Restrictive cardiomyopathy

1. Restrictive and Infiltrative Cardiomyopathies
Amit Gulati, Fellow, CV diseases
MSBI/MSW/MSM

3. Introduction
In 1980, the World Health Organization (WHO) defined cardiomyopathies as "heart muscle
diseases of unknown cause" to distinguish cardiomyopathy from cardiac dysfunction due to
known cardiovascular entities such as hypertension, ischemic heart disease, or valvular
disease.

4. A 2006 AHA scientific statement proposed a contemporary definition and
classification of the cardiomyopathies. The expert consensus panel proposed
the following definition: "Cardiomyopathies are a heterogeneous group of
diseases of the myocardium associated with mechanical and/or electrical
dysfunction that usually (but not invariably) exhibit inappropriate ventricular
hypertrophy or dilation and are due to a variety of causes that frequently are
genetic. Cardiomyopathies either are confined to the heart or are a part of
generalized systemic disorders, often leading to cardiovascular death or
progressive heart failure-related disability."

5. The 3 principal classifications based on their phenotype are dilated, hypertrophic, and
restrictive cardiomyopathies (RCMs), ARVC/D, Unclassified
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.

8. 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. Many of the gene variants
known to cause RCM overlap with gene variants that cause hypertrophic cardiomyopathy.
Scleroderma, Noonan syndrome.

9. RCM Characteristics
Systolic function measured by ejection fraction is typically normal until advanced
stages of disease ensue.
The ventricular myocardium has increased stiffness that results in severe diastolic
dysfunction, restrictive filling pattern with elevated filling pressures, normal left
ventricular (LV) cavity size and dilated atria.
The noncompliant left ventricle demonstrates rapid elevation in filling pressures with
only small increases in volume.
Most conditions affect both the right and left ventricles and may cause signs and
symptoms of right, left, or biventricular failure.

10. Clinical Characteristics
Heart failure is the most common initial manifestation, with dyspnea on exertion a typical
feature.
Exercise intolerance is frequently present due to the inability of the ventricle to fill
adequately at higher heart rates.
Fatigue and lower extremity edema are also prominent features.
Chest pain may occur, but is infrequent.

11. 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. Extracardiac
manifestations of amyloidosis include kidney function impairment, proteinuria, peripheral
neuropathy, carpal tunnel syndrome, and gastrointestinal symptoms (malabsorption).
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. Extracardiac features of sarcoidosis
include cough, cutaneous findings (keloid formation), and visual changes.

12. 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

13. Physical Exam Findings
Prominent right-sided findings including jugular venous distention and prominent x and y
descents, Kussmaul’s sign.
The apical impulse may be mildly displaced but is usually palpable. S1 and S2 are normal;
there is typically a loud S4 gallop, and an S3 gallop is not infrequently audible.
Hepatomegaly, ascites, and marked pedal edema may occur as the disease progresses.
Mitral and tricuspid regurgitation are frequently present.

14. Investigations – CXR & EKG
The chest film usually shows a normally sized ventricular silhouette with enlarged atria and
varying degrees of pulmonary congestion.
Electrocardiogram (ECG) exhibits sinus rhythm with large P waves indicative of biatrial
enlargement accompanied by nonspecific repolarization abnormalities.
Atrial fibrillation, however, is not uncommon.
Low voltage, a pseudoinfarction pattern, bundle branch block, and AV block should suggest
an infiltrative process or sarcoidosis.

15. Echocardiography
Echocardiography in RCM typically demonstrates: normal right and LV ejection fraction,
normal chamber volumes with biatrial enlargement, restrictive diastolic filling parameters
Increased LV wall thickness after excluding causes such as hypertensive heart disease and
HCM is seen with infiltrative processes

17. Increased early diastolic filling velocity (E waves) reflecting elevated left atrial pressure,
decreased atrial filling velocity (A-wave) due to elevated ventricular diastolic pressures, E/A
ratios >1.5, Decreased mitral deceleration time (DT <120 ms).
A markedly decreased systolic/diastolic pulmonary venous flow ratio is typically seen due to
high atrial filling pressures and augmented atrial reversal velocity consequent to decreased
ventricular compliance.
Doppler tissue imaging reveals reduced early mitral annular velocities (eʹ) with an increased
E/eʹ ratio.

18. Restrictive vs Constrictive on Echo
In constrictive pericarditis, echocardiography may detect the presence of a thickened (>4
mm) pericardium.
The most specific sign on echocardiography of constrictive pericarditis is shifting of the
septum during the respiratory cycle, caused by the variability in venous return in
exaggerated interventricular dependence.
Of all echocardiographic parameters, the most useful to distinguish the two conditions is
TDI. A normal tissue Doppler e’ velocity (>8 cm/s) indicates normal LV relaxation and
virtually excludes RCM.

19. Cardiac MRI
 value of CMR lies in its ability to accurately
characterize myocardial tissue based upon the
intrinsic magnetic properties of different tissues
and the distribution patterns of gadolinium-
based contrast agents
 T2-weighted sequences or quantitative
T2 mapping may indicate myocardial edema and
inflammation that appear as hyperintense areas,
and in contrast, decreased T2-weighted signal
intensities are seen in iron overload myocardial
disorders
 Contrast-enhanced T1 mapping is useful in
quantifying diffuse myocardial fibrosis

20. Cardiac Catherization
 Hemodynamic findings on cardiac catheterization
include elevation of right- and left-sided filling
pressures with reduction in cardiac index.
 Right atrial pressure is elevated with prominent x and y
descents.
 The classic square root sign (i.e., a prominent early
decrease in ventricular diastolic pressure followed by a
rapid rise to a plateau phase) characterizes restrictive
physiology.

21. Endomyocardial Biopsy
 Endomyocardial biopsy plays an important role in the diagnostic evaluation of
patients with restrictive disease (AHA/ACC Class IIa recommendation)
 Cardiac involvement in systemic diseases such as amyloidosis and
hemochromatosis can be definitively established by right ventricular biopsy
 Although CMR has increasingly diminished the need of performing an
endomyocardial biopsy from a diagnostic perspective, a tissue diagnosis is
sometimes needed to identify forms of RCM with targeted therapies
(i.e., sarcoidosis, amyloidosis, and Fabry disease)

22. General Treatment Principles
 Conventional treatment should be aimed at relieving congestive symptoms
 Judicious use of loop diuretics
 However, even mild hypovolemia due to overdiuresis in the presence of a nondilated, nondistensible ventricle
can lead to further decline in stroke volume and cause hypotension and a low-output state
 Supraventricular arrhythmias, particularly atrial fibrillation, occur commonly and are poorly tolerated
 Rhythm control with the use of antiarrhythmic agents rather than rate control may contribute to
normal atrial contractility and improve diastolic filling to preserve stroke volume
 Bradyarrhythmias, although uncommon in restrictive or infiltrative heart disease, may require
permanent pacer implantation
 No pharmacological treatment has been shown to specifically improve diastolic filling or to prolong
survival except heart transplantation in eligible patients
 Therapy should be directed toward the specific underlying disease etiologies when identified

24. Idiopathic RCM
 Primary (idiopathic) RCM is a rare disease that may present at any age
 Increased myofilament sensitivity to calcium, increased deposition of collagen type
III, and marked deposition of desmin have all been implicated in the pathogenesis
of this condition
 Familial disease as well as sporadic cases has been described
 Autosomal dominant inheritance with variable penetrance characterizes familial
cases
 Skeletal myopathy, particularly affecting distal muscles of the extremities, as well as
atrioventricular block are present in some familial cases

25. Iron Overload RCM
 Characterized in early stages by an RCM with prominent early diastolic dysfunction that
inevitably progresses to an end-stage DCM
 Excess iron accumulation usually occurs due to increased iron absorption by the
gastrointestinal tract (e.g., hemochromatosis) or high parenteral iron administration,
generally due to frequent red blood cell transfusions, especially in hereditary anemias
such as thalassemia major and sickle cell disease
 Pathologic iron deposition initially begins in the epicardium, extends to the myocardium
and finally to the endocardium, which partially explains preservation of systolic function
until late in the disease
 Cardiac magnetic resonance imaging (MRI) is the only available noninvasive method
with the potential to accurately quantitatively assess iron load
 Iron’s paramagnetic effect produces changes in the MR signal intensity, shortens the T2-
weighted relaxation time, and darkens the image more quickly
 T2 relaxation time is an excellent measure of myocardial iron deposition and is useful for serial
assessment of response to iron chelation therapy

26. Iron Overload RCM

27. Radiation Induced RCM
 Manifestations are myriad and may include accelerated coronary artery disease,
valvular dysfunction, RCM, aortopathy, and constrictive pericarditis
 RIHD typically occurs with a latent period of 10-15 years
 Management is symptomatic and consists largely of diuretics to control volume
overload
 In advanced cases, cardiac transplantation has been successful in a limited number
of radiation-induced RCM patients
 However, multicenter 5-year post-transplant survival was lower when compared to
transplant for other types of RCM likely related to the presence of concomitant
mediastinal fibrosis and radiation lung disease and prior cardiac surgeries leading to
increased early postoperative deaths

28. RCM – Endomyocardial fibrosis
 Endomyocardial diseases are another rare cause of restrictive cardiomyopathy (RCM); the most
common is endomyocardial fibrosis (EMF). Other diseases are endocardial fibroelastosis (EFE),
hypereosinophilic syndromes, and carcinoid heart disease
 EMF is the most common cause of RCM, commonly seen in equatorial countries such as Uganda,
Nigeria, and Brazil
 Other conditions such as hypereosinophilic syndrome may mimic this disorder
 EMF typically affects impoverished young adults with a bimodal distribution peaking at 10 and 30
years of age
 The natural history of EMF includes
 a) an active phase with inflammation and eosinophilia that progresses to a chronic phase leading to
restrictive heart disease
 b) the chronic phase where biventricular involvement is the most common presentation (>50% of cases),
followed by isolated right-sided heart involvement
 Atrial fibrillation occurs in >30% of patients, and embolic complications are common.
 Therapeutic options include sodium and fluid restriction, diuretics, and aspirin or anticoagulation in
view of the potential for intracardiac thrombi
 Where surgical expertise exists, EMF may be successfully treated with surgical endocardectomy and
valve repair or replacement

29. RCM - Endocardial fibroelastosis
 EFE is extremely rare and is characterized by diffuse thickening of the left ventricular (LV)
endocardium secondary to proliferation of fibrous and elastic tissue
 Two forms have been described
 dilated form (dilated cardiomyopathy [DCM] phenotype), in which the LV is enlarged
 contracted form (RCM phenotype), in which the LV cavity is small
 A familial pattern is seen in the majority with presentation commonly during infancy
 The primary form of EFE invariably affects the LV with significant involvement of the mitral and
aortic valves
 Isolated RV involvement is rare. The “contracted” form produces restrictive hemodynamics and a
clinical picture of left-sided obstructive disease, particularly if the mitral valve is involved
 EFE may respond to surgery

30. RCM – Hypereosinophilic Syndrome
 Hypereosinophic syndromes affecting the heart (formerly known as Loeffler’s endocarditis),
although very rare, can cause substantial morbidity and mortality through the release of
substances that damage the endothelium and myocardium that leads to eosinophilic
myocarditis
 Most patients are diagnosed between the ages of 20 and 50 years
 Etiology of hypereosinophilia (an absolute peripheral blood eosinophil count that is >1500
cells/L and persists for longer than a month or pathologic evidence of hypereosinophilic tissue
invasion) is variable and includes helminthic and parasitic infections, malignancies,
eosinophilic leukemia, allergic drug reactions, idiopathic causes or associated with genetic
aberrations
 Other etiologies include hypersensitivity, and eosinophilic granulomatsosis with polyangiitis.

31. RCM – Hypereosinophilic Syndrome
 Eosinophilic heart disease has been categorized into three stages:
 an acute necrotic phase
 an intermediate phase with thrombus formation
 a fibrotic stage characterized by impaired cardiac function, HF due to RCM, and/or fibrotic
deformation of chordal structures leading to mitral and tricuspid regurgitation

32. RCM – Hypereosinophilic Syndrome
 Therapy can be effective in the early stages of disease
 Corticosteroids alone or in combination with cytolytic therapies (hydroxyurea, inferon
alpha) have been shown to improve the acute necrotic stage of disease
 AC should be instituted for patients who have thrombi and have sustained a prior
embolic eventThe fibrotic stage may occasionally require cardiac surgery, which
may include resection of endocardial scar as well as subchordal repair and/or valve
repair or replacement.
 The need for cardiac surgery has declined during the last decade due to aggressive
management strategies aimed at preventing unregulated eosinophil proliferation
 Surgical replacement of the mitral or aortic valves must be accompanied by
pharmacologic measures designed to control ongoing eosinophilia
 Bioprosthetic valves are preferable to mechanical valves due to the thrombotic tendency
of HES

33. Infiltrative Cardiomyopathies: Lysosomal Storage
Diseases
 Of the 40 storage disorders caused by deficient enzymatic activity of lysosomal enzymes, Anderson-Fabry
disease, Danon disease)–deficient cardiomyopathy are the principal diseases associated with cardiac
involvement
 Anderson-Fabry disease is the most common glycogen storage disorder, due to reduced or absent activity
of alpha-galactosidase A caused by mutations in the GLA gene
 Cardiac manifestations often present in the third decade in males and later in heterozygous females
 ECG abnormalities include a short PR interval, right bundle branch block, LV hypertrophy, and giant
negative T waves
 This disorder is not associated with diminished QRS voltage, as the abnormal deposition occurs in the
cardiomyocyte rather than the interstitium. LV wall thickness and mass increases as age and disease
severity progress.
 Tissue Doppler echocardiography shows a decrease in systolic and diastolic myocardial velocities, even
before the development of LVH.
 CMR often demonstrates midmyocardial late enhancement involving the basilar inferolateral wall with
sparing of the subendomyocardium, or a more diffuse pattern in patients with severe LVH.

34. Infiltrative Cardiomyopathies: Lysosomal
Storage Diseases
 Danon disease, a glycogen storage disorder, is a rare X-linked dominant disease due to primary
deficiency of LAMP2.
 Excess glycogen accumulates in cardiomyocytes and skeletal muscle fibers.
 Typically affected adolescent males present with the triad of heart failure, predominantly an HCM
phenotype, skeletal myopathy, and mental retardation.
 ECG findings demonstrate increased QRS voltage and deeply inverted T-wave abnormalities.
 Wolff-Parkinson-White syndrome occurs in both men and women.
 Echocardiographic features include LV hypertrophy (mimicking HCM) with extreme hypertrophy
noted in some cases (maximal wall thickness >60 mm).
 Clinical deterioration with rapidly progressive heart failure or sudden death before the age of 25
years is characteristic of the disease.
 Although there is no specific replacement therapy, catheter ablation can be effective in eliminating
supraventricular tachycardia in patients with Wolff-Parkinson-White syndrome. Cardiac
transplantation can also be considered in highly selected individuals.

35. Infiltrative CM – Cardiac Amyloidosis
 Cardiac amyloidosis is considered to be the prototype of the infiltrative form of RCM
 Despite the fact that cardiac amyloid types share common clinical manifestations and cardiac imaging
findings, the diseases are very different in clinical presentation, diagnostic strategy, and prognosis,
depending on the source and nature of the precursor protein.
 TrThere are two main types of amyloid that commonly affect the heart: immunoglobulin light chain
associated amyloid (AL, previously called “primary systemic amyloidosis) and transthyretin amyloid (ATTR).
 ATTR is further divided into a hereditary form due to a pathogenic transthyretin DNA mutation (ATTR-m)
and the “wild-type” (ATTR-wt) in which a mutation is not identified.
 There are other more rare forms of cardiac amyloid that can be identified with use of a proper diagnostic
strategy.
 Treatment of all types of amyloidosis is directed at the underlying precursor protein. The mainstay of
therapy is to stop production of the protein and to reduce the burden of amyloid infiltration.
 ATTR is generally much more slowly progressive than AL

36. Infiltrative CM – Cardiac Sarcoidosis
 Sarcoidosis is a multisystem, granulomatous disease of unknown etiology
 Non-caseating granulomas are the pathologic hallmark of the disease and are most
often associated with pulmonary and lymph node involvement; however, the heart is
also frequently involved
 Most disease (70%) occurs in patients between 25 and 60 years of age
 The clinical spectrum is highly varied and includes asymptomatic cardiac involvement,
atrial or ventricular arrhythmias including sudden cardiac death, varying degrees of
atrioventricular block, LV dysfunction (either restrictive [less common] or dilated [more
common] phenotype), or overt HF
 Cardiac MRI has proven extremely useful in the initial diagnosis and subsequent follow-
up of patients with cardiac sarcoidosis.
 While T2 imaging can identify myocardial edema associated with active inflammation, no
specific pattern of late gadolinium enhancement (LGE) has been shown to be diagnostic for
cardiac sarcoidosis; its distribution is usually patchy and multifocal with sparing of the
endocardium.
 Positron emission tomographic (PET) imaging with 18F-fluorodeoxyglucose has been
shown to correlate with histologic activity of sarcoidosis.
 Management of cardiac sarcoidosis involves both immunosuppressive therapy as well as
cardiac-specific treatments for ventricular dysfunction and heart rhythm abnormalities.