Version June 2024
INTRODUCTION — Restrictive cardiomyopathy (RCM) is a broad classification of heart disease characterized by the predominance of severe diastolic dysfunction, normal or mildly increased ventricular wall thickness, and either normal or mildly reduced ejection fraction. RCM may be idiopathic, toxic, or caused by genetic, infiltrative, inflammatory, or other disorders.
This topic covers the clinical presentation, diagnostic evaluation, treatment, and prognosis of patients with RCM. The classification of cardiomyopathies and the diagnosis and treatment of other forms of diastolic heart failure (HF; eg, HF with preserved ejection fraction) are discussed separately. (See "Definition and classification of the cardiomyopathies" and "Treatment and prognosis of heart failure with preserved ejection fraction".)
EPIDEMIOLOGY — RCM is a rare form of cardiomyopathy [1,2]. The prevalence of RCM and the incidence of RCM among persons with causative diseases or exposures are unclear due to difficulties with proper classification and reporting [3].
ETIOLOGY — RCMs are caused by a broad range of diseases (most commonly amyloidosis and sarcoidosis), medical therapies (eg, radiation therapy), and genetic mutations [4]. Patients without an identifiable cause are considered to have idiopathic RCM.
Grouping the etiologies of RCMs is difficult given the imperfect separation between the origin of causative diseases and mechanisms of myocardial injury (eg, storage diseases have a genetic origin, but cause myocardial injury via infiltration). The following categories focus on the primary mechanism of injury to the myocardium:
●Infiltrative disorders – RCM can be caused by infiltration of the myocardium by protein (eg, amyloid), iron, eosinophils, carbohydrate, fat, metabolic products (eg, cystine), and tumors [5-9]. Among adults, two representative disorders causing infiltrative RCM are cardiac amyloidosis and, less commonly, hemochromatosis [3]. In rare cases, RCM can be caused by diseases that result in eosinophilic infiltration of the myocardium (eg, hypersensitivity myocarditis, endomyocardial fibrosis) [8]. RCM can also be caused by an inborn error of metabolism that results in myocardial infiltration by carbohydrate (eg, mucopolysaccharide) or fat (eg, sphingolipid); such patients typically present during childhood, although a metabolic evaluation in young adults may reveal the diagnosis [7]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Cardiac iron overload' and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis" and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Cardiac disease' and "Inborn errors of metabolism: Identifying the specific disorder".)
●Inflammatory disorders – Cardiac sarcoidosis can present as an RCM or as a dilated cardiomyopathy. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)
●Treatment-related cardiotoxicity – RCM is commonly caused by a variety of medical treatments, with the most common being mediastinal radiation. Radiation therapy for breast cancer, Hodgkin lymphoma, and other chest malignancies may damage cardiac structures, causing fibrosis of the myocardium and resulting in an RCM, sometimes many years after initial treatment [10-13]. The extent of radiation injury depends upon the strength of radiation and the response of the affected structures. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies" and "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies".)
Hydroxychloroquine, commonly used to treat autoimmune disorders, can cause RCM, and reports of hydroxychloroquine-induced cardiomyopathy suggest an average length of use of 13 years and average cumulative dose over 1800 g among those affected [14-17]. Anthracyclines have been reported to cause RCM; however, concomitant treatment with radiation in patients receiving anthracyclines may have confounded this association [18-24]. Other drugs that may cause RCM include methysergide, serotonin analogs, ergotamines, mercurial agents, and busulfan [25-28].
●Genetic causes – Gene variants represent an important cause of RCM, and variants in genes encoding myosin, troponin, titin, actin, lamin, desmoplakin, desmin, BAG cochaperone 3, and filamin C have all been associated with RCM phenotypes [29-32]. Many of the gene variants known to cause RCM overlap with gene variants that cause hypertrophic cardiomyopathy. (See 'Genetic testing' below.)
●Other causes – Scleroderma, Noonan syndrome, and Werner syndrome are rare or uncertain causes of RCM [33-37].
●Idiopathic – RCM is considered idiopathic if no underlying etiology can be identified after a comprehensive diagnostic evaluation. (See 'Diagnostic evaluation' below.)
CLINICAL FEATURES
Clinical presentations — Most patients with RCM present with signs and symptoms of HF (eg, dyspnea with exertion, edema) progressing over months or years. Some patients may present earlier in the course of the disease with a subtle decrease in exercise tolerance, whereas others may present later with more severe symptoms and signs of end-organ dysfunction. Some patients may present with atrial fibrillation (AF) as the first manifestation [38]. Occasionally, patients with mixed restrictive-constrictive disease may present with persistent HF due to RCM following pericardiectomy for treatment of constrictive pericardial disease. (See "Constrictive pericarditis: Management and prognosis", section on 'Treatment of late (chronic) disease'.)
While most patients with RCM will present as described above, patients with RCM associated with amyloidosis or sarcoidosis have complex and distinctive presentations that include cardiac and extracardiac features:
●Amyloidosis may present with HF, syncope, AF, and, rarely, sudden death [39,40]. Extracardiac manifestations of amyloidosis include kidney function impairment, proteinuria, peripheral neuropathy, carpal tunnel syndrome, and gastrointestinal symptoms (eg, malabsorption). (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis" and "Overview of amyloidosis", section on 'Clinical manifestations'.)
●The clinical features of sarcoidosis vary according to the organ system that is predominantly affected. Cardiac manifestations of sarcoidosis include chest pain, HF, ventricular arrhythmias, syncope, and sudden cardiac arrest [41]. Extracardiac features of sarcoidosis include cough, cutaneous findings (eg, keloid formation), and visual changes. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Typical presentations'.)
Examination findings — Patients with RCM commonly present with examination findings characteristic of chronic and decompensated left- and right-sided HF (eg, hypotension, tachycardia). Signs of left-sided HF include a third heart sound (S3) and pulmonary edema. Signs of right-sided HF include elevation of the jugular venous pressure that increases with inspiration (ie, Kussmaul sign), a prominent y-descent of the jugular venous pulse, peripheral edema (sometimes severe), hepatomegaly, and ascites. In patients with end-stage RCM, signs of malnutrition (eg, cachexia, muscle wasting) or liver or kidney dysfunction (eg, jaundice, asterixis) may also be present. (See "Auscultation of heart sounds" and "Examination of the jugular venous pulse".)
DIAGNOSTIC EVALUATION
When to suspect RCM — The diagnosis of RCM should be suspected in patients with symptoms and signs of HF and one or more of the following features:
●Prior history of chest irradiation
●Prior exposure to medications or drugs that are associated with RCM (eg, hydroxychloroquine, anthracyclines)
●Family history (1st or 2nd degree relative) of RCM or hypertrophic cardiomyopathy
●History of multiple myeloma, amyloidosis, sarcoidosis, or hemochromatosis
●Peripheral blood eosinophilia
Initial evaluation — In patients who are suspected of having RCM, the initial evaluation focuses on differentiating RCM from other cardiomyopathies and evaluating for potential secondary causes. All patients should have a focused history, echocardiography, electrocardiogram (ECG; if not already performed), chest imaging, and laboratory testing, as discussed below.
History — The initial evaluation of the patient suspected of having RCM begins with a thorough history focused on identifying risk factors, family history, or diseases associated with RCM (see 'Etiology' above). We assess for the following:
●History of mediastinal radiation.
●History of prior exposure to hydroxychloroquine therapy.
●History of sarcoidosis, amyloidosis, hemochromatosis, or inborn error metabolism.
●Family history (1st or 2nd degree relative) of RCM, HF, hypertrophic cardiomyopathy, arrhythmias, sudden cardiac arrest, amyloidosis, or heart transplantation.
●Family member with a known pathologic gene variant associated with RCM. (See 'Etiology' above.)
Echocardiography — All patients suspected of RCM should undergo echocardiography to demonstrate the characteristic pattern of findings that define RCM and to exclude or identify other causes of HF (eg, dilated cardiomyopathy, valvular heart disease, pericardial disease, or pulmonary hypertension). While there is no formal echocardiographic definition of RCM, the signs that characterize RCM include the following (image 1):
●Normal or near normal left ventricular (LV) systolic function and cavity size
●Marked enlargement of one or both atria
●Abnormal diastolic function
In the presence of clinical HF, this pattern of echocardiographic signs warrants further testing for specific causes of RCM. Severe diastolic dysfunction alone (eg, restrictive filling, low mitral annular E’ velocity) does not confirm the presence of RCM and is commonly present in many forms of severely decompensated HF (figure 1).
Once the characteristic pattern of RCM is identified, the echocardiogram should be reviewed for features that may help identify a specific etiology of RCM. As examples:
●Cardiac amyloidosis (all forms) – In cardiac amyloidosis, the left and right ventricular walls are often mildly and symmetrically thickened, the myocardium may have a granular appearance, and myocardial strain imaging may show preserved apical function (image 2). However, these signs neither confirm nor exclude cardiac amyloidosis, and further testing is required to confirm the diagnosis [42]. (See 'Approach to additional testing' below and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Echocardiography'.)
●Radiation-induced RCM – In radiation-induced RCM, the echocardiogram reveals structural abnormalities within the field of radiation, such as calcified heart valves, a thickened pericardium, or focal wall motion abnormalities (from coronary artery stenosis). (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies".)
●Cardiac sarcoidosis – Sarcoidosis can cause global or regional (typically basal posterior and lateral) LV wall motion abnormalities. The most common finding is myocardial thinning, while less common findings include myocardial aneurysms, hypertrophy, and pericardial effusion. Additional cardiac and noncardiac testing for sarcoidosis is required to confirm the diagnosis. (See 'Approach to additional testing' below and "Clinical manifestations and diagnosis of cardiac sarcoidosis".)
●Hypereosinophilic syndrome – In eosinophilic myocarditis or hypereosinophilic syndrome, the echocardiogram is often unrevealing during the initial necrotic stage of eosinophilic endocardial and myocardial infiltration. In the thrombotic stage of the disease, the damaged endocardium may have associated thrombus, predominantly at the ventricular apices. During the subsequent fibrotic stage, increased endomyocardial echogenicity is seen affecting one or both ventricles, sometimes with overlying thrombus; in addition, ventricular filling is restricted, and atrioventricular valve leaflets may be tethered. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Cardiac disease'.)
●Endomyocardial fibrosis – Endomyocardial fibrosis may be a form of eosinophilic cardiomyopathy and is characterized by LV, right ventricular, or biventricular apical fibrosis. Specific diagnostic criteria for endomyocardial fibrosis are discussed separately. (See "Endomyocardial fibrosis".)
Echocardiography is also helpful in differentiating RCM from constrictive pericarditis. (See "Differentiating constrictive pericarditis and restrictive cardiomyopathy", section on 'Noninvasive testing'.)
Electrocardiogram — Among patients presenting with HF, the ECG may suggest specific diseases causing RCM. In general, ECG abnormalities in RCM are common and nonspecific and include atrial fibrillation (AF), premature atrial complexes, atrioventricular block, intraventricular conduction delay, LV hypertrophy, and ST-T wave abnormalities. While specific rhythms are not diagnostic of RCM, AF is common, and the presence of atrioventricular block suggests the diagnosis of either sarcoidosis or amyloidosis. Amyloidosis may present with either low voltage (60 percent of patients with light chain amyloidosis) or LV hypertrophy (30 percent of patients with wild-type transthyretin amyloidosis) [43-45]. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Electrocardiogram' and "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Arrhythmias'.)
Chest imaging — A chest radiograph should be obtained to determine the severity of HF. RCM generally demonstrates cardiomegaly secondary to significant atrial enlargement with or without pulmonary venous congestion and pleural effusions.
A chest radiograph may also reveal findings characteristic of a specific cause of RCM. Patients with sarcoidosis, for example, may have evidence of interstitial lung disease or mediastinal lymphadenopathy. Patients with radiation-induced RCM or those with mixed restrictive/constrictive disease may demonstrate localized pericardial calcification, which is best seen on the lateral view.
Laboratory testing — In patients with suspected RCM, we obtain the following laboratory tests to assess the severity of disease (ie, end-organ dysfunction) and to evaluate for possible secondary causes of RCM:
●Serum creatinine and electrolytes.
●Liver function tests.
●Complete blood count with differential.
●Cardiac troponin T or I level.
●Plasma B-type natriuretic peptide.
●Iron studies (serum iron, total iron-binding capacity, serum ferritin).
●Monoclonal protein studies (serum protein electrophoresis with immunofixation and serum free light chain assay).
We do not routinely order serum angiotensin-converting enzyme levels to evaluate for the possibility of cardiac sarcoidosis, as the diagnostic utility of this test is unproven. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Proposed activity tests, including angiotensin converting enzyme (ACE) level'.)
The following laboratory patterns may suggest a specific cause of RCM:
●The presence of abnormal blood counts (eg, anemia, thrombocytopenia), kidney function impairment, albuminuria, and a detectable monoclonal protein is suggestive of immunoglobulin light chain amyloidosis. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)
●A mild elevation in cardiac troponin T or I suggests the possibility of cardiac amyloidosis, but is not diagnostic. [46].
●The presence of polycythemia, elevated serum ferritin levels, or abnormal liver function tests is suggestive of hemochromatosis. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
●A persistent elevation in the absolute eosinophil count may be seen in patients with eosinophilic myocarditis or endomyocardial fibrosis. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Cardiac disease' and "Endomyocardial fibrosis", section on 'Diagnosis'.)
Additional testing
Approach to additional testing — Our approach to additional diagnostic testing for a cause of RCM depends on the results of the initial evaluation (see 'Initial evaluation' above), which generally leads to one of the following scenarios:
●A cause of RCM is suspected - If the initial evaluation suggests one or more of the following potential causes of RCM, we take the following approach:
•For patients suspected of cardiac amyloidosis, cardiac sarcoidosis, hereditary hemochromatosis, or hypereosinophilic syndrome, additional disease-specific testing should be performed to confirm the diagnosis or to distinguish between alternative diagnoses. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Diagnostic evaluation' and "Endomyocardial fibrosis", section on 'Diagnosis'.)
•For patients suspected of having a genetic cause of RCM (based upon a family history of RCM or HF), we obtain genetic testing. (See 'Genetic testing' below.)
•For patients suspected of radiation-induced toxicity, no additional testing is required.
●No cause of RCM is suspected – For patients in whom the initial evaluation does not identify a potential cause of RCM, a diagnosis may be suggested by cardiovascular magnetic resonance (CMR) imaging, nuclear imaging, genetic testing, and/or endomyocardial biopsy. These tests are obtained to screen for potential causes of RCM using the following step-wise approach (algorithm 1):
•In all patients in whom the initial evaluation does not identify a potential cause of RCM, we begin by obtaining CMR imaging with late gadolinium enhancement (LGE). CMR imaging can identify a broad range of imaging findings that can suggest diseases not detected by the initial evaluation. If CMR imaging identifies findings suggestive of cardiac infiltration or inflammation (such as those seen in amyloidosis or sarcoidosis), we pursue confirmatory testing for the suspected disease. If CMR imaging does not show any evidence of cardiac infiltration or inflammation, we obtain genetic testing and do not obtain additional tests for amyloidosis or sarcoidosis. (See 'Cardiac magnetic resonance' below and 'Genetic testing' below.)
•If the results of CMR imaging cannot fully exclude the possibility of amyloidosis (eg, due to low-quality images or indeterminate findings) or CMR imaging cannot be performed (eg, patients with a pacemaker, patients with advanced chronic kidney disease), the choice of subsequent testing depends upon the patient’s age:
-If the patient is ≥50 years old, we screen for transthyretin amyloid cardiomyopathy (ATTR-CM) using bone tracer cardiac scintigraphy (eg, 99mTc-labeled pyrophosphate [PYP] scan). If the results of bone tracer cardiac scintigraphy are not consistent with cardiac amyloidosis, then we obtain genetic testing to screen for pathogenic gene variants associated with RCM. (See 'Nuclear imaging' below and 'Genetic testing' below.)
-If the patient is <50 years old, we obtain genetic testing to screen for pathogenic gene variants associated with RCM. (See 'Genetic testing' below.)
•If all imaging studies and genetic testing are negative, we obtain an endomyocardial biopsy (EMB) if EMB is expected to confirm or exclude a diagnosis that would change management. If all testing is negative or an EMB cannot be performed, the patient is provisionally diagnosed with idiopathic RCM. (See 'Endomyocardial biopsy' below.)
Interpretation of findings
Cardiac magnetic resonance — In patients in whom the initial evaluation does not identify a potential cause of RCM, CMR imaging with LGE can provide additional diagnostic information that suggests diseases not detected by the initial evaluation [47,48]. (See 'Approach to additional testing' above.)
CMR imaging findings that suggest a specific cause of RCM include:
●Diffuse or subendocardial LGE of the LV, right ventricle, or atria suggest the presence of amyloidosis. CMR imaging has high sensitivity (86 percent) and specificity (92 percent) for the detection of amyloid when compared with the gold-standard of EMB [49]. If this pattern of LGE is present, cardiac deposition of transthyretin amyloid (ATTR) or light chain amyloid may be the cause of RCM, and further testing is required to confirm either diagnosis. (See 'Nuclear imaging' below and 'Genetic testing' below and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)
●Patchy LGE in a noncoronary distribution (eg, base of the septum or base of the inferolateral wall) or basal thinning of the LV suggests cardiac sarcoidosis but is nondiagnostic and must be correlated with other data to establish the diagnosis of sarcoidosis. For many patients who undergo CMR imaging and who have findings suggestive of sarcoidosis, we obtain additional nuclear imaging (18F-fluorodeoxyglucose-positron emission tomography) to assess for the presence of active myocardial inflammation. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Cardiovascular magnetic resonance' and "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'FDG-PET'.)
●Pericardial thickening or inflammation suggests the presence of constrictive pericarditis. If present, we pursue an evaluation to differentiate between RCM and constrictive pericarditis (ie, pericardectomy or general treatment of RCM) [50]. (See "Differentiating constrictive pericarditis and restrictive cardiomyopathy".)
●An increase in the cardiac T2* time suggests the presence of myocardial iron overload, which is seen in hereditary hemochromatosis or acquired iron overload syndromes. Such patients should be evaluated for hereditary hemochromatosis. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Cardiac iron overload' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'MRI'.)
Nuclear imaging — In patients in whom the initial evaluation does not identify a potential cause of RCM or exclude the diagnosis of amyloidosis (eg, contraindications to CMR imaging with gadolinium, indeterminate CMR images) and who are ≥50 years old, we obtain a 99mTc-labeled PYP scan to screen for the presence of cardiac amyloid deposition. (See 'Approach to additional testing' above.)
Radiolabeled PYP localizes to sites of transthyretin amyloid deposition, and high cardiac uptake of PYP confirms the diagnosis of transthyretin cardiomyopathy (ATTR-CM). In most cases of RCM, no further testing is necessary following a positive PYP scan [49,51]. Additional information on the clinical indications and technical details of PYP scans and other bone tracer cardiac scintigraphy scans is discussed separately. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Bone tracer cardiac scintigraphy'.)
Genetic testing — Genetic testing is performed in certain clinical settings to assess for the presence of pathologic gene variants. (See 'Approach to additional testing' above.)
Given the large number of pathologic gene variants associated with RCM, we refer patients for genetic counseling or consultation with a geneticist to help guide the selection and interpretation of genetic testing (see "Genetic testing", section on 'Basic principles'). Some genetic variants known to cause RCM include variants in genes coding for transthyretin (TTR), sarcomeric proteins (eg, TTN, MYH7), desmosomal proteins (eg, DSP, JUP), filament proteins (eg, LMNA, FLNC), and other gene loci [31,52-58].
The interpretation of genetic testing depends upon the clinical scenario:
●In the patient with a family history of inherited cardiomyopathy and a known pathologic gene variant, positive testing for the same variant confirms the diagnosis of a genetic RCM.
●In the patient with a family history suspicious for an inherited cardiomyopathy but without a known pathologic gene variant, positive testing for a known pathogenic gene variant or a variant of unknown significance may support the diagnosis of genetic RCM. Confirmation of the diagnosis requires expert interpretation and correlation with clinical findings.
●In the patient without a family history suspicious for an inherited cardiomyopathy, positive testing supports the diagnosis of genetic RCM. Confirmation of the diagnosis requires expert interpretation and correlation with clinical findings.
Endomyocardial biopsy — EMB is usually performed in patients in whom all imaging studies and genetic testing are negative, if a tissue sample is likely to confirm a diagnosis or exclude a diagnosis that would change clinical management.
In idiopathic RCM, light microscopic examination commonly reveals patchy endocardial and interstitial fibrosis with increased collagen deposition, myocellular hypertrophy without myofiber necrosis, or myocardial disarray. The pathologic findings of specific diseases are covered in separate topic reviews.
Other aspects of EMB are discussed separately. (See "Endomyocardial biopsy".)
DIFFERENTIAL DIAGNOSIS — In patients presenting with chronic HF and with echocardiographic evidence of LV hypertrophy, atrial enlargement, or severe diastolic dysfunction, the diagnosis of RCM should be differentiated from constrictive pericarditis and hypertrophic cardiomyopathy (HCM).
●Constrictive pericarditis – RCM and constrictive pericarditis can present with similar clinical features, including chronic severe HF, biatrial enlargement with normal systolic function, and impairment in ventricular filling. While details of the clinical history are sometimes helpful, the distinction often requires careful echocardiographic and hemodynamic assessment, pericardial imaging, and even endomyocardial biopsy. A more detailed discussion on differentiating RCM from constrictive pericarditis is presented separately. (See 'Initial evaluation' above and "Differentiating constrictive pericarditis and restrictive cardiomyopathy".)
●Hypertrophic cardiomyopathy – RCM and HCM can be differentiated by characteristic clinical features and imaging findings. Typically, patients with RCM present later in life, while patients with HCM present earlier (eg, young adulthood). Although patients with RCM and HCM can both present with dyspnea and fatigue, those with RCM commonly have more severe HF, and those with HCM may additionally present with chest pain, syncope, or palpitations. Echocardiography in patients with RCM often demonstrates symmetric hypertrophy of both ventricles and severe biatrial enlargement, while patients with HCM often have marked asymmetric hypertrophy of the left ventricle (eg, septal hypertrophy >15 mm) with varying degrees of LV outflow tract obstruction or systolic anterior motion of the mitral valve. However, differentiating RCM from end-stage HCM can be particularly challenging if the degree of HF is severe and, in the case of HCM, the characteristic signs of HCM are absent due to cardiac remodeling. Lastly, members of the same family may present with features of RCM or HCM, which suggests that RCM and HCM can be different morphologic forms of the same sarcomeric disease [59]. The clinical manifestations and diagnosis of HCM can be found elsewhere. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".)
TREATMENT — There is no specific therapy for idiopathic RCM, whereas specific therapies may be available for certain causes of secondary RCM (eg, amyloidosis, sarcoidosis, hemochromatosis). Regardless of the etiology, the general management of patients with RCM involves management of volume status to reduce pulmonary and central venous congestion and management of end-organ (eg, liver, kidney) dysfunction. Given the progressive nature of most forms of RCM, patients should be referred early for heart transplantation.
Treatment of the underlying cause — In patients who have an underlying cause of RCM, we treat the underlying cause as appropriate. Medications associated with RCM (eg, hydroxychloroquine) should be discontinued. Treatment of certain underlying diseases associated with RCM (such as amyloidosis, sarcoidosis, and hemochromatosis) may increase survival, improve quality of life, and delay the need for heart transplantation. The management of these disorders is discussed in detail separately:
●Cardiac amyloidosis (see "Cardiac amyloidosis: Treatment and prognosis")
●Cardiac sarcoidosis (see "Management and prognosis of cardiac sarcoidosis")
●Hemochromatosis (see "Approach to the patient with suspected iron overload")
General management
Volume management — The general approach to volume management in patients with RCM is similar to that used for other forms of HF. Such an approach consists of the following components:
●The use of diuretics. (See "Use of diuretics in patients with heart failure".)
●The use of echocardiography and pulmonary artery catheterization to assess volume status. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults", section on 'Echocardiography' and "Approach to diagnosis and evaluation of acute decompensated heart failure in adults", section on 'Additional tests'.)
●Referral of patients with moderate to severe HF to a chronic disease management program. (See "Systems-based strategies to reduce hospitalizations in patients with heart failure", section on 'Outpatient strategies'.)
If the patient’s volume status is difficult to manage despite optimized medical therapy (eg, multiple readmissions for volume overload, frequent and marked changes in weight complicating outpatient management), placement of an invasive hemodynamic pulmonary pressure monitor, which provides daily readings of intracardiac filling pressures, may assist with diuretic management. However, there are no data to support this approach in patients with RCM. (See "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Device-based therapies'.)
Heart failure therapies — Most of the pharmacologic and device therapies used to manage patients with other forms of HF (HF with reduced ejection fraction [HFrEF] or HF with preserved ejection fraction [HFpEF]) have not been shown to be beneficial or feasible in the management of patients with RCM. Our approach to the use of these therapies is based primarily upon our clinical experience:
●We do not routinely administer agents that are commonly used to treat patients with HFrEF or HFpEF, such as renin-angiotensin-aldosterone system inhibitors, neprilysin inhibitors, beta blockers, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, since there is no evidence to support their use in patients with RCM. However, such therapies may be used for the treatment of specific indications (eg, angiotensin-converting enzyme inhibitors for treatment of hypertension, beta blockers for rate control of atrial fibrillation, or SGLT-2 inhibitors for treatment of diabetes).
●For patients with severely decompensated RCM, we do not routinely use of intravenous vasodilator therapy (eg, nitroprusside, nitroglycerin, hydralazine) to treat refractory HF.
●For patients with end-stage RCM, mechanical circulatory support (MCS) devices are a potential therapeutic option, but their efficacy in patients with RCM is not well established, and their utility is typically limited by the presence of biventricular diastolic dysfunction and end-organ dysfunction. In addition, normal or small ventricular size typically limits the feasibility of MCS device placement. The Total Artificial Heart may be used as a bridge to transplant in highly selected patients, though the efficacy of this strategy is not well described. (See "Short-term mechanical circulatory assist devices" and "Treatment of advanced heart failure with a durable mechanical circulatory support device", section on 'Indications'.)
Management of arrhythmias — Patients with RCM who have atrial fibrillation should be treated similarly to patients with other forms of HF, as discussed separately. (See "The management of atrial fibrillation in patients with heart failure".)
End-organ dysfunction — In our experience, end-organ dysfunction is more common and less likely to be reversible in patients with RCM compared with other forms of HF. Thus, patients with RCM may require additional testing to detect and manage end-organ dysfunction. The diagnosis and treatment of syndromes commonly encountered in RCM include:
●Liver congestion and cirrhosis. (See "Congestive hepatopathy".)
●Chronic kidney disease. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology" and "Cardiorenal syndrome: Prognosis and treatment".)
●Pulmonary hypertension. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults".)
Heart transplantation — Heart transplantation may be of benefit to patients with RCM who have treatment-refractory HF symptoms and are considered to have reasonable long-term survival. Similar to all patients with advanced HF, early referral (eg, before end-organ dysfunction is severe or irreversible) may increase the likelihood of successful transplantation. Indications and contraindications for heart transplantation, including considerations specific for patients with RCM, are discussed separately. (See "Heart transplantation in adults: Indications and contraindications", section on 'Indications for cardiac transplantation' and "Heart transplantation in adults: Indications and contraindications", section on 'Considerations for hypertrophic or restrictive cardiomyopathy'.)
Patients with HF caused by RCM have the highest waitlist mortality relative to other causes of severe HF [60-62]. This may be due to end-organ dysfunction common to patients with RCM and the limited number of available therapies for severe RCM. However, despite the high waitlist mortality, patients with RCM who are successfully transplanted have reasonable, though lower, posttransplant survival relative to recipients with other HF etiologies [63,64]. As an example, in a study of 38,190 adult heart transplant recipients from the United Network of Organ Sharing (UNOS) registry, of whom 544 (1.4 percent) had RCM, 1-, 5-, and 10-year survival among patients with RCM were 84, 66, and 45 percent, respectively, compared with 85, 70, and 50 percent, respectively, for non-RCM patients.
PROGNOSIS — Data on the prognosis of patients with RCM are limited. In patients with idiopathic RCM, the prognosis is generally poor, with most patients eventually progressing to end-stage HF. As an example, in a study of patients presenting with 94 symptomatic idiopathic RCM between 1979 and 1996, patients with RCM had worse survival compared with age- and sex-matched controls (64 versus 85 percent at five years and 37 versus 70 percent at 10 years (figure 2)) [38]. Approximately two-thirds of deaths among the patients with idiopathic RCM were cardiovascular, primarily due to HF, sudden death, arrhythmia, or a cerebrovascular accident. Among the survivors, 28, 46, and 17 percent were in New York Heart Association (NYHA) functional class I, II, and III, respectively, while 9 percent had undergone cardiac transplantation. Risk factors for mortality included male sex, age greater than 70, each increment in NYHA functional class, and left atrial diameter >60 mm.
The prognosis for RCMs caused by specific diseases is also difficult to estimate due to the low prevalence of RCM. The overall prognosis and cardiovascular prognosis for diseases causing RCM, which are often not RCM-specific, are discussed separately.
●Cardiac amyloidosis. (See "Cardiac amyloidosis: Treatment and prognosis".)
●Cardiac sarcoidosis. (See "Management and prognosis of cardiac sarcoidosis", section on 'Prognosis'.)
●Radiation-induced RCM. (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies".)
●Hereditary hemochromatosis. (See "Management and prognosis of hereditary hemochromatosis".)
SUMMARY AND RECOMMENDATIONS
●General principles – Restrictive cardiomyopathy (RCM) is a broad classification of heart disease characterized by the predominance of severe diastolic dysfunction, normal or mildly increased ventricular wall thickness, and either normal or mildly reduced ejection fraction. RCM may be idiopathic, toxic, or caused by genetic, infiltrative, inflammatory, or other disorders. (See 'Epidemiology' above and 'Etiology' above.)
●Clinical features – Most patients with RCM present with signs and symptoms of heart failure (HF; eg, dyspnea with exertion, edema) progressing over months or years. Some patients may present earlier in the course of the disease with a subtle decrease in exercise tolerance, whereas others may present later with more severe symptoms and signs of end-organ dysfunction. Patients with RCM associated with amyloidosis or sarcoidosis have complex and distinctive presentations that include cardiac and extracardiac features. (See 'Clinical features' above.)
●Diagnostic evaluation
•The diagnosis of RCM should be suspected in patients with symptoms and signs of HF and one or more of the following features: prior history of chest irradiation; prior exposure to medications associated with RCM (eg, hydroxychloroquine, anthracyclines); family history (1st or 2nd degree relative) of RCM or hypertrophic cardiomyopathy; history of multiple myeloma, amyloidosis, sarcoidosis, or hemochromatosis; or peripheral blood eosinophilia. (See 'When to suspect RCM' above.)
•In patients who are suspected of having RCM, the initial evaluation focuses on differentiating RCM from other cardiomyopathies and evaluating for potential secondary causes. All patients should have a focused history, echocardiography, electrocardiogram (if not already performed), chest imaging, and laboratory testing. (See 'Initial evaluation' above.)
•Additional testing for a cause of RCM is directed by the results of the initial evaluation (algorithm 1). If the initial evaluation raises suspicion for a disease known to cause RCM, we follow the diagnostic evaluation for that disease. For patients in whom the initial evaluation does not identify a potential cause of RCM, a diagnosis may be suggested by cardiovascular magnetic resonance imaging, nuclear imaging, genetic testing, and/or endomyocardial biopsy. These tests are obtained to screen for potential causes of RCM using a step-wise approach. (See 'Approach to additional testing' above.)
●Treatment - There is no specific therapy for idiopathic RCM, whereas specific therapies may be available for certain causes of secondary RCM (eg, amyloidosis, sarcoidosis, hemochromatosis). Regardless of the etiology, the general management of patients with RCM involves management of volume status to reduce pulmonary and central venous congestion and management of end-organ (eg, liver, kidney) dysfunction. Given the progressive nature of most forms of RCM, patients should be referred early for heart transplantation. (See 'Treatment of the underlying cause' above and 'General management' above and 'Heart transplantation' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel Jacoby, MD, and A Jamil Tajik, MD, who contributed to earlier versions of this topic review.
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