Residency · Residency · Cardiology

Restrictive and Infiltrative Cardiomyopathies

Overview and Pathophysiology

Defining Features

Restrictive cardiomyopathy is characterized by impaired ventricular filling due to increased myocardial stiffness, with preserved or near-normal systolic function and normal or near-normal wall thickness, except in infiltrative causes where increased wall thickness is a hallmark. The hemodynamic signature includes elevated filling pressures bilaterally, the classic "dip-and-plateau" or "square root sign" on ventricular pressure tracings, and equalization of diastolic pressures across chambers. Biatrial enlargement develops as a consequence of chronically elevated filling pressures, while ventricular cavities remain normal or small. A critical diagnostic challenge lies in differentiating restrictive cardiomyopathy from constrictive pericarditis, as both share overlapping clinical and hemodynamic features but demand fundamentally different therapeutic approaches.

Classification

Restrictive cardiomyopathies are classified into several categories based on pathophysiology. Infiltrative diseases include amyloidosis, both AL and ATTR types, and sarcoidosis. Storage diseases encompass hemochromatosis, Fabry disease, and glycogen storage diseases such as Danon and Pompe. Endomyocardial causes include endomyocardial fibrosis, hypereosinophilic syndrome with Loeffler endocarditis, carcinoid heart disease, and radiation-induced cardiomyopathy. Non-infiltrative causes include idiopathic restrictive cardiomyopathy and scleroderma.

Cardiac Amyloidosis

Types

AL amyloidosis results from monoclonal immunoglobulin light chain deposition and represents a systemic disease affecting the kidneys, liver, and peripheral nerves. Clinical features include periorbital purpura and macroglossia. Prognosis is the worst among amyloidosis subtypes, with a median survival of 6 to 12 months when cardiac involvement is present and the disease goes untreated.

Transthyretin amyloidosis exists in two forms. Wild-type ATTR, formerly termed senile systemic amyloidosis, predominantly affects males over 65 years of age with cardiac-dominant disease and a striking male predominance of approximately 50:1. It is characteristically associated with bilateral carpal tunnel syndrome, spinal stenosis, and biceps tendon rupture that often precede the cardiac diagnosis by 5 to 10 years. Hereditary ATTR follows autosomal dominant inheritance of TTR gene mutations, with over 130 known mutations. The V122I mutation carries a prevalence of 3 to 4% among African Americans and produces a cardiac-predominant phenotype. The T60A mutation causes mixed cardiac and neurologic disease, while the V30M mutation is neuropathy-predominant. ATTR prognosis is better than AL, with median survival of 3 to 5 years with cardiac involvement.

Clinical Features

The cardiac manifestations of amyloidosis include biventricular wall thickening, which reflects amyloid deposition rather than true hypertrophy. Patients develop heart failure with preserved or mildly reduced ejection fraction, presenting with exertional dyspnea, peripheral edema, and elevated jugular venous pressure. The electrocardiogram characteristically shows low-voltage QRS complexes despite increased wall thickness on imaging, a mismatch that is pathognomonic. A pseudo-infarct pattern with Q waves in the absence of coronary artery disease is frequently observed. Conduction disease is common, including AV block, bundle branch block with right bundle branch block particularly common in ATTR, and orthostatic hypotension from autonomic neuropathy. A key clinical consideration is the intolerance to standard heart failure medications: ACE inhibitors, ARBs, and beta-blockers are poorly tolerated due to hypotension and bradycardia, while digoxin is particularly dangerous because amyloid fibrils bind digoxin, causing toxicity at otherwise therapeutic levels.

Diagnosis

Non-Invasive

Echocardiography reveals increased biventricular wall thickness, granular sparkling of the myocardium (though less specific with modern imaging equipment), biatrial enlargement, grade II to III diastolic dysfunction, small pericardial effusion, and thickened interatrial septum and valve leaflets. The global longitudinal strain pattern with apical sparing, often described as the "cherry on top" or bullseye pattern, is highly suggestive, demonstrating relative preservation of apical strain with severely reduced basal and mid-wall strain, with sensitivity of approximately 90% and specificity of approximately 85%.

Cardiac MRI shows diffuse subendocardial or transmural late gadolinium enhancement with a characteristic inability to null the myocardium on the TI scout sequence. Native T1 values are elevated, typically above 1100 ms at 1.5T, and extracellular volume fraction exceeds 0.40. Gadolinium is contraindicated in severe renal failure, which affects many AL patients.

The Tc-99m pyrophosphate scan provides a transformative diagnostic capability. Grade 2 to 3 myocardial uptake, or a heart-to-contralateral ratio of 1.5 or greater at one hour, combined with the confirmed absence of monoclonal protein, is diagnostic of ATTR amyloidosis without the need for biopsy, according to the Gillmore criteria. This approach offers sensitivity of approximately 99% and specificity of approximately 86% for ATTR. However, false positives can occur with AL amyloidosis, making it mandatory to exclude AL through serum free light chains and serum and urine immunofixation electrophoresis before accepting a non-invasive ATTR diagnosis. BNP or NT-proBNP and troponin are elevated in cardiac amyloidosis and serve important roles in staging and prognosis assessment.

Tissue Diagnosis

Endomyocardial biopsy is the gold standard, demonstrating Congo red staining with apple-green birefringence under polarized light and allowing typing through immunohistochemistry or mass spectrometry to differentiate AL from ATTR. Fat pad aspirate offers a less invasive alternative with sensitivity of 70 to 80% for AL but lower for ATTR. Bone marrow biopsy is essential for AL staging and plasma cell assessment. Genetic testing with TTR gene sequencing is required for all ATTR patients to differentiate wild-type from hereditary disease.

Treatment

AL Amyloidosis

Treatment is directed by hematology and targets the clonal plasma cells responsible for light chain production. First-line therapy consists of bortezomib-based regimens, specifically the CyBorD combination of cyclophosphamide, bortezomib, and dexamethasone. The addition of daratumumab, an anti-CD38 monoclonal antibody, was validated in the ANDROMEDA trial. Autologous stem cell transplant is considered in selected patients meeting specific criteria: ejection fraction above 40%, troponin T below 0.06, NT-proBNP below 5000, no severe autonomic neuropathy, and age below 70. The Mayo 2012 staging system uses troponin, NT-proBNP, and the difference between involved and uninvolved free light chains to stratify prognosis, with Stage IV patients having all markers elevated and a median survival under 6 months.

ATTR Amyloidosis

Tafamidis functions as a TTR stabilizer and represents the landmark therapy for ATTR cardiomyopathy. The ATTR-ACT trial demonstrated a 30% reduction in all-cause mortality and a 32% reduction in cardiovascular hospitalization, with benefit most pronounced in NYHA Class I to II patients, emphasizing the importance of early initiation. The drug is available as tafamidis meglumine 80 mg daily or tafamidis free acid 61 mg daily. Acoramidis is a next-generation TTR stabilizer with positive results from the ATTRibute-CM trial. Patisiran, an RNA interference agent that silences hepatic TTR production, showed benefits in the APOLLO trial for neuropathy and the APOLLO-B trial for cardiomyopathy, including improved functional capacity, NT-proBNP, and global longitudinal strain. Inotersen, an antisense oligonucleotide against TTR mRNA, carries risks of thrombocytopenia and glomerulonephritis requiring monitoring. Eplontersen offers an improved safety profile as a subcutaneous antisense oligonucleotide.

Supportive heart failure therapy centers on diuretics, often at high doses, with caution regarding beta-blockers due to chronotropic dependence, ACE inhibitors and ARBs due to hypotension, and absolute avoidance of digoxin. Pacemaker implantation is indicated for symptomatic bradycardia or high-degree AV block, both common in ATTR. Heart transplant is considered for selected patients with isolated cardiac involvement, and combined heart-liver transplant is an option for hereditary ATTR since the liver is the source of mutant TTR.

<image> A diagnostic algorithm for cardiac amyloidosis. Start with "Clinical Suspicion: unexplained LVH, HFpEF, low-voltage ECG, carpal tunnel, autonomic neuropathy." Step 1: "Echocardiography with GLS" showing a bullseye strain map with apical sparing pattern (blue at apex, red at base) and increased wall thickness. Step 2: "Serum free light chains + serum/urine immunofixation" with two branches. If abnormal: "Suspect AL amyloidosis → tissue biopsy (EMB or fat pad) → Congo red + mass spectrometry → Hematology referral." If normal: "Proceed to Tc-99m PYP bone scintigraphy." PYP results: Grade 0-1 or H/CL ratio < 1.5: "ATTR unlikely, consider EMB if suspicion high." Grade 2-3 or H/CL >= 1.5 with confirmed absence of monoclonal protein: "ATTR amyloidosis confirmed WITHOUT biopsy → TTR genetic testing (wild-type vs hereditary)." Include small representative images: echo with thick walls, PYP scan showing Grade 2-3 uptake (intense cardiac signal), and a GLS bullseye map. Use red pathway for AL, blue for ATTR. </image>

Cardiac Sarcoidosis

Epidemiology and Pathology

Cardiac involvement occurs in 20 to 30% of systemic sarcoidosis cases at autopsy, though it is clinically apparent in only 5 to 10%. Isolated cardiac sarcoidosis without extracardiac disease accounts for 25 to 40% of cardiac sarcoidosis cases. The hallmark pathologic finding is non-caseating granulomas with predilection for the basal septum, left ventricular free wall, papillary muscles, and conduction system. The progression from granulomatous inflammation to fibrosis may lead to aneurysm formation, most commonly in the basal septum.

Clinical Manifestations

Conduction disease represents the most common presentation, with AV block being the leading manifestation, especially in young patients under 55 with unexplained high-degree AV block. Bundle branch block is also frequently seen. Ventricular arrhythmias, both monomorphic and polymorphic VT, carry significant sudden cardiac death risk. Heart failure may present as a dilated cardiomyopathy-like phenotype or as a restrictive pattern, and left ventricular aneurysm in the basal septum is characteristic. Any unexplained new cardiomyopathy in a young patient should prompt evaluation for cardiac sarcoidosis.

Diagnosis

FDG-PET/CT demonstrates focal myocardial FDG uptake on a suppressed background, requiring an 18 to 24-hour high-fat, low-carbohydrate diet or more than 12 hours of fasting to suppress normal myocardial glucose uptake. Sensitivity is approximately 89% with specificity of approximately 78%. Cardiac MRI reveals late gadolinium enhancement in a non-coronary distribution with patchy, mid-wall, or transmural patterns. T2 signal indicates active inflammation, and basal septal thinning with aneurysm formation may be observed. The combination of PET and CMR provides complementary information, with PET assessing active inflammation to guide immunosuppression and CMR characterizing scar to assess arrhythmia risk. Endomyocardial biopsy has low sensitivity of 25 to 30% due to the patchy nature of disease, but a positive biopsy is definitive. The HRS 2014 Expert Consensus Criteria allow definitive diagnosis from endomyocardial biopsy histology or probable clinical diagnosis based on extracardiac biopsy-proven sarcoidosis combined with cardiac findings such as unexplained AV block, VT, heart failure, or abnormal imaging.

Treatment

Immunosuppression forms the cornerstone, beginning with prednisone at 30 to 40 mg daily or equivalent for one to three months, followed by tapering over 6 to 12 months to the lowest effective dose, guided by FDG-PET response. Steroid-sparing agents include methotrexate at 10 to 25 mg weekly, azathioprine, and mycophenolate for maintenance, with infliximab reserved for refractory cases. ICD implantation is recommended for sustained VT, VF, or ejection fraction below 35%, and should be considered when there is significant late gadolinium enhancement burden on CMR or persistent AV block. Antiarrhythmic therapy with amiodarone or sotalol addresses VT suppression, with catheter ablation considered for drug-refractory VT, recognizing that epicardial involvement is common. Pacemaker implantation is indicated for high-degree AV block, with CRT-D considered if patients become pacing-dependent with reduced ejection fraction. Transplant evaluation is appropriate for refractory heart failure or arrhythmias, with the understanding that sarcoid may recur in the allograft in approximately 10% of cases.

Other Infiltrative and Storage Diseases

Fabry Disease

Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency, leading to accumulation of globotrianosylceramide. Males present with the classic phenotype beginning in childhood, including pain crises, angiokeratomas, renal failure, and concentric left ventricular hypertrophy developing by age 30 to 40. Females have an attenuated, later-onset presentation with variable expression. Cardiac manifestations include progressive concentric LVH that may mimic hypertrophic cardiomyopathy, diastolic dysfunction, arrhythmias including short PR and AV block, and coronary microvascular disease. Cardiac MRI reveals characteristic late gadolinium enhancement in the basal inferolateral wall and, distinctively, reduced native T1 values, which differentiate Fabry from amyloidosis where T1 is elevated. Global longitudinal strain is reduced in the basal inferolateral segment before wall thickness increases. Diagnosis relies on alpha-galactosidase A enzyme activity for males and genetic testing for females, in whom enzyme activity may be normal. Treatment with enzyme replacement therapy using agalsidase alfa or beta, or oral chaperone therapy with migalastat for amenable GLA mutations, is most effective when started before significant fibrosis has developed.

Hemochromatosis

Iron overload cardiomyopathy results from hereditary hemochromatosis, most commonly HFE gene C282Y homozygosity, or secondary causes such as transfusion-dependent anemias. Cardiac involvement initially manifests as diastolic dysfunction with restrictive physiology, progressing to systolic dysfunction with a DCM-like phenotype in advanced disease. Cardiac MRI with T2 mapping is the key diagnostic tool: T2 values below 20 ms indicate cardiac iron overload, and values below 10 ms are associated with heart failure and arrhythmias. Serial T2* monitoring guides chelation intensity. Treatment consists of phlebotomy for hereditary forms or iron chelation with deferasirox, deferoxamine, or deferiprone for transfusional iron overload. Cardiac function can improve or normalize with adequate iron depletion.

Carcinoid Heart Disease

Carcinoid heart disease results from serotonin-mediated fibrosis affecting right-sided valve leaflets, producing tricuspid regurgitation as the most common valvular lesion along with pulmonic stenosis. The leaflets become thickened, retracted, and fixed. Left-sided involvement is rare because pulmonary metabolism of serotonin normally prevents left-sided exposure, unless a patent foramen ovale, bronchial carcinoid, or very high serotonin levels are present. Diagnosis relies on elevated 5-HIAA in urine or plasma and echocardiographic demonstration of characteristic valve thickening. Treatment includes somatostatin analogs such as octreotide and lanreotide for serotonin control, telotristat ethyl as a tryptophan hydroxylase inhibitor, and valve surgery when symptomatic severe valve disease develops.

Differentiating Restrictive Cardiomyopathy from Constrictive Pericarditis

Shared Features (Diagnostic Challenge)

Both conditions present with elevated filling pressures, peripheral edema, ascites, and hepatomegaly. Both demonstrate the dip-and-plateau pattern on ventricular pressure tracings and elevated jugular venous pressure with a rapid y descent. These overlapping features make differentiation one of the most important diagnostic challenges in clinical cardiology.

Key Differentiating Features

The most reliable distinguishing feature is ventricular interdependence, which is enhanced in constrictive pericarditis with a characteristic respirophasic septal bounce, while it is absent in restrictive cardiomyopathy. On echocardiography, the respiratory septal bounce with the septum shifting toward the left ventricle during inspiration is characteristic of constriction and absent in restriction. Mitral inflow E velocity shows greater than 25% respiratory variation in constriction compared with less than 15% in restriction. Tissue Doppler e' velocity provides the single most useful parameter: it is preserved or elevated in constriction, creating the annulus paradoxus phenomenon in which a stiff pericardium constrains the heart but the myocardium itself is normal, while e' is reduced in restriction due to abnormal myocardium. Annulus reversus, where medial e' exceeds lateral e', occurs in constriction because the lateral annulus is restricted by the pericardium, whereas the opposite pattern is seen in restriction.

Hemodynamically, the key finding is discordance of right and left ventricular diastolic pressures with respiration in constriction, where right ventricular pressure rises while left ventricular pressure falls with inspiration, in contrast to concordance in restriction. CT or MRI may demonstrate pericardial thickening above 4 mm or calcification in constriction, though these findings may be absent in transient constriction. BNP tends to be mildly elevated or normal in constriction but is significantly elevated in restriction.

<image> A side-by-side comparison diagram of restrictive cardiomyopathy versus constrictive pericarditis. Two columns with five rows each. Row 1 - M-mode: RCM shows flat septal motion; CP shows respirophasic septal bounce (septal shift toward LV with inspiration, marked with arrows). Row 2 - Mitral inflow PW Doppler: RCM shows < 15% E-velocity variation with respiration; CP shows > 25% respiratory variation (first beat tall E, next beat short E with respiratory marker). Row 3 - Tissue Doppler: RCM shows reduced e' (< 7 cm/s) at both annuli; CP shows preserved/elevated e' (> 8 cm/s) with annulus reversus (medial e' > lateral e'). Row 4 - Hemodynamic tracings: RCM shows concordant LV and RV pressure changes with respiration (both rise and fall together); CP shows discordant changes (RV rises while LV falls with inspiration). Row 5 - CT imaging: RCM shows normal pericardium; CP shows thickened/calcified pericardium. Each panel clearly labeled "Restrictive" or "Constrictive" with key finding highlighted in red text. </image>

Key Clinical Pearls

• The voltage-mass mismatch (low QRS voltage on ECG with increased wall thickness on echo) is the single most suggestive finding for cardiac amyloidosis -- always check for it
• Tc-99m PYP scan can diagnose ATTR amyloidosis without biopsy ONLY if monoclonal protein is excluded first -- a positive PYP scan with abnormal free light chains could be AL amyloidosis, which requires tissue confirmation
• Tafamidis should be started early in ATTR-CM (NYHA I-II) for maximum benefit; the ATTR-ACT trial showed no benefit when started in NYHA III
• Cardiac sarcoidosis should be considered in any patient < 55 years with unexplained high-degree AV block, new VT, or new cardiomyopathy -- FDG-PET is the best initial test after CMR
• Digoxin is CONTRAINDICATED in cardiac amyloidosis -- amyloid fibrils bind digoxin, causing toxicity at therapeutic serum levels
• The tissue Doppler e' velocity is the single most useful parameter for distinguishing constriction (preserved e') from restriction (reduced e') -- always measure it

References

• Garcia-Pavia P, et al. Diagnosis and Treatment of Cardiac Amyloidosis: A Position Statement of the ESC Working Group. Eur Heart J. 2021;42:1554-1568.
• Maurer MS, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-ACT). NEJM. 2018;379:1007-1016.
• Gillmore JD, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016;133:2404-2412.
• Birnie DH, et al. HRS Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated with Cardiac Sarcoidosis. Heart Rhythm. 2014;11:1305-1323.
• Kittleson MM, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient with Cardiac Amyloidosis. JACC. 2023;81:1076-1126.

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