para>RCM prognosis is especially poor in children who have progressed to heart failure.
EMF occurs most commonly in children in Sub-Saharan Africa.
PATHOPHYSIOLOGY
- RCM is often related to myocardial infiltration or fibrosis leading to increased ventricular stiffness.
- Increased ventricular stiffness leads to increases in ventricular filling pressures.
- Heart failure symptoms are related to the increased filling pressures and inability to augment stroke volume with exercise.
ETIOLOGY
MYOCARDIAL
- Infiltrative
- Amyloidosis: deposition of abnormally folded protein fibrils. The predominant amyloid types which involve the myocardium and progress to heart failure include light-chain (AL) (formerly "primary " ) amyloidosis, wild-type transthyretin (TTR) (formerly "senile " amyloidosis), and mutant-type TTR (formerly "hereditary TTR " amyloidosis).
- Cardiac sarcoidosis may rarely cause an RCM.
- Noninfiltrative
- Diabetic cardiomyopathy/metabolic syndrome/obesity associated: spectrum of disease ranging from mild diastolic dysfunction to severe restrictive phenotype
- Idiopathic cardiomyopathy: Described in children and adults, but median age of diagnosis is approximately 68 years. Prognosis appears to be worse in children than in adults. Diagnosis of exclusion and biopsy is indicated to rule out other causes.
- Familial RCM
- Scleroderma
- Churg-Strauss syndrome
- Pseudoxanthoma elasticum
- Storage disease
- Iron overload cardiomyopathy
- Fabry disease
- Glycogen storage disease
- Gaucher disease
- Hurler disease (mucopolysaccharidosis type I)
- Endomyocardial
- EMF: marked by intense endomyocardial fibrotic thickening of the apex and subvalvular regions, markedly enlarged atria
- Hypereosinophilic syndrome (Loffler endocarditis)
- Carcinoid heart disease
- Metastatic cancers
- Radiation carditis
- Drug-induced: anthracycline (especially if treated during childhood); serotonin; methysergide; ergotamine; chloroquine; busulfan
Genetics
RCM is commonly associated with systemic diseases, some of which are inherited (i.e., hereditary amyloidosis, hemochromatosis), while others are multifactorial (i.e., diabetic cardiomyopathy). Familial RCM are rare and may share genetic abnormalities with hypertrophic obstructive cardiomyopathy but with different phenotypic expression.
RISK FACTORS
- Family history of RCM
- Inherited diseases (such as hereditary hemochromatosis, Fabry disease, mutant-type [hereditary] TTR amyloidosis, etc.)
- Frequent blood transfusions " secondary hemochromatosis
- Prior anthracycline use in childhood, exposure to other toxic agents (as noted above)
- Eosinophilic syndrome or chronic parasitic infection
- Thoracic radiation
COMMONLY ASSOCIATED CONDITIONS
- Heart failure, biventricular
- Pleural effusion, ascites
- Thromboembolism is common due to stasis, atrial arrhythmias, and elevated proinflammatory cytokines.
- Atrial arrhythmias
- Conduction system disease
- Extracardiac manifestations depending on underlying etiology
DIAGNOSIS
HISTORY
- Patients typically present with symptoms of heart failure including dyspnea, orthopnea, paroxysmal nocturnal dyspnea (PND), ascites, lower extremity swelling, generalized weakness, and fatigue.
- The underlying cause of the RCM may not be obvious on presentation and requires a comprehensive history, review of systems, medications history, current or previous malignancy, recent pericarditis, and family history of heart disease or any other inherited diseases. Ask about carpal tunnel syndrome, tendon rupture, peripheral neuropathy, orthostasis, enlarged tongue (macroglossia), and easy bruising (especially periorbital) for amyloidosis.
- Up to 1/3 of patient with idiopathic RCM may present with thromboembolic complications.
- Syncope can occur due to a variety of causes including arrhythmia and autonomic dysfunction (as may be the case in amyloidosis with associated neuropathy).
PHYSICAL EXAM
- A thorough examination should look for extracardiac manifestations of the underlying disorder (i.e., macroglossia and carpal tunnel in amyloidosis, hepatomegaly and hyperpigmentation in hemochromatosis, angiokeratoma in Fabry disease)
- Weight loss and cachexia are frequently observed.
- Jugular venous distention with possible Kussmaul sign
- S3, S4, or both
- Pericardial knock (high-pitched S3) is suggestive of constrictive pericarditis.
- Ascites and lower extremity edema
- Breath sounds may be decreased due to pleural effusions which can be bilateral. Rales can be heard.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Labs should be directed at the suspected etiology. CBC with differential to look for anemia, eosinophilia, and thrombocytopenia; hepatic and renal function tests; serum and urine protein electrophoresis; and measurement of serum-free light chains.
- Plasma brain natriuretic peptide is often elevated.
- In iron overload, transferrin saturation is >50%, serum ferritin levels are elevated.
- α-Galactosidase A activity (serum test) decreased in males with Fabry disease (females may have a normal level and genetic testing may be required)
- TTR genotype analysis to determine if TTR amyloid is mutant-type rather than wild-type
- Imaging
- ECG: Pseudoinfarct pattern and low QRS voltage in the limb lead are observed in amyloidosis; in contrast, other infiltrative disorders have normal or increased voltage. There may be nonspecific ST-T wave abnormalities. Rhythm disorders, in particular atrial fibrillation, are frequently seen. Conduction abnormalities such as atrioventricular block and bundle branch blocks may be seen.
- Chest x-ray: Cardiac silhouette may reveal biatrial enlargement. Pulmonary congestion and pleural effusions may be present. Pericardial calcification has a high specificity for constrictive pericarditis.
- Transthoracic echocardiogram
- Left ventricular hypertrophy, although wall thickness may be normal. Small or normal left ventricular cavity size, decreased tissue Doppler velocity and E:A ratio >2:1 with a short E wave deceleration time. Decreased tissue Doppler velocity (this is not the case in constrictive pericarditis); may have right ventricular hypertrophy, biatrial enlargement, pulmonary hypertension
- Increased thickness of the pericardium and respirophasic septal shift favors constrictive pericarditis.
- Cardiac MRI: Global subendocardial late gadolinium enhancement and thickened intra-atrial septum are seen in amyloidosis (1)[C]. Evidence of ventricular interdependence and possibly increased pericardial thickness is seen in constrictive pericarditis. Presence and quantity of iron can be measured in iron overload cardiomyopathy using T2-star sequence.
- Hemodynamic evaluation: right heart catheterization: The characteristic hemodynamic feature is a deep and rapid early decline in ventricular pressure at the onset of diastole, with rapid rise to a plateau in early diastole (the "square root sign " or "dip and plateau " ). Atrial pressure wave forms demonstrate rapid x and y descents. Right and left ventricular end diastolic pressures are nearly equal. Simultaneous right and left ventricular pressure measurement is helpful to distinguish constrictive pericarditis from RCM (in constrictive pericarditis, right ventricular systolic pressure increases with inspiration and left ventricular systolic pressure decreases; therefore, pressures are "discordant " related to exaggerated ventricular interdependence, ventricular pressures are "concordant " in RCM).
- Biopsy
- Endomyocardial biopsy should be considered for patients in whom diagnosis is not clear by other methods of evaluation (2)[C]. Endomyocardial or less commonly pericardial biopsies may be helpful when hemodynamic and imaging studies fail to establish the diagnosis. In particular, if AL amyloidosis is suspected, there should be a low threshold for endomyocardial biopsy since this diagnosis requires prompt treatment with chemotherapy +/ ’ stem cell transplantation.
- Abdominal fat aspirate has a modest sensitivity (around 70%) for detecting amyloid deposition in AL amyloidosis and a poor sensitivity (around 30%) for detecting TTR deposition in wild-type TTR amyloidosis.
- Biopsy of other involved organs (i.e., kidney) may be useful in certain conditions such as AL amyloidosis to achieve a pathologic diagnosis without requiring an endomyocardial biopsy.
DIFFERENTIAL DIAGNOSIS
- Constrictive pericarditis: RCM bears functional resemblance to constrictive pericarditis. Differentiation of the two conditions is essential because of the potential for successful surgical cure of pericardial constriction.
- Miscellaneous: hypertensive heart disease, aortic stenosis with associated left ventricular hypertrophy, hypertrophic cardiomyopathy
TREATMENT
GENERAL MEASURES
- RCM treatment is aimed at lowering left ventricular filling pressures without affecting cardiac output adversely.
- Therapeutic modalities aimed at treating the underlying cause should be considered.
- Heart transplantation may be an option in selected patients with advanced heart failure or refractory ventricular arrhythmias.
MEDICATION
- Diuretics (loop or thiazide): used to treat congestion in the pulmonary and systemic circulation. However, these should be used cautiously, as excessive reduction of left ventricular filling pressures can lead to decreased cardiac output and hypotension.
- ²-Adrenergic blockers and nondihydropyridine calcium channel blockers: These can be used for rate control in atrial arrhythmias such as atrial fibrillation. Excessive rate control may lead to an inability to augment cardiac output with exercise.
- Digoxin may be used to treat atrial fibrillation. Avoid use in patients with amyloidosis, as these patients can be digoxin-sensitive (arrhythmogenic) as a result of possible accumulation in amyloidotic tissues despite "normal " serum levels.
- ACE inhibitors and/or ARBs: typically avoided in normotensive patients due to significant hypotensive response even at small doses and lack of mortality benefit with their use
- Amiodarone: Development of atrial fibrillation with the removal of atrial contribution to ventricular filling may worsen existing diastolic dysfunction. It is, therefore, important to maintain sinus rhythm in patients who experience worsening of symptoms (dyspnea, fluid retention) while in atrial fibrillation, antiarrhythmics (i.e., amiodarone) or atrial fibrillation ablation may be required to maintain sinus rhythm given.
- Anticoagulation: for thromboembolic prophylaxis in atrial fibrillation and for treatment of intracardiac thrombi. Anticoagulation should also be considered in patients with atrial standstill related to infiltrative diseases without atrial arrhythmias because there is risk of thrombus formation as a consequence of stasis in the atria. Screening for atrial fibrillation is reasonable in patients with RCM who do not have other indications for systemic anticoagulation.
ADDITIONAL THERAPIES
- AL amyloidosis: Melphalan (alkylating agent) with or without stem cell transplantation (3)[C], or cyclophosphamide-bortezomib-dexamethasone (CyBorD) have been used with success in reducing light chain levels and improving overall survival.
- TTR amyloidosis: liver transplantation in mutant type (hereditary) TTR amyloidosis. Diflunisal (NSAID) may stabilize TTR tetramers in wild-type or mutant-type TTR amyloidosis and may slow the progression of disease. Tafamidis may also stabilize TTR tetramers. Emerging therapies include small interfering ribonucleic acid (siRNA) particles which reduce mutant- and wild-type TTR levels, monoclonal antibodies which target serum amyloid P component (found in all types of amyloidosis) which is then cleared by CPHPC may be useful in reducing levels of amyloid proteins (4)[B].
- Loeffler endocarditis/hypereosinophilic syndrome (HES): Corticosteroids help reduce eosinophil count and counteract inflammation. In addition, patients with neoplastic etiology of HES should be treated with tyrosine kinase inhibitor (imatinib) (5)[C]. Echocardiography should be used to follow documented cardiac disease at frequent intervals (<6 months).
- EMF: Endomyocardectomy along with valve repair and replacement may have significant effect on symptoms and outcomes (6)[B].
- Iron overload cardiomyopathy: Early diagnosis and treatment with phlebotomy or iron-chelation therapy may reverse hemodynamic abnormalities associated with heart failure (7)[A]. Combined heart and liver transplantation in a patient with heart and liver failure due to primary or secondary hemochromatosis can be considered in selected patients.
SURGERY/OTHER PROCEDURES
- Heart transplantation can be considered in selected patients.
- Permanent pacemakers: indicated in high-grade AV block or sinus node dysfunction
- Implantable cardioverter defibrillators should be considered on a case-by-case basis for primary and secondary prevention of sudden cardiac death. No good method for risk stratification currently exists beyond ejection fraction ( ≤35%) to determine the need for a primary prevention defibrillator.
- Electrical cardioversion or atrial fibrillation ablation may be necessary for atrial fibrillation; atrial fibrillation is typically poorly tolerated.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Close follow-up after hospital discharge with aims to reduce readmission
Patient Monitoring
- Change in degree of dyspnea or NYHA class
- Edema, ascites
- Daily weights
DIET
Modest sodium and fluid restriction may be helpful in managing volume.
PROGNOSIS
Course of disease depends on underlying disease process; most causes of RCM are progressive disease with the most common cause of death related to heart failure.
REFERENCES
11 Gupta A, Singh Gulati G, Seth S, et al. Cardiac MRI in restrictive cardiomyopathy. Clin Radiol. 2012;67(2):95 " 105.22 Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol. 2007;50(19):1914 " 1931.33 Chaulagain CP, Comenzo RL. How we treat systemic light-chain amyloidosis. Clin Adv Hematol Oncol. 2015;13(5):315 " 324.44 Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819 " 829.55 Mankad R, Bonnichsen C, Mankad S. Hypereosinophilic syndrome: cardiac diagnosis and management. Heart. 2016;102(2):100 " 106.66 Schneider U, Jenni R, Turina J, et al. Long-term follow up of patients with endomyocardial fibrosis: effects of surgery. Heart. 1998;79(4):362 " 367.77 Kremastinos D, Farmakis D. Iron overload cardiomyopathy in clinical practice. Circulation. 2011;124:2253 " 2263.
ADDITIONAL READING
- Artz G, Wynne J. Restrictive cardiomyopathy. Curr Treat Options Cardiovasc Med. 2000;2(5):431 " 438.
- Towbin JA. Inherited cardiomyopathies. Circ J. 2014;78(10):2347 " 2356.
CODES
ICD10
I42.5 Other restrictive cardiomyopathy
ICD9
425.4 Other primary cardiomyopathies
SNOMED
- Restrictive cardiomyopathy (disorder)
- Restrictive cardiomyopathy secondary to amyloidosis (disorder)
- Restrictive cardiomyopathy secondary to endocardial fibroelastosis (disorder)
CLINICAL PEARLS
- Maintain high index of suspicion to diagnose RCM, especially in cases of recurrent heart failure decompensation. The most common cause of RCM is cardiac amyloidosis; increased wall thickness on echocardiogram with low (or low normal) limb lead voltage on ECG should prompt further investigation, as the diagnosis and treatment is time-sensitive (in particular for the AL or light chain subtype).
- Detailed attention to family history may help unmask hereditary causes of RCM.
- Keep constrictive pericarditis in the differential, especially because of the potential for successful surgical treatment of constriction.
- Beyond disease-specific management considerations, careful balance of volume status and management of atrial arrhythmias are important in improving symptoms related to RCM.