy, Restrictive, Chest Pain, Echocardiography, Electrocardiography, Endomyocardial Fibrosis, Fabry Disease, Heart Failure, Hypotension, Infarction, Magnetic Resonance Imaging, Myocardium, Neoplasms, Pericarditis, Constrictive, Pericardium, Sarcoidosis, Sodium Potassium Chloride Symporter Inhibitors, Stroke Volume, Tomography, Tricuspid Valve Insufficiency, Valsalva Maneuver

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