Restrictive cardiomyopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maneesha Nandimandalam, M.B.B.S.[2] Synonyms and keywords: Infiltrative cardiomyopathy; RCM; stiff heart; stiffening of the heart; heart stiffening; stiffened heart

Overview

Restrictive cardiomyopathy (RCMP) is a rare form among other cardiomyopathies, characterized by increased stiffness of the ventricles in the presence of normal diastolic volume and normal ventricular wall thickness. It may be classified into primary i.e EMF(endomyocardial fibrosis),Loffler’s endocarditis, Idiopathic restrictive cardiomyopathy and secondary i.e, infiltrative diseases(e.g., amyloidosis, sarcoidosis, and radiation carditis) and storage diseases (e.g., hemochromatosis, glycogen storage disorders, and Fabry’s disease). Cardiac amyloidosis is the most common cause of restrictive cardiomyopathy. Mainly due to deposition of amyloid fibrils in the extracellular space and misfolding into β-pleated sheets which are antiparallel to each other making them resistant to proteolysis, and also cause oxidative stress as a result leading to myocardial damage. Sarcoidosis characterized by noncaseating granulomas formation in various tissues including heart and hemochromatosis due to excessive accumulation of iron within the cells of various organs liver, pancreas, heart, and several endocrine glands leading to cirrhosis, diabetes, heart failure, skin pigmentation is also the common causes. Cardiac genes for desmin, α-actin, troponin I and troponin T are involved in the pathogenesis of restrictive cardiomyopathy. Restrictive cardiomyopathy should be differentiated from dilated cardiomyopathy, hypertrophic cardiomyopathy, congestive heart failure. Restrictive cardiomyopathy is very rare among all other types and accounts for approximately 5% of all cases. Its prevalence varies depending on regionality, ethnicity, age, and gender. Amyloidosis affects men and women equally. The wild-type transthyretin amyloidosis is most often found in the elderly population. Common complications of restrictive cardiomyopathy include thromboembolism, rhythm abnormalities(dysrhythmias), cardiac cirrhosis, heart failure, pulmonary hypertension. Common symptoms include dyspnea, fatigue, palpitations, syncope. Jugular venous distension is noted sometimes with Kussmaul sign and Hepatojugular reflux.S3 and S4 gallops seen. ECG shows Low QRS voltages, conduction disturbances, nonspecific ST abnormalities. Transmitral spectral Doppler often shows restrictive filling pattern and Ejection fraction (EF) is normal. The main purpose of treatment in restrictive cardiomyopathy (RCM) is to reduce symptoms by decreasing the elevated filling pressures without significantly lowering the cardiac output.Pharmacologic therapy may include Beta blockers, Amiodarone, Cardioselective [[calcium channel blockers], Diuretics, Anticoagulants for patients with atrial fibrillation, Melphalan (for antiplasma cell therapy in systemic amyloidosis), Chemotherapy (in amyloidosis). Other approaches like Pacemaker implantation and endomyocardectomy are also available.

Historical Perspective

• In 1957 for the first time Brigden coined the term ‘cardiomyopathy’ to describe group of uncommon, non-coronary myocardial diseases.
• But later in 1961 Goodwin redefined cardiomyopathies as “myocardial diseases of unknown cause”. Infact he is the one who put them into 3 seperate entities “dilated, hypertrophic and restrictive”, which we are still using today.
• In 1980 World Health Organization (WHO) and International Society and Federation of Cardiology (ISFC) combinedly published a classification which included the three subgroups proposed by Goodwin.

Classification

• There is no established system for the classification of restrictive cardiomyopathy
• It may be classified into:
• Primary
  • EMF(endomyocardial fibrosis)
  • Loffler’s endocarditis
  • Idiopathic restrictive cardiomyopathy
• Secondary
  • Infiltrative diseases(e.g., amyloidosis, sarcoidosis, and radiation carditis)
  • Storage diseases (e.g., hemochromatosis, glycogen storage disorders, and Fabry’s disease)

Pathophysiology

Pathogenesis

• The exact pathogenesis of restrictive cardiomyopathy is not completely understood.
• Mainly characterized by impaired ventricular filling and reduced diastolic volume of one or both ventricles, with either normal or near-normal systolic function.
• Hemodynamic abnormalities constitute the main pathological aspect of restrictive cardiomyopathy.
• The primary abnormality of restrictive cardiomyopathy is impaired myocardial relaxation along with interstitial fibrosis as well as calcifications.
• Restrictive filling can been seen which is due to higher diastolic pressure.

Cardiac Amyloidosis

• It is the most common cause of restrictive cardiomyopathy(RCM).
• Mainly due to deposition of amyloid fibrils in the extracellular space and misfolding into β-pleated sheets which are antiparallel to each other making them resistant to proteolysis, and also cause oxidative stress as a result leading to myocardial damage.

Sarcoidosis

• Characterised by noncaseating granulomas formation in various tissues including heart.
• The usual location is basal septum, AV node, bundle of His, the ventricular free walls, and papillary muscles.
• Formation of granuloma includes 3 histological stages: edema, granulomatous infiltration, and fibrosis.

Hemochromatosis

• Due to excessive accumulation of iron within the cells of various organs liver, pancreas, heart, and several endocrine glands leading to cirrhosis, diabetes, heart failure, skin pigmentation.

Genetics

Genes involved in the pathogenesis of restrictive cardiomyopathy include:

• Cardiac genes for desmin, α-actin, troponin I and troponin T.
• Missense mutation (D190H) in the region of the cTnI gene (TNNI3).
• De novo mutations (R192H and K178E) in the TNNI3 gene.
• Mutations in the α-cardiac actin (ACTC), β-myosin heavy chain (β-MHC), and cTnT (TNNT2) genes have been noticed to have etiological causes of restrictive cardiomyopathy.

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Left side of the heart from a 3-year-old castrated male domestic short-haired catwith the endomyocardial form of restrictive cardiomyopathy (RCM), showing extensiveendocardial fibrosis involving substantial portions of the left ventricular cavity, Affiliation: Laboratory of Veterinary Clinical Oncology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.https://openi.nlm.nih.gov/detailedresult?img=PMC4905831_jvms-78-781-g001&query=restrictive%20cardiomyopathy&it=xg&req=4&npos=2

Microscopic Pathology

On microscopic histopathological analysis, restrictive cardiomyopathy will show features suggestive of the cause.

• Cardiac Amyloidosis:
  • On H&E stain it shows the pink color and demonstrates apple-green birefringence when viewed under polarized light.

https://commons.wikimedia.org/wiki/File:Cardiac_amyloidosis_very_high_mag_he.jpg

• Sarcoidosis:
  • Consists of granulomas with macrophages and epithelioid histiocytes and lymphocytes.
• Niemann-Pick: foam cells are seen
• Mucopolysaccharidosis type II: glycosaminoglycans
• Hereditary hemochromatosis: Deposition of iron is seen
• Gaucher disease: Gaucher cells (lipid-laden macrophages) are seen

Causes

The main Causes of restrictive cardiomyopathy are enlisted below:

• Amyloidosis (AL, ATTR, SSA)
• Sarcoidosis
• Hemochromatosis
• Eosinophilic myocardial disease
• Idiopathic RCM
• Progressive systemic sclerosis (scleroderma)
• Postradiation therapy (Hodgkin's lymphoma, breast cancer etc)
• Anderson Fabry disease
• Danon's disease
• Friedreich's ataxia
• Diabetic cardiomyopathy (restrictive phenotype)
• Drug induced (anthracycline toxicity, methysergide, ergotamine, mercurial agents, etc.)
• Mucopolysaccharidoses (Hurler's cardiomyopathy)
• Myocardial oxalosis
• Wegener's granulomatosis
• Metastatic malignancies

Differentiating restrictive cardiomyopathy from Other Diseases

Restrictive cardiomyopathy should be differentiated from dilated cardiomyopathy, hypertrophic cardiomyopathy, congestive heart failure ect ,

Differentiating restrictive cardiomyopathy from Other Diseases

Type of disease	History	Physical examination	Chest X-ray	ECG	2D echo	Doppler echo	CT	MRI	Catheterization hemodynamics	Biopsy
Restrictive cardiomyopathy	Systemic disease (e.g., sarcoidosis, hemochromatosis).	± Kussmaul sign S3 and S4 gallop, murmurs of mitral and tricuspid regurgitation	Atrial dilatation	Low QRS voltages (mainly amyloidosis), conduction disturbances, nonspecific ST abnormalities	± Wall and valvular thickening, sparkling myocardium	Decreased variation in mitral and/or tricuspid inflow E velocity, increased hepatic vein inspiratory diastolic flow reversal, presence of mitral and tricuspid regurgitation	Normal pericardium	Measurement of iron overload, various types of LGE (late gadolinium enhancement)	LVEDP – RVEDP ≥ 5 mmHg RVSP ≥ 55 mmHg RVEDP/RVSP ≤ 0.33	May reveal underlying cause.
Constrictive pericarditis	Prior history of pericarditis or conditions affecting the pericardium.	Pericardial knock	Pericardial calcification	Nonspecific ST and T abnormalities, low QRS voltage (<50%)	± Pericardial thickening, respiratory ventricular septal shift.	Increased variation in mitral and/or tricuspid inflow E velocity, hepatic vein expiratory diastolic reversal ratio ≥ 0.79 medial e′/lateral e′ ≥ 0.91 (Annulus Reversus)	Thickened/calcified pericardium	Thickened pericardium	LVEDP – RVEDP < 5 mmHg RVSP < 55 mmHg RVEDP/RVSP > 0.33 Inspiratory decrease in RAP < 5 mmHg Systolic area index > 1.1 (Ref CP in the modern era) Left ventricular height of rapid filling wave > 7 mmHg	Normal myocardium
Hypertrophic cardiomyopathy(HCM)	Commonly asymptomatic/minimally symptomatic. Exertional dyspnea or syncope.	In LVOT obstruction, a harsh, midsystolic, Grade 3–4/6 murmur loudest between the apex and the left sternal border is usually audible. Precordial impulse is forceful and displaced leftward and the peripheral arterial pulses are brisk.		Voltage changes of LVH, ST-T wave changes, T-wave inversions Pathological deep Q waves Complete bundle branch block	Left ventricular asymmetric hypertrophy Left ventricular diastolic dysfunction SAM (systolic anterior motion) of the mitral leaflet.					Enlarged cardiac myocytes in disarray, fibrotic replacement of the myocardium β-myosin heavy chain and myosin-binding protein C genes
Dilated Cardiomyopathy	Alcohol, HIV, Cocaine, CAD	Lateral displacement of the point of maximal impulse (PMI) Right ventricular heave S3 S4 S3 Gallops	Enlarged left ventricle and atria Pulmonary edema Associated pleural effusions.	T wave and ST segment changes to septal pathological Q waves Wide QRS complex	LV dilation with diffuse hypokinetic walls	Functional MR and TR and a different degree of diastolic dysfunction			Increased LVEDP, pulmonary artery wedge pressure. Left ventriculography may show ventricular dilation with global hypokinesis

Epidemiology and Demographics

Incidence

Restrictive cardiomyopathy is very rare among all other types and accounts for approximately 5% of all cases.

Prevalance

• Its prevalence varies depending on regionality, ethnicity, age, and gender.
• Amyloidosis: It affects men and women equally. The wild-type transthyretin amyloidosis is most often found in the elderly population.
• Sarcoidosis: More common in women than men. The highest prevalence is among black women. The highest incidence worldwide is in Japan.
• Hemochromatosis: Affects both men and women equally.
• Loffler endocarditis: More Common in tropical climates and sub-Saharan Africa.

Risk Factors

• Any family history of restrictive cardiomyopathy
• Inherited diseases (such as hereditary hemochromatosis, Fabry disease, mutant-type [hereditary] TTR amyloidosis, etc.)
• Increased number of blood transfusions leading to secondary hemochromatosis.
• Prior anthracycline use in childhood, exposure to other toxic agents.
• Eosinophilic syndrome or chronic parasitic infection
• Exposure to any radiation to the chest.

Screening

Natural History, Complications, and Prognosis

Natural History

• The symptoms of (disease name) usually develop in the first/ second/ third decade of life, and start with symptoms such as ___.
• The symptoms of (disease name) typically develop ___ years after exposure to ___.
• If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

Complications

• Common complications of restrictive cardiomyopathy include:
  • Thromboembolism
  • Rhythm abnormalities(dysrhythmias)
  • Cardiac cirrhosis
  • Heart failure
  • Pulmonary hypertension

Prognosis

• Restrictive cardiomyopathy (RCM) has the worst prognosis among all types of cardiomyopathies.
• Prognosis is generally poor, and the 2/5-year mortality rate of patients is approximately 50% and 70%, respectively.
• There is an estimated 2-5 year survival rate after diagnosis.

Diagnosis

Diagnostic Study of Choice

History and Symptoms

• The majority of patients with [disease name] are asymptomatic.

OR

• The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].
• Symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. 

History

Patients with [disease name]] may have a positive history of:

• [History finding 1]
• [History finding 2]
• [History finding 3]

Common Symptoms

Common symptoms of include:

• Dyspnea
• Fatigue
• Limited exercise capacity
• Palpitations
• Syncope

Less Common Symptoms

Less common symptoms of restrictive cardiomyopathy include

• Angina

Physical Examination

Physical examination of patients with restrictive cardiomyopathy is usually abnormal with characteristic findings in cardiovascular and pulmonary systems.

Appearance of the Patient

• Patients with restrictive cardiomyopathy usually appear normal.

Vital Signs

They are usually with in normal limitis.

Skin

• Skin examination of patients with restrictive cardiomyopathy is usually normal except in hemochromatosis which may show classic bronze skin

HEENT

• HEENT examination of patients with restrictive cardiomyopathy is usually normal.

Neck

• Jugular venous distension is noted sometimes with kussmaul sign
• Hepatojugular reflux

Lungs

• Fine/coarse crackles upon auscultation of the lung bases/apices unilaterally/bilaterally
• Rhonchi

Heart

• S1
• S2
• S3
• S4
• Gallops

Abdomen

• Hepatomegaly

Back

• Back examination of patients with restrictive cardiomyopathy is usually normal.

Genitourinary

• Genitourinary examination of patients with restrictive cardiomyopathy is usually normal.

Neuromuscular

• Neuromuscular examination of patients with restrictive cardiomyopathy is usually normal.

Extremities

• Peripheral edema of the lower extremities

Laboratory Findings

• The laboratory findings depends on the cause of the cardiomyopathy.
• Hematocrit, serum electrolytes, blood urea nitrogen (BUN), creatinine, 24 hr urine total protein, and liver function should be assessed.
• Arterial blood gas (ABG) should be checked for possibility of hypoxia.
• Serum brain natriuretic peptide (BNP) or N-terminal pro-b-type natriuretic peptide (NT-proBNP) and troponin T are indicative of the heart failure.
• Other Specific lab findings will depend upon the cause (angiotensin converting enzyme (ACE) in sarcoidosis, complete blood count (CBC) with peripheral smear helping to establish eosinophilia in hypereosinophilic syndromes, serum iron concentrations, total iron-binding capacity and ferritin levels in hemocromatosis, immunoglobulin free light κ, λ chain testing, and serum and urine immunofixation in amyloidosis, etc.

Electrocardiogram

Shown below is an example of restrictive cardiomyopathy with low voltage and flipped anterior T waves.

X-ray

A chest X-ray may show atrial dilatation most of the times.

Echocardiography and Ultrasound

Echocardiography may be helpful in the diagnosis of restrictive cardiomyopathy. Findings on an echocardiography suggestive of restrictive cardiomyopathy include:

• Normal or increased wall thickness
• Transmitral spectral Doppler often shows restrictive filling pattern.
• Marked left or biatrial dilatation usually as a consequence of chronically elevated filling pressures.
• Ejection fraction (EF) is normal or near normal.
• The main purpose of echo is the differential diagnosis between constrictive pericarditis(CP) and resrictive cardiomyopathy(RCM).
• Both present as heart failure with normal-sized ventricles and preserved EF, dilated atria, and doppler findings of increased filling pressure often seen in restrictive cardiomyopathy.

CT scan

MRI

• Magnetic Resonance imaging and late gadolinium enhancement (LGE) is very helpful in providing information about anatomic structures, perfusion, ventricular function, as well as tissue characterization.
• Late gadolinium enhancement (LGE) depending on the pattern of scar formation can help the doctor in establishing the diagnosis to specific subtypes of restrictive cardiomyopathy(RCM).
• MRI can also quantify the myocardial iron load in patients with haemochromatosis or thalassemia who receive transfusions.

Other Imaging Findings

• Radionuclide imaging using single-photon emission computed tomography (SPECT), or positron emission tomography (PET), is also used for the diagnostic work-up of amyloidosis.
• An increased myocardial uptake of Tc-99m pyrophosphate or Tc-99m 3,3-diphosphono-1,2-propanodicarboxylic acid helps to identify patients with familial transthyretin-related amyloidosis(ATTR) and also it can differentiate them from those with light chain amyloid(AL).
• Radionuclide imaging with 18fluorodeoxyglucose- (FDG-) PET is recently being used to assist in the diagnosis of cardiac sarcoidosis.
• Decrease in myocardial perfusion with enhanced 18FDG uptake is consistent with inflammation, while decreased perfusion with reduced 18FDG uptake is associated with scarring.

Other Diagnostic Studies

Treatment

Medical Therapy

• Restrictive cardiomyopathy has no definitive treatment. But However, the ones directed at individual causes have been proven to be effective.
• The main purpose of treatment in restrictive cardiomyopathy (RCM) is to reduce symptoms by decreasing the elevated filling pressures without significantly lowering the cardiac output.
• Pharmacologic therapy may include:
  • Beta blockers
  • Amiodarone
  • Cardioselective calcium channel blockers
  • Diuretics
  • Anticoagulants for patients with atrial fibrillation
  • Digoxin (use with caution)
  • Melphalan (for antiplasma cell therapy in systemic amyloidosis)
  • Chemotherapy (in amyloidosis)
  • Corticosteroids, cytotoxic agents (eg, hydroxyurea), and interferon (in Loeffler endocarditis)
  • Chelation therapy or therapeutic phlebotomy (in hemochromatosis)
• Other treatments:
  • Pacemaker implantation
  • Endomyocardectomy
  • Cardiac transplantation
  • Novel approches (eg, RNA interference or gene silencing molecules that target abnormal protein production in familial amyloidosis)

Surgery

Primary Prevention

Secondary Prevention

References

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