Restrictive Cardiomyopathy and Constrictive Pericarditis

Restrictive Cardiomyopathy

• Myocardial infiltration or fibrosis: Abnormal myocardial tissue (amyloid, iron, sarcoidosis, fibrosis) replaces normal contractile elements, reducing myocardial compliance. In cardiac amyloidosis, misfolded proteins deposit in the myocardium, causing restrictive physiology and conduction abnormalities. In hemochromatosis, iron oxidizes to generate free radicals causing myocardial necrosis and fibrosis. In endomyocardial fibrosis, thick fibrous tissue obliterates the ventricular apex and endocardium, severely restricting cavity expansion.
• Impaired ventricular relaxation: Diastolic dysfunction with elevated ventricular stiffness produces a characteristic "square root sign" on ventricular pressure curves—rapid rise in early diastole followed by abrupt plateau. This results from inability of ventricles to expand normally during diastole despite normal systolic function.
• Pressure transmission abnormality: In restrictive disease, atrial contraction is essential for ventricular filling (loss of normal ventricular suction); atrial pressures rise significantly, transmitting backward to cause venous congestion without proportional ventricular volume increase. Pulmonary and systemic venous pressures become severely elevated while cardiac output paradoxically remains relatively preserved until late disease.

Constrictive Pericarditis

• Mechanical constraint: A thick (typically >3-4 mm), inelastic pericardial shell physically restricts ventricular expansion. Unlike normal pericardium which accommodates volume changes, the constricted pericardium provides fixed volume constraint. Ventricular interdependence becomes exaggerated—septal shift occurs with respiration as filling of one ventricle displaces the septum into the other.
• Annulus paradoxus: Early rapid ventricular filling is followed by abrupt cessation when the pericardial constraint is reached, producing the pathognomonic "square root sign" on pressure tracings—identical to RCM but mechanisms differ fundamentally.
• Equalization of diastolic pressures: Right atrial, right ventricular diastolic, left atrial, and left ventricular diastolic pressures all equilibrate within 5 mmHg due to the mechanical constraint. This is less consistent in RCM where diastolic pressures may differ by 10-15 mmHg.
• Respiratory variation: Marked (>10-15%) variation in mitral and tricuspid inflow velocities with respiration distinguishes CP from RCM, reflecting ventricular interdependence in the fixed pericardial space.

Restrictive Cardiomyopathy Etiologies

• Infiltrative disorders:
• Cardiac amyloidosis (AL amyloid, ATTR amyloid—both hereditary TTR and wild-type TTR, AA amyloid in chronic inflammation)
• Cardiac sarcoidosis (noncaseating granulomas in myocardium)
• Hemochromatosis (secondary iron overload from multiple transfusions or primary hereditary hemochromatosis)
• Fabry disease (α-galactosidase A deficiency, glycosphingolipid accumulation)
• Gaucher disease and other lysosomal storage disorders
• Fibrotic/obliterative disorders:
• Endomyocardial fibrosis (idiopathic in tropical Africa; associated with eosinophilic syndromes)
• Eosinophilic cardiomyopathy/Loeffler endocarditis (hypereosinophilia from hematologic malignancy or idiopathic)
• Radiation-induced cardiomyopathy (after chest radiation)
• Anthracycline cardiotoxicity (chemotherapy-related)
• Genetic/familial: Familial RCM (autosomal dominant with mutations in sarcomeric proteins: troponin I, troponin T, α-tropomyosin, MYH7, desmoplakin)
• Idiopathic: ~50% of cases in developed countries

Constrictive Pericarditis Etiologies

• Post-inflammatory: Viral, bacterial (especially tuberculosis), fungal, or idiopathic pericarditis (develops months to years after acute episode)
• Post-cardiac surgery: Dressler syndrome or late surgical constriction (weeks to years after cardiac surgery)
• Malignancy: Direct pericardial infiltration or radiation-induced fibrosis from thoracic radiation
• Tuberculosis: Most common cause worldwide; tuberculous pericarditis progresses to constriction in 10-20% of cases
• Radiation therapy: Mediastinal radiation for lymphoma or other cancers (latency 5-20 years)
• Other: Rheumatoid arthritis, systemic lupus erythematosus, uremia, asbestos exposure, cardiac trauma

Cardinal Symptoms

• Dyspnea on exertion and at rest: Orthopnea and paroxysmal nocturnal dyspnea from elevated pulmonary venous pressure; may be out of proportion to systolic dysfunction severity
• Fatigue and exercise intolerance: Limited cardiac output reserve; exertional syncope indicates severe disease
• Abdominal fullness and bloating: Hepatic congestion (fluid-responsive initially in CP; refractory in advanced RCM)
• Edema: Peripheral edema; may be disproportionately elevated in lower extremities if RV predominantly affected

Physical Examination Findings

• Elevated jugular venous pressure (JVP): Prominent, with rapid y-descent (rapid early diastolic collapse reflecting abrupt cessation of filling). "Square root sign" on jugular venous tracing.
• Kussmaul sign: Paradoxical rise in JVP with inspiration (loss of normal venous return increase during inspiration due to constrained right ventricle). More common in CP but also seen in RCM.
• Cardiac auscultation:
• S3 gallop: Present in many cases; reflects rapid ventricular filling phase
• Pericardial knock: Early diastolic sound (earlier than S3, typically at 80-100 ms after A2) pathognomonic for CP, caused by abrupt cessation of ventricular expansion
• Normal S2 splitting: Unlike restrictive physiology from other causes
• Quiet heart sounds (if significant pericardial thickening in CP)
• Hepatomegaly: Firm, pulsatile liver edge reflecting systemic venous congestion; hepatic pulsation less prominent in CP than RCM
• Atrial fibrillation: Frequent in both conditions due to elevated atrial pressures and chronic stretch

Distinguishing Features on Exam

• RCM features: Proportionally more prominent pulmonary congestion relative to peripheral edema; systolic murmurs of mitral regurgitation common (from papillary muscle dysfunction); pulsatile hepatomegaly
• CP features: Pericardial knock, more prominent peripheral edema and ascites, pulsus paradoxus in some cases

Clinical Assessment

• Electrocardiography (ECG):
• RCM: Nonspecific ST-T changes, left axis deviation; conduction abnormalities if infiltrative (amyloidosis: low voltage despite thick wall—"low voltage in the face of thick walls"; conduction delays in sarcoidosis)
• CP: Usually normal or nonspecific; atrial fibrillation common; may show low voltage if significant pericardial fluid
• Cardiac amyloidosis: Pseudo-infarct pattern (Q waves in precordial leads without coronary disease); low voltage

Echocardiography (2D, Doppler, Tissue Doppler)

• RCM:
• Normal or mildly reduced left ventricular size (LVEF typically >40%)
• Bilateral atrial enlargement (markedly dilated atria disproportionate to small-normal ventricles—"big atria, small ventricles")
• Restrictive filling pattern: E/A ratio >1.5 with decreased deceleration time (<150 ms); increased E/e' ratio (>14-15)
• Normal or mildly increased wall thickness (depends on etiology; thick walls in amyloidosis or hypertrophic RCM variants)
• Doppler tissue imaging: Abnormally low mitral annular velocity (e' <8 cm/s)
• No significant respiratory variation in mitral/tricuspid inflow velocities (typically <10%)

• CP:
• Normal or nearly normal ventricular size and systolic function
• Bilateral atrial enlargement
• "Septal bounce": Abnormal septal motion during early diastole due to ventricular interdependence
• Thickened pericardium (>3-4 mm, best seen with TEE or on posterior wall)
• Pronounced respiratory variation in mitral (>25%) and tricuspid (>40%) inflow velocities; variation in tissue velocities
• Restrictive filling pattern similar to RCM, but respiratory variation distinguishes CP
• Dilated inferior vena cava without collapse with inspiration (loss of normal venous return response)

Cardiac Catheterization (Gold Standard for Hemodynamic Assessment)

• RCM findings:
• "Square root sign" on LV and RV pressure curves (rapid early diastolic rise, abrupt plateau)
• Diastolic pressures: RV and LV diastolic pressures elevated but may differ by >5 mmHg (RV typically higher than LV in RCM)
• Right atrial pressure elevated with prominent x-descent (normal) and reduced y-descent
• Cardiac output typically normal or mildly reduced at rest; fails to increase normally with exercise
• Discordant ventricular filling: RV and LV pressures do NOT equalize during diastole (pathognomonic for RCM vs. CP)

• CP findings:
• "Square root sign" with abrupt diastolic plateau (identical to RCM)
• Equalization of diastolic pressures: Within 5 mmHg—RV diastolic = LV diastolic = RA diastolic (hallmark finding)
• Elevated right atrial pressure with prominent x-descent (sharp) and y-descent (sharp/brisk—"M" or "W" configuration)
• Pulsus paradoxus in some cases (>10 mmHg drop in systolic BP with inspiration)
• Concordant ventricular pressures: RV and LV systolic pressures rise together with inspiration (ventricular interdependence)
• Normal cardiac output at rest; may decline with exercise

Advanced Imaging

• Cardiac MRI:
• RCM: Identifies infiltrative patterns; late gadolinium enhancement (LGE) shows subendocardial or transmural pattern; tissue characterization (T1 and T2 mapping for amyloidosis, iron content for hemochromatosis)
• CP: Confirms thickened pericardium; may visualize calcification; pericardial LGE; pericardial stripping artifact
• MRI is superior to echocardiography for RCM/CP differentiation, showing pericardial thickening or myocardial infiltration

• CT Imaging: Demonstrates pericardial calcification and thickening better than MRI; useful when pericardial disease is main consideration

Laboratory Tests

• Biomarkers:
• BNP/NT-proBNP: Elevated in both conditions (less specific)
• Troponin: May be elevated in infiltrative RCM (amyloidosis, sarcoidosis) indicating myocardial injury
• In cardiac amyloidosis: Transthyretin (TTR), serum/urine immunofixation, free light chains, bone marrow biopsy

• Etiology-specific testing:
• Iron studies (ferritin, transferrin saturation) for hemochromatosis; cardiac MRI with T2* imaging
• ACE level and calcium for sarcoidosis; PET imaging may show myocardial inflammation
• Genetic testing for familial RCM (troponin genes) and hereditary ATTR amyloidosis (TTR sequencing)
• Eosinophil count and bone marrow examination for eosinophilic cardiomyopathy
• Testing for systemic disease: ESR, rheumatoid factor, ANA (for rheumatologic etiologies of CP)

Diagnostic Criteria Summary

Restrictive Cardiomyopathy

• Diuretics (first-line for congestion): Loop diuretics for pulmonary/systemic congestion; judicious use to avoid excessive preload reduction (patients depend on high filling pressures for adequate cardiac output). Cautious titration; monitor renal function.
• Avoid negative inotropes: ACE inhibitors and beta-blockers often poorly tolerated; use with caution only if hypertensive or in specific subtypes (e.g., sarcoidal RCM)
• Anticoagulation: Consider warfarin or DOAC for atrial fibrillation or if severe ventricular dysfunction with reduced ejection fraction
• ICD/pacing: Implantable cardioverter-defibrillator for secondary prevention if prior arrhythmia; permanent pacemaker if conduction disease (sarcoidosis)

• Cardiac amyloidosis (AL): Chemotherapy with bortezomib, melphalan, dexamethasone (BMD) or newer combinations; autologous stem cell transplant in selected cases; tafamidis (kinetic stabilizer) or diflunisal for ATTR; gene silencing therapy (inotersen, patisiran) for hereditary ATTR
• Hemochromatosis: Phlebotomy or chelation therapy (deferoxamine, deferasirox) to reduce iron burden and prevent progression
• Sarcoidosis: Corticosteroids for myocardial inflammation; immunosuppressive therapy for resistant cases; assess for conduction disease
• Eosinophilic cardiomyopathy: Corticosteroids; imatinib or other tyrosine kinase inhibitors if associated with hematologic malignancy; cytoreduction for clonal eosinophilia

• Heart transplantation: Considered in advanced, refractory cases with NYHA Class III-IV symptoms despite optimal medical therapy; limited by availability and comorbidities; contraindicated in systemic amyloidosis unless

Disease-related — cardiac

• Progressive low-output heart failure: A stiff ventricle cannot increase stroke volume, so cardiac output becomes rate-dependent and eventually fixed; signaled by narrowing pulse pressure, falling systolic BP, cool extremities, and rising creatinine despite congestion. Cardiogenic shock in this setting is an emergency.
• Atrial fibrillation and thromboembolism: Chronic atrial stretch plus, in amyloidosis, direct atrial infiltration causes atrial electromechanical dissociation ("atrial standstill") — intracardiac thrombus and stroke can occur even in sinus rhythm. The 2022 AHA/ACC/HFSA heart failure guideline supports anticoagulation in amyloid cardiomyopathy with AF largely irrespective of CHA₂DS₂-VASc score. New stroke or limb ischemia is an emergency.
• High-grade AV block and ventricular arrhythmia: Granulomatous or amyloid infiltration of the conduction system; syncope, bradycardia, or wide-complex tachycardia in a patient with cardiac sarcoidosis mandates urgent monitoring and device evaluation per the HRS expert consensus on arrhythmias in sarcoidosis. Complete heart block and ventricular fibrillation / pulseless VT are emergencies.

Disease-related — systemic

• Cardiac cirrhosis, ascites, and protein-losing enteropathy: Sustained systemic venous hypertension, classically in long-standing constriction; suspect with refractory ascites out of proportion to edema, hypoalbuminemia, and cardiac cachexia.
• Extracardiac AL amyloid disease: Nephrotic-range proteinuria, autonomic neuropathy with orthostatic hypotension, and periorbital purpura — these limit tolerance of any vasoactive therapy.

Treatment-related

• Over-diuresis: These ventricles are preload-dependent; excessive loop diuretic produces hypotension, syncope, and prerenal AKI with a rising BUN/creatinine ratio.
• Drug intolerance in amyloidosis: Because stroke volume is fixed and output is rate- and preload-dependent, beta blockers, ACE inhibitors/ARNI, and nondihydropyridine calcium channel blockers frequently provoke symptomatic hypotension; the 2022 AHA/ACC/HFSA heart failure guideline notes that standard neurohormonal HFrEF therapy is often poorly tolerated and not clearly beneficial in amyloid cardiomyopathy.
• Pericardiectomy complications: Perioperative low-output syndrome, bleeding, and phrenic nerve injury; mortality is highest in radiation-induced constriction and advanced NYHA class, so late referral worsens outcome.

• Low QRS voltage with thick walls: Voltage–mass mismatch on ECG plus echocardiographic "hypertrophy" is cardiac amyloidosis until proven otherwise — the walls are thick from infiltration, not myocyte hypertrophy. Add a pseudo-infarct pattern (anterior Q waves without CAD) and granular sparkling myocardium.
• Single best next step in suspected amyloid: Screen for a monoclonal protein first — serum and urine immunofixation plus serum free light chain ratio. Only if these are negative does a positive ⁹⁹ᵐTc-pyrophosphate (PYP) bone scintigraphy scan establish ATTR noninvasively, per the ACC expert consensus decision pathway on cardiac amyloidosis. Missing an AL clone delays urgent hematology referral, since untreated AL is rapidly fatal.
• The one association examiners test: Pericardial calcification on lateral chest film or CT plus pericardial knock and Kussmaul sign = constrictive pericarditis, and the definitive treatment is pericardiectomy — the curable member of this pair.
• Respiration is the discriminator: Marked respirophasic mitral/tricuspid inflow variation, septal bounce, and discordant RV–LV systolic pressure change on catheterization (RV systolic pressure rises while LV systolic pressure falls with inspiration; systolic area index >1.1) indicate constriction — the signature of exaggerated ventricular interdependence within a fixed pericardial shell. Concordant RV–LV systolic pressure change (both fall together with inspiration), with RV and LV diastolic pressures differing by more than ~5 mmHg, indicates restrictive cardiomyopathy.
• Common distractor — tamponade vs constriction: Tamponade gives a blunted y-descent with prominent x-descent and pronounced pulsus paradoxus; constriction gives a prominent, sharp y-descent (M or W waveform) and Kussmaul sign. Kussmaul sign is characteristically absent in tamponade.
• Drug traps: Amyloid fibrils bind digoxin and verapamil, producing heightened digoxin sensitivity — toxicity can occur at conventionally therapeutic serum levels, so use only with caution and close monitoring. Aggressive diuresis crashes a preload-dependent ventricle.
• Tissue is the answer when imaging is equivocal: Endomyocardial biopsy showing Congo red apple-green birefringence under polarized light confirms amyloid; typing (mass spectrometry) then drives therapy — tafamidis for ATTR versus plasma-cell–directed chemotherapy for AL.
• Hypereosinophilia plus apical obliteration and mural thrombus = Löffler endocarditis, the temperate-climate counterpart of tropical endomyocardial fibrosis.