Restrictive Cardiomyopathy

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CHAPTER 63 Restrictive Cardiomyopathy

Restrictive cardiomyopathy (RCM) is the least common cardiomyopathy, and is characterized by diastolic dysfunction with restrictive ventricular filling with normal or near-normal systolic function and wall thickness.1 RCM may be idiopathic or associated with other infiltrative diseases, such as amyloidosis, endomyocardial disease, sarcoidosis, iron deposition disease, and storage diseases. Numerous other diseases may have a prominent restrictive component. Presentation of RCM is variable, and diagnosis is often difficult. The prognosis for most forms of RCM is poor, and it is important to distinguish RCM from constrictive pericarditis, which may have a similar clinical presentation


Prevalence and Epidemiology

Primary amyloidosis is a rare but devastating disease, with an incidence of 9 per 1 million and mean survival of approximately 13 months after diagnosis.2 Cardiac involvement in primary amyloidosis is common, with 60% of patients exhibiting ECG or echocardiographic abnormalities. Death is attributed to cardiac causes in at least 50% of patients with primary amyloidosis who die either from heart failure or from a malignant arrhythmia.2

Senile amyloidosis predominantly affects men older than 70 years and involves the heart in 25% of individuals older than 80 years.3 Senile cardiac amyloidosis is often clinically silent; however, extensive amyloid deposition can lead to significant clinical symptoms.

Etiology and Pathophysiology

Amyloidosis can arise from numerous diverse diseases, and 24 heterogeneous proteins have been identified within amyloid deposits. These misfolded proteins result from mutations or excessive production and form a β-pleated sheet that aligns in an antiparallel manner. The sheets form insoluble amyloid fibrils that resist proteolysis, cause mechanical disruption, and generate local oxidative stress in various organs.

Amyloid deposits, regardless of their protein composition, all have a characteristic appearance on light microscopy, staining pink with Congo red dye and exhibiting apple-green birefringence under polarized light microscopy. Nearly all organ systems can be involved, including the kidneys, heart, blood vessels, central and peripheral nervous system, liver, bowel, lungs, eyes, skin, and bones. Cardiac amyloidosis is a devastating progressive process that leads to congestive heart failure, angina, and arrhythmias.1

Cardiac amyloidosis is classified by the protein precursor as primary, secondary, senile systemic, hereditary, isolated atrial, and hemodialysis-associated amyloidosis. Primary amyloidosis (AL) is caused by abnormalities of plasma cells that result in production of amyloidogenic immunoglobulin light chain proteins. Secondary amyloidosis (AA) results from accumulation of fibrils formed from an acute-phase reactant, serum amyloid A protein, and may be associated with rheumatoid arthritis, familial Mediterranean fever, chronic infections, and inflammatory bowel disease. Secondary cardiac amyloidosis is most often clinically insignificant, and the major pathology involves the kidney, with development of proteinuria and renal failure.

Senile systemic amyloidosis is an age-related disorder with amyloid deposits formed by wild-type transthyretin TTR, a transport protein synthesized in the liver and choroid plexus. Hereditary amyloidosis is an autosomal dominant disease resulting from mutations in apolipoprotein 1 and TTR. Isolated atrial amyloidosis is also associated with advanced age and results from secretion of atrial natriuretic peptide by atrial myocytes. Hemodialysis-related amyloidosis can develop from accumulation of β2-microglobulin secondary to chronic uremia.

Cardiac amyloidosis causes numerous pathophysiologic consequences. Amyloid filaments deposited within the myocardial interstitial space result in stiffening of the myocardium and diastolic dysfunction with elevated filling pressures. As the disease progresses, the atria dilate in response to increased diastolic filling pressures. Thickening of the ventricles may occur, and eventually systolic function is also affected.

In addition to mechanical effects on myocardial stiffness, amyloid deposition induces oxidative stress that depresses myocyte contractile function. Myocardial ischemia may also result from microvascular disease. Amyloid deposits typically spare the epicardial vessels, whereas involvement of intramyocardial vasculature is seen in more than 90% of patients with AL amyloidosis.4

Manifestations of Disease

Imaging Techniques and Findings


Increased wall thickness without dilation of the ventricular cavity and preserved systolic function until relatively advanced stages of the disease are hallmarks of cardiac amyloidosis on echocardiography (Fig. 63-1). Amyloid deposits may involve nearly all regions of the heart, including valves, myocardium, interatrial septum, and pericardium, and manifestations of this involvement can be seen as multivalvular regurgitation, thickening of the interatrial septum, atrial dilation, pericardial effusions, and diffuse thickening of the right ventricular and left ventricular (LV) myocardium.5 A classic finding of myocardial amyloidosis is a granular sparkling pattern on two-dimensional echocardiography. This pattern is not specific for amyloidosis, however, and can be seen in patients with hypertensive cardiomyopathy, glycogen storage disorders, and hypertrophic cardiomyopathy. Atrial and ventricular thrombi are common findings, particularly in advanced disease.

Pulsed wave Doppler echocardiography is helpful in assessing diastolic dysfunction in cardiac amyloidosis. The initial diastolic abnormality is abnormal relaxation (grade 1 diastolic dysfunction) resulting from increased ventricular wall thickness; the pattern becomes restrictive (grades 3 to 4) when progressive amyloid infiltration decreases LV compliance and increases left atrial pressure. The filling pattern may normalize temporarily (pseudonormalization—grade 2 diastolic dysfunction) as a result of combined relaxation abnormality and moderate increase in left atrial filling pressure before becoming frankly restrictive. Deceleration time is an important prognostic variable in cardiac amyloidosis; the average survival for patients with a deceleration time less than 150 ms is less than 1 year versus 3 years for patients with a deceleration time greater than 150 ms.6 A combination of LV wall thickness greater than 15 mm and fractional shortening of less than 20% (thought to reflect combined systolic and diastolic dysfunction) is associated with a median survival of 4 months.7 Right ventricular function has also been correlated with poor prognosis in patients with cardiac amyloidosis.8

Tissue Doppler imaging (TDI) has emerged more recently as a useful technique in assessment of LV regional wall motion and diastolic dysfunction in patients with cardiac amyloidosis. Koyama and colleagues9 showed that TDI measurements differentiated patients without from patients with cardiac amyloidosis, and amyloidosis patients with and without heart failure. TDI more clearly documented diastolic function than conventional Doppler-derived indices. Myocardial strain and strain rate imaging have also been investigated in cardiac amyloidosis, and these techniques have documented early impairment in systolic function before the onset of clinical heart failure.10

Magnetic Resonance Imaging

MRI has shown considerable promise in diagnosis and characterization of cardiac amyloidosis.1114 Cine steady-state free precession (SSFP) images readily show findings of ventricular thickening with normal chamber size, atrial enlargement, and preserved systolic function (Fig. 63-3). Pleural and pericardial effusions are common and are well depicted on MRI. Impaired diastolic relaxation is often appreciated on cine SSFP images, and mitral inflow measurements can be obtained using cine phase contrast pulse sequences to obtain information analogous to Doppler echocardiography.

After administration of contrast medium, striking abnormalities are often seen on MDE pulse sequences, with patients with cardiac amyloidosis typically showing diffuse irregular hyperenhancement in noncoronary distributions (Fig. 63-4). A circumferential subendocardial hyperenhancement pattern has been described and correlated with predominant amyloid deposition in the subendocardial myocardium; however, in our experience, patterns of hyperenhancement are quite variable. Right ventricular late enhancement is a notable feature of amyloidosis and can help to distinguish this from hypertrophic cardiomyopathy with foci of enhancing fibrotic tissue.

Abnormalities of myocardial nulling are also common in amyloidosis and can help to distinguish this disease from other pathologies. A cine multi-TI inversion recovery sequence, in which each image or phase is acquired with a slightly longer inversion time (TI), is often used to select the optimal TI for the delayed enhancement acquisition. As TI increases, blood and myocardium pass through a null point at which signal is minimized. Generally, the blood pool contains a higher concentration of gadolinium, has a shorter T1 relaxation time, and passes through the null point before myocardium. In many amyloid patients, this progression is reversed, with myocardial tissue reaching the null point before the blood pool (Fig. 63-5).


Manifestations of Disease