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REVIEW TOPIC OF THE WEEK

Constrictive Pericarditis VersusRestrictive Cardiomyopathy?

Mario J. Garcia, MD

ABSTRACT

Fro

rep

Ma

About one-half of the patients with congestive heart failure have preserved left ventricular ejection fraction (HFpEF).

Although the etiology of HFpEF is most commonly related to long-standing hypertension and atherosclerosis, a signif-

icant number of suspected HFpEF patients have a restrictive cardiomyopathy or chronic pericardial disease. Recognizing

these syndromes is important because early diagnosis may lead to instituting specific therapy that may prolong survival,

improve quality of life, and/or recognize and treat an underlying systemic disorder. Advances in diagnostic imaging,

biomarkers, and genetic testing today allow identification of the specific etiology in most cases. Novel pharmacological,

immunologic, and surgical therapies are leading to improved quality of life and survival.

(J Am Coll Cardiol 2016;67:2061–76) © 2016 by the American College of Cardiology Foundation.

A pproximately one-half of all patients withheart failure (HF) have preserved ejectionfraction (HFpEF) (1). Whereas hypertension,

coronary artery disease, and/or abnormal vascularcompliance are identified as the cause in most pa-tients with HFpEF (2), as many as 10% to 15% have arestrictive cardiomyopathy, a group of conditionswith diverse etiologies characterized by intrinsic ab-normalities of the myocyte and/or the intercellularmatrix that result in impaired left ventricular (LV)relaxation and/or increased LV stiffness (3). Thedifferential diagnosis of the restrictive cardiomyopa-thies includes constrictive pericarditis, a syndromethat has a similar insidious clinical presentation andshares many common features in diagnostic imagingtests (4). Patients with restrictive cardiomyopathiesand constrictive pericarditis are often excluded orunder-represented in large randomized clinical trials(2,5,6), making it difficult to make inferences fromthe prognostic and treatment features that apply toother HFpEF patients. Untreated, patients withrestrictive cardiomyopathies have, in general, pooroutcomes (7). However, early diagnosis can lead toimproved symptoms, prevent end-organ damage,

m the Division of Cardiology, Montefiore Medical Center–Albert Einstein C

orted that he has no relationships relevant to the contents of this paper

nuscript received November 24, 2015; revised manuscript received Janua

and improve survival. Table 1 summarizes generaland specific diagnostic features of these syndromes.

RESTRICTIVE CARDIOMYOPATHIES

The restrictive cardiomyopathies have been tradi-tionally classified as primary or secondary to otherdiseases, such as storage or infiltrative disorders (3).The definition of restrictive cardiomyopathies is onthe basis of anatomic, histological, and physiologicalcriteria, namely the presence of abnormal LV diastolicfilling associated with intracellular or interstitialinfiltration and/or fibrosis in the absence of LV dila-tion. Many infiltrative myocardial disorders (e.g.,hemochromatosis) may manifest as either restrictiveor dilated cardiomyopathy. Others, such as cardiacsarcoidosis, present almost exclusively with a dilatedphenotype, whereas some forms of hypertrophiccardiomyopathy present with a restrictive phenotype(8). This review is limited to only those conditionsthat may present with a restrictive phenotype.

COMMON FEATURES. Patients with restrictivecardiomyopathy typically exhibit HF symptoms,such as dyspnea and fatigue. Findings on physical

ollege of Medicine, Bronx, New York. Dr. Garcia has

to disclose.

ry 14, 2016, accepted January 28, 2016.

ABBR EV I A T I ON S

AND ACRONYMS

AL = amyloid light-chain

CMR = cardiac magnetic

resonance

CT = computed tomography

E = pulsed Doppler early left

ventricular filling velocity

e0 = tissue Doppler early

myocardial velocity

ECG = electrocardiographic/

electrocardiogram

EMF = endomyocardial fibrosis

HF = heart failure

HFpEF = heart failure with

preserved ejection fraction

LV = left ventricle/ventricular

LVH = left ventricular

hypertrophy

m-TTR = mutant transthyretin

RV = right ventricle/ventricular

SCD = sudden cardiac death

wt-TTR = wild-type

transthyretin

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examination include elevated jugular venouspressure, presence of a third or fourth heartsound, pulmonary rales, ascites, and periph-eral edema. Atrial fibrillation and electrocar-diographic (ECG) conduction abnormalitiesare common.

Patients with restrictive cardiomyopathieshave normal or increased LV wall thicknessand normal or reduced LV cavity size.Impaired LV relaxation may be detected byDoppler echocardiography before the onsetof symptoms. Decreased LV chambercompliance is often a late manifestation (9).The resulting steep increase in LV pressurewith small changes in LV volume causes achronic increase in diastolic filling pressuresthat leads to atrial enlargement. The CentralIllustration compares the morphological andhemodynamic features of normal, restrictive,and constrictive hearts.

Echocardiography and cardiac magneticresonance (CMR) imaging detect the typical,albeit nonspecific morphological alterationsthat characterize the restrictive cardiomyop-

athies. LV ejection fraction is usually preserved, butmay be decreased in advanced stages. Left and rightventricular (RV) wall thickness is normal or mildlyincreased in primary restrictive cardiomyopathy, butmore commonly increased in the secondary forms.Severe atrial enlargement is a classic, albeit nonspe-cific feature. Advanced impairment of LV diastolicfilling is invariably present. On echocardiographystudies, tissue Doppler typically demonstratesreduced early diastolic myocardial velocity (e0). LVfilling pulsed Doppler may show impaired relaxation(E/A ratio <1), pseudonormalization, or a restrictivefilling pattern (short E deceleration time), whichcorrelate with stage of progression, symptoms, andprognosis. B-type natriuretic peptide and amino-terminal pro–B-type natriuretic peptide are typicallyelevated in patients with HF secondary to restrictivecardiomyopathy. Table 2 summarizes general andspecific treatments for restrictive cardiomyopathies.

PRIMARY RESTRICTIVE CARDIOMYOPATHY. Pri-mary (idiopathic) restrictive cardiomyopathy is a rarecondition that may present in both children andadults (10,11). Increased myofilament sensitivity tocalcium, as well as increased accumulation of desminand collagen type III, has been implicated in thepathophysiology of this condition (12–15). Both fa-milial and sporadic cases have been described (16,17).Familial cases are usually characterized by autosomaldominant inheritance with incomplete penetrance.

Mutations in genes encoding the sarcomeric proteinstroponin I, troponin T, alpha cardiac actin, andbeta-myosin heavy chain, which are similar to thoseassociated with hypertrophic cardiomyopathy, areimplicated (18,19). Skeletal myopathy may also bepresent. Heart transplantation is an effective therapyfor patients with end-stage primary restrictive car-diomyopathy (20,21), but is contraindicated in thepresence of severe pulmonary hypertension, which iscommonly present in this condition.

SECONDARY RESTRICTIVE CARDIOMYOPATHIES.

Secondary restrictive cardiomyopathies are sub-classified as infiltrative, noninfiltrative, and storagedisorders. In infiltrative disorders, abnormal depositsoccur in the interstitial space, whereas in storagedisorders, deposits occur within the cell.Endomyocard ia l fibros i s (EMF) . EMF is probablythe most common cause of restrictive cardiomyopa-thy, affecting an estimated 12 million people world-wide (22). EMF is endemic in tropical and subtropicalAfrica, Asia, and South America, but is also occa-sionally encountered outside the tropics (23–25).Parasitic infections, autoimmune disorders, andhematologic malignancies lead to an initial, acuteinflammatory phase with fever and pancarditis,frequently associated with eosinophilia, facial andperiorbital swelling, and urticaria, also known asLoeffler endocarditis (26,27). This is followed by anintermediate phase associated with LV and RVthrombus formation. The final stage occurs months toyears later with endocardial fibrosis. Mitral andtricuspid regurgitation are common due to tetheringof the leaflets. Echocardiography may show endo-myocardial thickening, ventricular apical oblitera-tion, and involvement of the posterior mitral leaflet(28). CMR often provides additional diagnostic in-formation due to its ability to detect subendocardialfibrosis and its greater sensitivity for ventricularthrombus detection (Figure 1) (29,30).Card iac amylo idos i s . Cardiac amyloidosis is aninfiltrative disorder caused by deposition of insolublefibrillar protein in the interstitial space, which classi-cally displays as apple-green birefringence underpolarized light microscopy with Congo Red staining(31). It typically presents as a systemic disorder, withinfiltration also occurring in the liver, kidney, bowel,nerves, skin, and tongue. Five major clinical types ofcardiac amyloidosis are recognized, each associatedwith a different precursor protein. Primary or systemicamyloid light-chain (AL) amyloidosis is the mostcommon form of amyloidosis and is associated withmonoclonal gammopathy of undetermined signifi-cance or plasma cell dyscrasias, such as multiple

TABLE 1 Diagnostic Features of Restrictive Cardiomyopathies and Constrictive Pericarditis

Clinical Findings Biomarkers ECG X-Ray/CT Echo/Doppler CMR Biopsy

Primary RCM Skeletal myopathy Atrial enlargement Diffuse fibrosis*

EMF H/O parasitic infestation,hematologic malignancy,autoimmune disorder

Eosinophilia(early stage)†

Atrial enlargement Apical thrombus andtethering withpreserved contractility‡

Apical thrombus,endocardial lateenhancement‡

Endocardial fibrosis,eosinophilic infiltrates‡

Amyloidosis Macroglosia, periorbitalecchymosis, orthostatichypotension

Monoclonalgammopathy*

Low voltage Atrial enlargement Increased LV wall thickness,valvular and intra-atrialseptal thickening*

Diffuse subendocardialand atrial lateenhancement‡

Apple-green birefringencein Congo Red staining,immunohistochemical stainingusing specific antibodies‡

Drug-induced Use of chloroquine,hydroxylchloroquine

Conductionabnormalities

Atrial and/orventricularenlargement

Increased LV wallthickness, valvethickening*

Curvilinear bodies, lysosomes,myeloid bodies, andglycogen granules‡

Post-radiation RCM H/O mediastinal radiation Radiation lunginjury, valvularcalcification†

Valvularcalcification*

Diffuse fibrosis*

Hemochromatosis Hyperpigmentation,liver failure,diabetes mellitus

Elevatedferritin*

Low voltage,conductionabnormalities

Atrial enlargement Decreased myocardial signalon T2 weighted images,decreased T2*‡

Prussian blue stainingpositive for iron

Anderson-Fabry Reduceda-galactoside‡

Short PR interval,LVH pattern*

Atrial enlargement Increased wall thickness* Mid-myocardial lateenhancement

Concentric lamellar bodies onelectron microscopy‡

Danon/Pompe/PRKAG2

Skeletal myopathy* Elevated CPK* Ventricularpre-excitation

Atrial enlargement Increased wallthickness*

Friedreich’sataxia

Ataxia, diabetes‡ LVH Atrial enlargement Increased LV wallthickness, LVOTobstruction

Diffuse, patchy lateenhancement

Reduced cardiacfrataxin, Fe-reactiveinclusions in cardiomyocytes

Constrictivepericarditis

Pericardialcalcification†

Septal bounce, high e0,exaggeratedrespiratory flow variability‡

Pericardial thickening,ventricular interdependence,pericardial late enhancement‡

Pericardial fibrosis/inflammation,normal myocardium

*Highly sensitive findings with low specificity. †Highly specific findings with low sensitivity. ‡Findings that are both highly sensitive and specific.

CMR ¼ cardiac magnetic resonance; CPK ¼ creatine phosphokinase; CT ¼ computed tomography; e0 ¼ tissue Doppler early myocardial velocity; ECG ¼ electrocardiogram; Echo ¼ echocardiography; EMF ¼ endomyocardial fibrosis; H/O ¼ history of; LV ¼ leftventricle/ventricular; LVH ¼ left ventricular hypertrophy; LVOT ¼ left ventricular outflow tract; PRKAG2 ¼ protein kinase AMP-activated noncatalytic subunit gamma 2; RCM ¼ restrictive cardiomyopathy.

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Restriction

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CENTRAL ILLUSTRATION Comparison of Morphological and Hemodynamic Characteristics of Normal, Restrictive,and Constrictive Hearts

Garcia, M.J. J Am Coll Cardiol. 2016;67(17):2061–76.

Normal (A), restrictive (B), and constrictive (C) hearts. In both restriction and constriction, LV chamber compliance is reduced. LV relaxation, seen as the rate of

LV pressure decay in early diastole, is abnormal only in restriction. LA ¼ left atrial; LV ¼ left ventricular.

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TABLE 2 Treatment of the Restrictive Cardiomyopathies

Treatment

Idiopathic RCM Heart transplant

EMF Steroids, warfarin,endocardiectomy

Amyloidosis

Primary (AL) Bortezomib-based chemotherapy,stem cell transplant, ICD

Senile (wt-TTR) Supportive only

Secondary (AA) Treat underlying condition

Hereditary (m-TTR) Heart and/or liver transplant, ICD

Post-radiation RCM Supportive only

Hemochromatosis Phlebotomy, iron-chelating agents

Anderson-Fabry Agalsidase beta

Danon, Pompe,PRKAG2 deficiency

Supportive only

Friedreich’s ataxia Supportive, ICD

AA ¼ amyloid A; AL ¼ amyloid light-chain; ICD ¼ implantable cardioverter-defibrillator; m-TTR ¼ mutant transthyretin; wt-TTR ¼ wild-type transthyretin;other abbreviations as in Table 1.

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myeloma. Cardiac involvement is associated with apoor prognosis, with a median survival from diagnosisof 1 year (32).

Wild-type transthyretin (wt-TTR) amyloidosis(previously referred to as senile amyloidosis) is seen in25% to 36% of patients above 80 years of age (33,34)and is caused by the interstitial deposition of normal,wt-TTR. The prognosis is better than with primaryamyloidosis, with a median survival of 6 years (35).Cardiac involvement is rare in amyloid A amyloidosis,seen in chronic inflammatory conditions, such asrheumatoid arthritis (36). Mutant TTR amyloidosis

FIGURE 1 CMR Obtained in a Patient With HFpEF Secondary to EMF

On standard cine sequences (A), a large mass is seen in the basal poste

gadolinium contrast injection (B), a thin area of endocardial late enhance

avascular mass composed by thrombus and necrotic material. CMR ¼ ca

heart failure with preserved ejection fraction; LV ¼ left ventricle.

(m-TTR) is a systemic autosomal dominant disorderdue to tissue deposition of various proteins, includingTTR and apolipoproteins A-I and A-II (37), and isoften associated with peripheral or autonomic neu-ropathy. The most common mutation (Val122Ile)associatedwithm-TTR is present in 3% to 4%of AfricanAmericans, who often have the disease misdiagnosedas hypertensive cardiomyopathy (38). The clinicalpresentation of m-TTR varies according to the specificassociated mutation. As of today, more than 80 mu-tations have been described. Cardiac involvementleading to HF is common, but is less aggressive thanin AL amyloidosis. A comprehensive review of TTRamyloidosis was recently published in the Journal (39).

Cardiac amyloid deposition also occurs in isolatedatrial and dialysis-related (b2 microglobulin)amyloidosis. HF is uncommon, although isolatedatrial amyloidosis is associated with development ofatrial fibrillation (40). About 90% of patients withprimary amyloidosis have a monoclonal gammop-athy. Troponin may also be increased, and elevatedserum levels of troponin and B-type natriuretic pep-tide are associated with a worse prognosis (41).

An ECG finding of low voltage in a HFpEF patientwith increased LV wall thickness by echocardiogra-phy should raise the suspicion of cardiac amyloid-osis. However, low voltage and a pseudoinfarctpattern are detected in <50% of patients withbiopsy-proven cardiac involvement (42). Echocardi-ography commonly demonstrates increased thick-ening of the ventricular wall, mitral and tricuspidleaflets, and interatrial septum. Nevertheless, LV

rolateral wall of the LV, involving the mitral valve apparatus. After

ment is evident between the normal myocardium and the amorphous,

rdiac magnetic resonance; EMF ¼ endomyocardial fibrosis; HFpEF ¼

FIGURE 2 Echocardiographic Views Demonstrating Increased LV Wall Thickness, LA Enlargement, and Thickened Valves in a Patient

With AL Amyloidosis

Parasternal long-axis (A), short-axis (B), and 4-chamber (C) views. The CMR obtained in the same patient (D) shows diffuse subendocardial and

atrial late enhancement. AL ¼ amyloid light-chain; LA ¼ left atrial; LV ¼ left ventricular.

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wall thickness may be normal in 5% of patients withhistologically confirmed cardiac involvement (43).LV wall thickness ($15 mm) (44), restrictive filling onDoppler echocardiography with an early mitralinflow (E) deceleration time <150 ms (45), andreduced LV ejection fraction have been associatedwith poor prognosis. More recently, decreased globallongitudinal strain has also been shown to be astrong predictor of reduced survival (46,47). CMR isvery useful to establish the presence and determinethe severity of amyloid infiltration. Cardiacamyloidosis is associated with short subendocardialT1 times and a distinctive pattern of diffuse, pre-dominantly subendocardial and mid-myocardialdelayed gadolinium late enhancement (Figure 2)(48). The radiotracer 99mTc-pyrophosphate localizesto TTR cardiac amyloid deposits and can distinguishbetween the AL and TTR forms of the disease (49).Diagnosis of systemic amyloidosis may be attemptedwith rectal submucosal or abdominal fat pad biopsy.

Rectal biopsy has been largely replaced by abdominalfat aspiration, which carries a lower risk of seriouscomplications and appears more sensitive (84% to88%) for AL and wt-TTR types (50). However, thesensitivity is much lower for detecting m-TTR amy-loid. A positive noncardiac biopsy supports thediagnosis of cardiac amyloidosis if cardiac imagingdiagnostic criteria are present. Direct endomyo-cardial biopsy can achieve nearly 100% sensitivity ifa minimum of 4 samples are obtained during thebiopsy procedure (51). Immunohistochemical stain-ing using specific antibodies can discriminate be-tween the different types of amyloidosis (52). Massspectrometry is superior to immunohistochemistry inidentifying amyloid type, with sensitivity and spec-ificity more than 98% (53).

The primary goal of treatment in cardiac amyloid-osis remains relief of symptoms. Diuretic therapy re-lieves congestion, but needs to be monitored closelydue to the risk of hypotension and renal failure.

FIGURE 3 Echocardiographic Images Obtained From a Patient With Radiation Heart Disease Showing Calcification of the Aortic Valve and

Mitral Valve Anterior Leaflet

Parasternal long-axis 2-dimensional (A) and color Doppler (B) images.

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Digoxin and calcium channel blockers are contra-indicated due to the high risk of heart block (54,55).Beta-blockers and angiotensin-converting enzymeinhibitors are poorly tolerated. Chemotherapy andstem cell transplantation for AL amyloid may prolongsurvival and increase quality of life if started early.Stem cell transplantation has shown some promisefor treatment of primary amyloidosis. However,compared with other hematologic malignancies, theearly post-procedural mortality is significantly higherin patients with amyloidosis (56,57). Bortezomib-based regimens have shown near complete remis-sion of plasma cell dyscrasias and are now consideredto be the preferred treatment option (58). Clinicaltrials of several drugs that seek to reduce amyloidprotein production in m-TTR are currently inprogress (59). Recent data support the benefit ofimplantable cardioverter-defibrillators for primaryprevention of sudden cardiac death (SCD) (60).Cardiac transplantation may be effective in patientswith m-TTR amyloid if there is limited hepatic andnerve involvement. Liver and combined liver–cardiactransplantation may improve survival in thesepatients when there is significant liver involvement.Drug- induced restr i c t ive card iomyopathy . Drug-induced restrictive cardiomyopathy is a rare disorderthat has been described with the long-term use of theantimalarial medications chloroquine and hydroxy-chloroquine. Endomyocardial biopsy shows disrup-tion of normal muscle fiber architecture, with loss ofz-lines and myosin filaments, and abundant curvi-linear bodies, lysosomes, myeloid bodies, andglycogen granules located between myofibrilsand perinuclear areas (61). Conduction abnormalitiesand valvular thickening are common findings.

Echocardiography demonstrates increased wallthickening and restrictive LV filling that may improveafter cessation of therapy (62).Post- rad ia t ion heart d isease . Post-radiation heartdisease is a noninfiltrative disorder that occurs as aresult of endothelial cell damage and subsequentmicrovascular dysfunction due to fibrosis. In theventricular tissue of irradiated hearts, there is a sig-nificant increase in total tissue collagen concentra-tion (63), leading to decreased distensibility.Radiation affects all tissues, including the coronaryvessels, heart valves, and pericardium (Figure 3).Echocardiographic findings typically demonstratenormal LV wall thickness, abnormal LV filling,valvular calcification, and, in many patients, featuresof pericardial constriction (64).Glycogen storage disorders . Glycogen storagedisorders, including Anderson-Fabry disease, Pompedisease, Danon disease (lysosome-associated mem-brane protein 2 [LAMP2]), and protein kinase AMP-activated noncatalytic subunit gamma 2 (PRKAG2)-deficient cardiomyopathy, are systemic diseasesassociated with variable degrees of cardiac involve-ment. The ECG and echocardiographic features aresimilar to those seen in hypertrophic cardiomyopathy(65,66). Anderson-Fabry disease is the most commonglycogen storage disorder, affecting approximately 1in 50,000 people. It is an X-linked recessive disorderthat results in reduced or absent activity of a-galac-tosidase and progressive lysosomal accumulation ofglycosphingolipids in kidneys, nerves, and cardiactissue. The disease presents during childhood oradulthood with varying degrees of mental retarda-tion, proteinuria, and/or unexplained left ventricularhypertrophy (LVH) and HFpEF (67). Other glycogen

FIGURE 4 CMR T2-Weighted Images Obtained From a Normal Subject and a Patient With Hemochromatosis

(A) Normal subject. (B) Patient with hemochromatosis. Both the myocardium and liver (L) show decrease signal intensity (dark) compared with

the trapezius (T) skeletal muscle (grey). CMR ¼ cardiac magnetic resonance.

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storage disorders are also associated with skeletalmyopathy and elevation of skeletal muscle enzymes(65,66). ECG changes associated with Anderson-Fabrydisease include a short PR interval (<0.12 ms),widened QRS interval with right bundle branch blockpattern, LVH, and giant negative T waves (68,69).Ventricular pre-excitation and Wolff-Parkinson-White syndrome are common in patients withDanon disease and PRKAG2-deficient cardiomyopa-thy (65). In patients with Anderson-Fabry disease,tissue Doppler echocardiography shows a decrease insystolic and diastolic myocardial velocities, evenbefore development of LVH (70). CMR may show amid-myocardial pattern of late enhancement of thebasal inferolateral wall, or a more diffuse pattern inpatients with severe LVH (71). Anderson-Fabry dis-ease was also reported to be associated with a pro-longed myocardial T2 relaxation time (72).Nevertheless, none of these findings are sufficientlysensitive or specific. Demonstration of decreased orabsent levels of serum a-galactosidase is required toestablish the diagnosis. Endomyocardial biopsy re-veals concentric lamellar bodies in the sarcoplasm ofmyocardial cells on electron microscopy (73). Cardiacbiopsy in Danon disease and PRKAG2-deficient car-diomyopathy shows the characteristic histologicalchanges of myocyte enlargement with pronouncedvacuole formation within the cells (65,74). Enzymereplacement therapy with agalsidase beta in patientswith Fabry disease reduces globotriaosylceramidelevels in infiltrated tissues throughout the body (75).Enzyme replacement therapy with agalsidase beta

has been reported to decrease LV wall thickness,decrease LV mass, and result in improved LV systolicand diastolic function (76–79). The use of this drug isrestricted by its limited availability and elevated cost.Hemochromatos is . Hemochromatosis is a storagedisorder that results from increased iron depositionin the sarcoplasmic reticulum of cells in a variety oforgans, including the liver, pancreas, heart, and go-nads. Primary, or hereditary, hemochromatosis is arelatively common autosomal recessive disorder,affecting up to 0.8% of Caucasians, and results inincreased intestinal absorption of iron (80). Second-ary hemochromatosis results from receiving multipleblood transfusions in conditions where there is inef-fective erythropoiesis, such as thalassemia major,sideroblastic anemia, and myelodysplastic syndrome.Approximately 15% of patients with hemochromato-sis present with cardiac symptoms (81). Early in thecourse of the disease, iron overload may cause dia-stolic dysfunction, including restrictive physiology(82). Most patients with clinical HF, however, exhibit adilated cardiomyopathy phenotype. Cardiac involve-mentmay result in supraventricular arrhythmias, suchas atrial fibrillation (83). CMR has high accuracy in thediagnosis of myocardial iron overload. Myocardialiron deposition results in lower T2 times, withdecreased myocardial signals on T2-weighted images(Figure 4) (84). A T2* time <20 ms has been associatedwith reduced LV function (85). CMR is superior toserum ferritin levels for determination of the extent ofcardiac involvement. In addition, serial assessment ofT2* times may be used to evaluate the response to

FIGURE 5 Proposed Diagnostic Algorithm to Establish the Etiology of HFpEF

Suspected HFpEF

Yes1 Long-standing/poorly controlled HTN? No

Yes ECG: LVH pattern? No

Reduced α-galactosidase? Echo: Normal/High e’,increased respiratory

flow variability?*

No

No

Four limb ataxia?Monoclonal gammopathy,

MRI: global subendocardial LE?No

No

No

Skeletal myopathy?

Increased wall thickness?

Use of antimalarial drugs?

No

Echo/MRI: apicalthrombus, endocardial LE?

No

High ferritin levelsMRI: decrease signal in T2?

No

H/O mediastinal radiation,valve calcification?

Yes2

Yes3

Yes4

Yes5

Yes6

Yes7

Yes8

Yes9

Yes10

Yes11

No12

In most cases, additional histological criteria and genetic analysis are required to confirm the specific diagnosis: 1 ¼ hypertensive heart disease;

2 ¼ Anderson-Fabry; 3 ¼ Friedreich’s ataxia; 4 ¼ Danon/Pompe’s/PRKAG2 deficiency; 5 ¼ hypertrophic cardiomyopathy with restrictive

phenotype; 6¼ constrictive pericarditis; 7 ¼ amyloidosis; 8¼ drug-induced; 9 ¼ EMF; 10 ¼ hemochromatosis; 11¼ post-radiation; 12¼ primary

RCM. *Some patients with constrictive pericarditis do not meet respiratory flow variability criteria. ECG ¼ electrocardiogram; Echo ¼ echo-

cardiography; H/O ¼ history of; HTN ¼ hypertension; LE ¼ late enhancement; LV ¼ left ventricular; LVH ¼ left ventricular hypertrophy;

PRKAG2 ¼ protein kinase AMP-activated noncatalytic subunit gamma 2; other abbreviations as in Figure 1.

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therapy (86). Cardiac biopsy shows abnormal depositsof granular, yellow-gray material within the sarco-plasm of the myocytes under light microscopy andPrussian blue stains positive for iron, which is diag-nostic of iron overload (87). Phlebotomy is the first-line treatment for primary hemochromatosis. In pa-tients who are anemic, iron chelation therapy with

either deferoxamine, deferasirox, or deferiprone isthe treatment of choice. Cardiac transplantationin patients who have advanced HF refractory tomedical therapy has been reported to achieve a10-year survival of 40% (88).Fr iedre ich ’s atax ia . Friedreich’s ataxia is an auto-somal recessive neurodegenerative disorder caused

FIGURE 6 Illustration of the Effects of Changes in Intrathoracic and Intracardiac

Pressures During Respiration in Normal Versus Constrictive Heart

0

0

0

0

0 0 0

00

0

04

10

APNEA

INSPIRATION

0

5-5-5

-5

-5

-5

-5

-5

-5-5

-5

-5

5

5

5

5

5

5 55

5

5

55

EXPIRATION

Normal Constriction

Normal Constriction

Normal Constriction

4

15 15

8

4

4

10

The diminished venous return to the left heart during inspiration results in a septal shift to

the left, with the opposite effect during expiration.

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by a mutation of the frataxin gene that manifests inthe second to third decade of life with diabetes mel-litus, ataxia, and HF (89). The disease is almostexclusively seen in Caucasians, with an estimatedprevalence of 1 in 50,000. Ventricular arrhythmias andSCD are common. Early in the course of the disease,ECG and echocardiographic findings resemble those of

hypertrophic cardiomyopathy, including symmetricLV hypertrophy, abnormal myocardial relaxation, andLV outflow obstruction (90). CMR shows nonspecificpatchy late enhancement, which correlates with theextent of cardiac fibrosis. Over time, the restrictivephenotype evolves into a dilated phenotype.Myocardial biopsy shows enlarged cardiomyocyteswith iron-reactive inclusions surrounded by in-creased interstitial fibrosis and reduced frataxin (91).There is no specific treatment for this conditionother than standard HF drugs. Implantablecardioverter-defibrillators are used for prevention ofSCD, but a survival benefit has not been demon-strated. A proposed algorithm to identify the prob-able etiology of HFpEF is shown in Figure 5.

CONSTRICTIVE PERICARDITIS. This syndrome oftenpresents as long-term sequela of acute and chronicpericarditis and post-pericardiotomy, although anidentifiable cause is not found in a significant pro-portion of cases (92). Tuberculous pericarditis isrelatively common in Africa and in Latin Americancountries. The clinical presentation of constrictivepericarditis may be acute, subacute, or chronicand insidious, with typical symptoms of exertionaldyspnea, fatigue, lower extremity edema, or abdom-inal distension (4), or with atypical presentationmasquerading as primary liver disease. Physicalfindings may vary, including manifestations of pre-dominantly right HF with elevated jugular venousdistension and a prominent “x” and rapid “y” descent,hepatomegaly and splenomegaly, ascites, and edema(93). Kussmaul’s sign, described as a failure todecrease or a paradoxical increase in jugular venouspressure during inspiration, is relatively specific whenpresent. Heart sounds may be reduced. When present,a pericardial knock occurring at the trough of the ydescent in early diastole is often confused with an S3(94). Bibasilar rales and dullness more commonlyrepresent pleural effusions than lung edema, becauseright HF is predominant. Pulsus paradoxus is rare andusually indicates effusive–constrictive disease.

The ECG is more often normal, but may show lowQRS voltage, nonspecific ST-segment changes, bia-trial enlargement, sinus tachycardia, or atrial fibril-lation. B-type natriuretic peptide and N-terminal pro–B-type natriuretic peptide levels are normal or mildlyelevated (95). Chest x-ray in patients with constric-tive pericarditis may show pleural effusions withoutsignificant alveolar edema and biatrial enlargement.LV and RV and pulmonary vessels are normal in size.Pericardial calcifications are rare, occurring in 20% to40% of constrictive cases and, more commonly, intuberculous pericarditis (96,97).

FIGURE 7 Pulsed Doppler Recordings of LV Inflow and Tissue Doppler Myocardial Velocities of the Basal Lateral Wall in RCM and

Constrictive Pericarditis

LV inflow (A and B) and tissue Doppler myocardial velocities of the basal lateral wall (C and D) obtained from a patient with RCM (A and C) and a patient

with constrictive pericarditis (B and D). In constriction, there is significant respiratory variability and exaggerated early diastolic myocardial velocities (e0).

LV ¼ left ventricular; RCM ¼ restrictive cardiomyopathy.

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Sodium restriction and diuretic agents are useful toreduce edema and hepatic congestion in patients withmild pericardial constriction (98), although peri-cardiectomy may eventually be required to normalizecardiac output (92,99–102). Pericardiectomy can beperformed with low mortality and result in significantimprovement in survival and quality of life. Failure toimprove or recurrence of symptoms is often due toincomplete pericardiectomy, thus warranting referralto experienced cardiac surgeons. Long-term out-comes depend on the etiology, with worse outcomesseen in patients post-irradiation because they oftenhave concomitant myocardial, coronary, and valvularinjury. Transient constrictive pericarditis due topost-pericardiotomy syndrome, tuberculous, or viralpericarditis may respond to anti-inflammatory ther-apy (103). A recent study reported that response toanti-inflammatory therapy is more likely to occur inpatients with evidence of significant pericardiallate enhancement and increased C-reactive protein

and erythrosedimentation rate (104). The relativeutility of contrast CMR or positron emission tomo-graphy with 18F-fluorodeoxyglucose versus serumbiomarkers of inflammation in guiding therapy,however, remains to be determined.

It is important to recognize the less commoneffusive–constrictive pericarditis syndrome. About10% of patients who are initially recognized as havingcardiac tamponade present with signs and symptomsof constriction following pericardiocentesis (105).The causes of effusive–constrictive pericarditis aresimilar to those of typical constriction, althoughpatients with this syndrome may have a more acutepresentation and are more likely to respond to anti-inflammatory therapy.

DIFFERENTIATING CONSTRICTION

FROM RESTRICTION

Even though the clinical presentation of constrictivepericarditis and restrictive cardiomyopathies is

FIGURE 8 CMR Real-Time, Low-Resolution Images Obtained at End-Diastole in a Patient With Constrictive Pericarditis

Images obtained during expiration (A and C) and during inspiration (B and D), demonstrating the changes in LV and RV volumes due to

exaggerated ventricular interdependence. RV ¼ right ventricular; other abbreviations as in Figure 1.

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similar, their pathophysiological and hemodynamicalterations differ. Both conditions may have reducedLV chamber compliance. In restrictive cardiomyopa-thy, reduced compliance is caused by abnormalelastic properties of the myocardium and/or inter-cellular matrix, whereas in constrictive pericarditis,reduced chamber compliance is imposed by theexternal pericardial constraint. Myocardial relaxationis impaired in restrictive cardiomyopathies, but istypically normal in constrictive pericarditis (106–108).As a result of pericardial encasement, patients withconstrictive pericarditis exhibit exaggerated inter-ventricular dependence and dissociation betweenintracardiac and intrathoracic pressures during respi-ration (Figure 6). Echocardiography, CMR, and/orinvasive catheterization can assess these pathophysi-ological changes (109,110). With inspiration, lowerintrathoracic pressure is transmitted to the pulmonaryveins, but not to the encased left atrium, thereforereducing the pressure gradient and venous return to

the left heart. As the intracardiac volume is fixed by theencased pericardium, venous return increases to theright heart through the inferior vena cava because thisvessel enters the right atrium directly from theabdomen and is not exposed to the intrathoracicpressure changes. Decreased venous return from thesuperior vena cava, which is exposed, is the hemody-namic alteration that produces Kussmaul’s sign (111).

Echocardiography may detect the presence of athickened (>4mm) pericardium, but is less useful thancomputed tomography (CT) and CMR to define thepericardial anatomy. Moreover, up to 20% ofconstrictive pericarditis cases occur with normal peri-cardial wall thickness (112). Doppler echocardiographyis very useful for evaluating the altered physiology.The presence of atrial dilation with normal ventricularchambers and a dilated inferior vena cava and hepaticveins, although nonspecific, support the diagnosis ofconstrictive pericarditis. The most specific sign ofconstrictive pericarditis by 2-dimensional imaging is

FIGURE 9 CMR Images Demonstrating Late Enhancement of the Pericardium in a Patient With Constriction

(A) Short axis and (B) 4-chamber views. CMR ¼ cardiac magnetic resonance.

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shifting of the septum during the respiratory cycle,caused by the variability in venous return and exag-gerated interventricular dependence (113). TheDoppler examination, utilizing mitral and tricuspidinflow, hepatic vein flow, and tissue Doppler arefundamental (Figure 7) (110,114–116). In both constric-tive pericarditis and in advanced restrictive cardio-myopathy, the deceleration time of the LV early fillingpulsed Doppler is short, consistent with a restrictivefilling pattern. However, significant respiratory varia-tion of mitral, tricuspid, pulmonary, and hepatic flowsoccurs only with constriction. The magnitude of theirvariability will depend, however, on the severity ofconstriction, the volume status of the patient, and theinspiratory effort during the study acquisition. Anormal tissue Doppler e0 velocity (>8 cm/s) indicatesnormal LV relaxation and virtually excludes restrictivecardiomyopathy (106,108). In constrictive pericarditis,e0 is invariably increased and, unlike normal subjects,patients with constriction have septal >lateral wall e0

(117). Invasive hemodynamic evaluation of patientswith suspected constrictive pericarditis and incon-clusive noninvasive test results may be required in asmall proportion of patients. Criteria for the diagnosisof constriction and differentiation from restrictioninclude equalization of diastolic RV and LV pressure,and absence of elevated RV systolic pressure (118). Inaddition, during respiration, changes in LV and RVsystolic pressure are discordant. Contrast-enhancedcardiac CT can identify pericardial thickening with orwithout calcifications in the appropriate clinical

scenario. Cardiac CT is also a useful tool for definingthe location and extent of the focal thickening andpericardial calcification in the pre-surgical planningstages. ECG-gated cine images can demonstrate aseptal bounce (119,120), although unlike echocardiog-raphy and CMR, cardiac CT is acquired over 1 to 4cardiac cycles and cannot be used to evaluaterespiratory-induced changes. In contrast to CT, evensignificant foci of calcification can be missed on CMR.However, CMR has superior ability to evaluate peri-cardial distensibility (119). Real-time low-resolutioncine sequences during free breathing can demonstrateventricular interdependence (Figure 8) (121). Pericar-dial late enhancement may be seen in the presence ofinflammation or extensive fibrosis (Figure 9).

Despite clinical, noninvasive, and hemodynamicassessment, the differentiation of restrictive cardio-myopathy from constrictive pericarditis remainsdifficult in a small subset of patients that present withmixed constrictive/restrictive physiology. This con-dition is more frequently encountered in patientswith radiation heart disease. Endomyocardial biopsymay be useful to avoid unnecessary thoracotomy inpatients with significant myocardial involvementwho may not respond to pericardiectomy (122).

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Mario J. Garcia, Division of Cardiology, MontefioreEinstein Center for Heart and Vascular Care, 111 East210th Street, Bronx, New York 10467. E-mail:mariogar@montefiore.org.

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RE F E RENCE S

1. Owan TE, Hodge DO, Herges RM, et al. Trends inprevalence and outcome of heart failure withpreserved ejection fraction. N Engl J Med 2006;355:251–9.

2. Massie BM, Carson PE, McMurray JJ, et al.,I-PRESERVE Investigators. Irbesartan in patientswith heart failure and preserved ejection fraction.N Engl J Med 2008;359:2456–67.

3. Richardson P, McKenna W, Bristow M, et al.Report of the 1995 World Health Organization/International Society and Federation of CardiologyTask Force on the Definition and Classification ofCardiomyopathies. Circulation 1996;93:841–2.

4. Myers RB, Spodick DH. Constrictive pericarditis:clinical and pathophysiologic characteristics. AmHeart J 1999;138:219–32.

5. Pitt B, Pfeffer MA, Assmann SF, et al., TOPCATInvestigators. Spironolactone for heart failure withpreserved ejection fraction. N Engl J Med 2014;370:1383–92.

6. Yusuf S, Pfeffer MA, Swedberg K, et al., CHARMInvestigators and Committees. Effects of cande-sartan in patients with chronic heart failure andpreserved left-ventricular ejection fraction: theCHARM-Preserved trial. Lancet 2003;362:777–81.

7. Ammash NM, Seward JB, Bailey KR, et al. Clin-ical profile and outcome of idiopathic restrictivecardiomyopathy. Circulation 2000;101:2490–6.

8. Kubo T, Gimeno JR, Bahl A, et al. Prevalence,clinical significance, and genetic basis of hyper-trophic cardiomyopathy with restrictive pheno-type. J Am Coll Cardiol 2007;49:2419–26.

9. Abelmann WH, Lorell BH. The challenge ofcardiomyopathy. J Am Coll Cardiol 1989;13:1219–39.

10. Cetta F, O’Leary PW, Seward JB, et al. Idio-pathic restrictive cardiomyopathy in childhood:diagnostic features and clinical course. Mayo ClinProc 1995;70:634–40.

11. Siegel RJ, Shah PK, Fishbein MC. Idiopathicrestrictive cardiomyopathy. Circulation 1984;70:165–9.

12. Zhang J, Kumar A, Stalker HJ, et al. Clinical andmolecular studies of a large family with desmin-associated restrictive cardiomyopathy. Clin Genet2001;59:248–56.

13. Hayashi T, Shimomura H, Terasaki F, et al.Collagen subtypes and matrix metalloproteinase inidiopathic restrictive cardiomyopathy. Int J Cardiol1998;64:109–16.

14. Davis J, Wen H, Edwards T, et al. Allele andspecies dependent contractile defects by restric-tive and hypertrophic cardiomyopathy-linkedtroponin I mutants. J Mol Cell Cardiol 2008;44:891–904.

15. Yumoto F, Lu QW, Morimoto S, et al. DrasticCa2þ sensitization of myofilament associated witha small structural change in troponin I in inheritedrestrictive cardiomyopathy. Biochem Biophys ResCommun 2005;338:1519–26.

16. Angelini A, Calzolari V, Thiene G, et al.Morphologic spectrum of primary restrictive car-diomyopathy. Am J Cardiol 1997;80:1046–50.

17. Katritsis D, Wilmshurst PT, Wendon JA, et al.Primary restrictive cardiomyopathy: clinical andpathologic characteristics. J Am Coll Cardiol 1991;18:1230–5.

18. Ware SM, Quinn ME, Ballard ET, et al. Pediatricrestrictive cardiomyopathy associated with amutation in beta-myosin heavy chain. Clin Genet2008;73:165–70.

19. Kaski JP, Syrris P, Burch M, et al. Idiopathicrestrictive cardiomyopathy in children is caused bymutations in cardiac sarcomere protein genes.Heart 2008;94:1478–84.

20. Bograd AJ, Mital S, Schwarzenberger JC, et al.Twenty-year experience with heart trans-plantation for infants and children with restrictivecardiomyopathy: 1986-2006. Am J Transplant2008;8:201–7.

21. Weller RJ, Weintraub R, Addonizio LJ, et al.Outcome of idiopathic restrictive cardiomyopathyin children. Am J Cardiol 2002;90:501–6.

22. Yacoub S, Kotit S, Mocumbi AO, et al.Neglected diseases in cardiology: a call for urgentaction. Nat Clin Pract Cardiovasc Med 2008;5:176–7.

23. Chew CY, Ziady GM, Raphael MJ, et al. Primaryrestrictive cardiomyopathy. Non-tropical endo-myocardial fibrosis and hypereosinophilic heartdisease. Br Heart J 1977;39:399–413.

24. Hassan WM, Fawzy ME, Al Helaly S, et al.Pitfalls in diagnosis and clinical, echocardio-graphic, and hemodynamic findings in endomyo-cardial fibrosis: a 25-year experience. Chest 2005;128:3985–92.

25. Schneider U, Jenni R, Turina J, et al. Long-termfollow up of patients with endomyocardialfibrosis: effects of surgery. Heart 1998;79:362–7.

26. Löffler W. Endocarditis parietalis fibroplasticamit Bluteosinophilic: ein eigenartiges Krank-heitsbild. Schweiz Med Wochenschr 1936;66:817–20.

27. Mocumbi AO, Yacoub S, Yacoub MH. Neglec-ted tropical cardiomyopathies: II. Endomyocardialfibrosis: myocardial disease. Heart 2008;94:384–90.

28. Ommen SR, Seward JB, Tajik AJ. Clinical andechocardiographic features of hypereosinophilicsyndromes. Am J Cardiol 2000;86:110–3.

29. Srichai MB, Junor C, Rodriguez LL, et al. Clin-ical, imaging, and pathological characteristics ofleft ventricular thrombus: a comparison ofcontrast-enhanced magnetic resonance imaging,transthoracic echocardiography, and trans-esophageal echocardiography with surgical orpathological validation. Am Heart J 2006;152:75–84.

30. Syed IS, Martinez MW, Feng DL, et al. Cardiacmagnetic resonance imaging of eosinophilicendomyocardial disease. Int J Cardiol 2008;126:e50–2.

31. Selvanayagam JB, Hawkins PN, Paul B, et al.Evaluation and management of the cardiacamyloidosis. J Am Coll Cardiol 2007;50:2101–10.

32. Dubrey SW, Cha K, Anderson J, et al. Theclinical features of immunoglobulin light-chain(AL) amyloidosis with heart involvement. QJM1998;91:141–57.

33. Cornwell GG III, Murdoch WL, Kyle RA,Westermark P, Pitkänen P. Frequency and distri-bution of senile cardiovascular amyloid. A clini-copathologic correlation. Am J Med 1983;75:618–23.

34. Tanskanen M, Kiuru-Enari S, Tienari P, et al.Senile systemic amyloidosis, cerebral amyloidangiopathy, and dementia in a very old Finnishpopulation. Amyloid 2006;13:164–9.

35. Ng B, Connors LH, Davidoff R, et al. Senilesystemic amyloidosis presenting with heart failure:a comparison with light chain-associatedamyloidosis. Arch Intern Med 2005;165:1425–9.

36. Dubrey SW, Cha K, Simms RW, et al. Electro-cardiography and Doppler echocardiography insecondary (AA) amyloidosis. Am J Cardiol 1996;77:313–5.

37. Saraiva MJ. Sporadic cases of hereditary sys-temic amyloidosis. N Engl J Med 2002;346:1818–9.

38. Jacobson DR, Pastore RD, Yaghoubian R, et al.Variant-sequence transthyretin (isoleucine 122) inlate-onset cardiac amyloidosis in black Americans.N Engl J Med 1997;336:466–73.

39. Gertz MA, Benson MD, Dyck PJ, et al. Diag-nosis, prognosis, and therapy of transthyretinamyloidosis. J Am Coll Cardiol 2015;66:2451–66.

40. Röcken C, Peters B, Juenemann G, et al. Atrialamyloidosis: an arrhythmogenic substrate forpersistent atrial fibrillation. Circulation 2002;106:2091–7.

41. Dispenzieri A, Gertz MA, Kyle RA, et al. Serumcardiac troponins and N-terminal pro-brain natri-uretic peptide: a staging system for primary sys-temic amyloidosis. J Clin Oncol 2004;22:3751–7.

42. Murtagh B, Hammill SC, Gertz MA, et al.Electrocardiographic findings in primary systemicamyloidosis and biopsy-proven cardiac involve-ment. Am J Cardiol 2005;95:535–7.

43. Gertz MA, Grogan M, Kyle RA, et al. Endo-myocardial biopsy-proven light chain amyloidosis(AL) without echocardiographic features of infil-trative cardiomyopathy. Am J Cardiol 1997;80:93–5.

44. Cueto-Garcia L, Reeder GS, Kyle RA, et al.Echocardiographic findings in systemic amyloid-osis: spectrum of cardiac involvement and relationto survival. J Am Coll Cardiol 1985;6:737–43.

45. Klein AL, Hatle LK, Taliercio CP, et al. Prog-nostic significance of Doppler measures of dia-stolic function in cardiac amyloidosis. A Dopplerechocardiography study. Circulation 1991;83:808–16.

46. Buss SJ, Emami M, Mereles D, et al. Longitu-dinal left ventricular function for prediction ofsurvival in systemic light-chain amyloidosis: in-cremental value compared with clinical andbiochemical markers. J Am Coll Cardiol 2012;60:1067–76.

J A C C V O L . 6 7 , N O . 1 7 , 2 0 1 6 GarciaM A Y 3 , 2 0 1 6 : 2 0 6 1 – 7 6 Constriction Versus Restriction

2075

47. Quarta CC, Solomon SD, Uraizee I, et al. Leftventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis.Circulation 2014;129:1840–9.

48. Maceira AM, Joshi J, Prasad SK, et al. Cardio-vascular magnetic resonance in cardiac amyloid-osis. Circulation 2005;111:186–93.

49. Bokhari S, Castaño A, Pozniakoff T, et al.99mTc-pyrophosphate scintigraphy for differenti-ating light-chain cardiac amyloidosis from thetransthyretin-related familial and senile cardiacamyloidoses. Circ Cardiovasc Imaging 2013;6:195–201.

50. Shah KB, Inoue Y, Mehra MR. Amyloidosis andthe heart: a comprehensive review. Arch InternMed 2006;166:1805–13.

51. Pellikka PA, Holmes DR Jr., Edwards WD, et al.Endomyocardial biopsy in 30 patients with primaryamyloidosis and suspected cardiac involvement.Arch Intern Med 1988;148:662–6.

52. Kebbel A, Röcken C. Immunohistochemicalclassification of amyloid in surgical pathologyrevisited. Am J Surg Pathol 2006;30:673–83.

53. Vrana JA, Gamez JD, Madden BJ, et al. Clas-sification of amyloidosis by laser microdissectionand mass spectrometry-based proteomic analysisin clinical biopsy specimens. Blood 2009;114:4957–9.

54. Gertz MA, Falk RH, Skinner M, et al. Worseningof congestive heart failure in amyloid heart dis-ease treated by calcium channel-blocking agents.Am J Cardiol 1985;55:1645.

55. Griffiths BE, Hughes P, Dowdle R, et al. Cardiacamyloidosis with asymmetrical septal hypertrophyand deterioration after nifedipine. Thorax 1982;37:711–2.

56. Moreau P, Leblond V, Bourquelot P, et al.Prognostic factors for survival and response afterhigh-dose therapy and autologous stem celltransplantation in systemic AL amyloidosis: areport on 21 patients. Br J Haematol 1998;101:766–9.

57. Comenzo RL, Vosburgh E, Simms RW, et al.Dose-intensive melphalan with blood stem cellsupport for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood 1996;88:2801–6.

58. Mikhael JR, Schuster SR, Jimenez-Zepeda VH,et al. Cyclophosphamide-bortezomib-dexametha-sone (CyBorD) produces rapid and complete he-matologic response in patients with ALamyloidosis. Blood 2012;119:4391–4.

59. Ackermann EJ, Guo S, Booten S, et al. Clinicaldevelopment of an antisense therapy for thetreatment of transthyretin-associated poly-neuropathy. Amyloid 2012;19 Suppl 1:43–4.

60. Varr BC, Zarafshar S, Coakley T, et al.Implantable cardioverter-defibrillator placementin patients with cardiac amyloidosis. Heart Rhythm2014;11:158–62.

61. Iglesias Cubero G, Rodriguez Reguero JJ, RojoOrtega JM. Restrictive cardiomyopathy caused bychloroquine. Brit Heart J 1993;69:451–2.

62. Cotroneo J, Sleik KM, Rene Rodriguez E, et al.Hydroxychloroquine-induced restrictive cardio-myopathy. Eur J Echocardiogr 2007;8:247–51.

63. Chello M, Mastroroberto P, Romano R, et al.Changes in the proportion of types I and IIIcollagen in the left ventricular wall of patientswith post-irradiative pericarditis. Cardiovasc Surg1996;4:222–6.

64. Adams MJ, Lipsitz SR, Colan SD, et al. Car-diovascular status in long-term survivors ofHodgkin’s disease treated with chest radiotherapy.J Clin Oncol 2004;22:3139–48.

65. Arad M, Maron BJ, Gorham JM, et al. Glycogenstorage diseases presenting as hypertrophic car-diomyopathy. N Engl J Med 2005;352:362–72.

66. Sachdev B, Takenaka T, Teraguchi H, et al.Prevalence of Anderson-Fabry disease in malepatients with late onset hypertrophic cardiomy-opathy. Circulation 2002;105:1407–11.

67. Linhart A, Kampmann C, Zamorano JL, et al.Cardiac manifestations of Anderson-Fabry disease:results from the international Fabry outcomesurvey. Eur Heart J 2007;28:1228–35.

68. Yokoyama A, Yamazoe M, Shibata A. A case ofheterozygous Fabry’s disease with a short PR in-terval and giant negative T waves. Br Heart J 1987;57:296–9.

69. Roudebush CP, Foerster JM, Bing OH. Theabbreviated PR interval of Fabry’s disease. N EnglJ Med 1973;289:357–8.

70. Pieroni M, Chimenti C, Ricci R, et al. Earlydetection of Fabry cardiomyopathy by tissueDoppler imaging. Circulation 2003;107:1978–84.

71. Moon JC, Sachdev B, Elkington AG, et al.Gadolinium enhanced cardiovascular magneticresonance in Anderson-Fabry disease. Evidence fora disease specific abnormality of the myocardialinterstitium. Eur Heart J 2003;24:2151–5.

72. Imbriaco M, Spinelli L, Cuocolo A, et al. MRIcharacterization of myocardial tissue in patientswith Fabry’s disease. AJR Am J Roentgenol 2007;188:850–3.

73. Desnick RJ, Brady R, Barranger J, et al. Fabrydisease, an under-recognized multisystemic dis-order: expert recommendations for diagnosis,management, and enzyme replacement therapy.Ann Intern Med 2003;138:338–46.

74. Arad M, Benson DW, Perez-Atayde AR, et al.Constitutively active AMP kinase mutations causeglycogen storage disease mimicking hypertrophiccardiomyopathy. J Clin Invest 2002;109:357–62.

75. Eng CM, Guffon N, Wilcox WR, et al., Inter-national Collaborative Fabry Disease Study Group.Safety and efficacy of recombinant human alpha-galactosidase A—replacement therapy in Fabry’sdisease. N Engl J Med 2001;345:9–16.

76. Hughes DA, Elliott PM, Shah J, et al. Effects ofenzyme replacement therapy on the cardiomyop-athy of Anderson-Fabry disease: a randomised,double-blind, placebo-controlled clinical trial ofagalsidase alfa. Heart 2008;94:153–8.

77. Beck M, Ricci R, Widmer U, et al. Fabry disease:overall effects of agalsidase alfa treatment. Eur JClin Invest 2004;34:838–44.

78. Spinelli L, Pisani A, Sabbatini M, et al. Enzymereplacement therapy with agalsidase beta im-proves cardiac involvement in Fabry’s disease. ClinGenet 2004;66:158–65.

79. Weidemann F, Breunig F, Beer M, et al.Improvement of cardiac function during enzymereplacement therapy in patients with Fabry dis-ease: a prospective strain rate imaging study.Circulation 2003;108:1299–301.

80. McCarthy GM, Crowe J, McCarthy CJ, et al.Hereditary hemochromatosis: a common, oftenunrecognized, genetic disease. Cleve Clin J Med2002;69:224–6, 229–30, 232–3 passim.

81. Cecchetti G, Binda A, Piperno A, et al. Cardiacalterations in 36 consecutive patients with idio-pathic haemochromatosis: polygraphic and echo-cardiographic evaluation. Eur Heart J 1991;12:224–30.

82. Palka P, Macdonald G, Lange A, et al. The roleof Doppler left ventricular filling indexes andDoppler tissue echocardiography in the assess-ment of cardiac involvement in hereditary hemo-chromatosis. J Am Soc Echocardiogr 2002;15:884–90.

83. Case records of the Massachusetts GeneralHospital. Weekly clinicopathological exercises.Case 31-1994. A 25-year-old man with the recentonset of diabetes mellitus and congestive heartfailure. N Engl J Med 1994;331:460–6.

84. Mavrogeni SI, Markussis V, Kaklamanis L, et al.A comparison of magnetic resonance imaging andcardiac biopsy in the evaluation of heart ironoverload in patients with b-thalassemia major. EurJ Haematol 2005;75:241–7.

85. Anderson LJ, Holden S, Davis B, et al. Car-diovascular T2-star (T2*) magnetic resonance forthe early diagnosis of myocardial iron overload.Eur Heart J 2001;22:2171–9.

86. Tanner MA, Galanello R, Dessi C, et al.A randomized, placebo-controlled, double-blindtrial of the effect of combined therapy withdeferoxamine and deferiprone on myocardial ironin thalassemia major using cardiovascular mag-netic resonance. Circulation 2007;115:1876–84.

87. Olson LJ, Edwards WD, Holmes DR Jr., et al.Endomyocardial biopsy in hemochromatosis: clin-icopathologic correlates in six cases. J Am CollCardiol 1989;13:116–20.

88. Caines AE, Kpodonu J, Massad MG, et al.Cardiac transplantation in patients with ironoverload cardiomyopathy. J Heart Lung Transplant2005;24:486–8.

89. Durr A, Cossee M, Agid Y, et al. Clinical andgenetic abnormalities in patients with Friedreich’sataxia. N Engl J Med 1996;335:1169–75.

90. Dutka DP, Donnelly JE, Nihoyannopoulos P,et al. Marked variation in the cardiomyopathyassociated with Friedreich’s ataxia. Heart 1999;81:141–7.

91. Koeppen AH, Ramirez RL, Becker AB, et al. Thepathogenesis of cardiomyopathy in Friedreichataxia. PLoS One 2015;10:e0116396.

92. Bertog SC, Thambidorai SK, Parakh K, et al.Constrictive pericarditis: etiology and cause-specific survival after pericardiectomy. J Am CollCardiol 2004;43:1445–52.

93. Manga P, Vythilingum S, Mitha AS. Pulsatilehepatomegaly in constrictive pericarditis. Br HeartJ 1984;52:465–7.

Garcia J A C C V O L . 6 7 , N O . 1 7 , 2 0 1 6

Constriction Versus Restriction M A Y 3 , 2 0 1 6 : 2 0 6 1 – 7 6

2076

94. Nicholson WJ, Cobbs BW Jr., Franch RH, et al.Early diastolic sound of constrictive pericarditis.Am J Cardiol 1980;45:378–82.

95. Leya FS, Arab D, Joyal D, et al. The efficacy ofbrain natriuretic peptide levels in differentiatingconstrictive pericarditis from restrictive cardio-myopathy. J Am Coll Cardiol 2005;45:1900–2.

96. Suh SY, Rha SW, Kim JW, et al. The usefulnessof three-dimensional multidetector computed to-mography to delineate pericardial calcification inconstrictive pericarditis. Int J Cardiol 2006;113:414–6.

97. Chen SJ, Li YW, Wu MH, et al. CT and MRIfindings in a child with constrictive pericarditis.Pediatr Cardiol 1998;19:259–62.

98. Anand IS, Ferrari R, Kalra GS, et al. Patho-genesis of edema in constrictive pericarditis.Studies of body water and sodium, renal function,hemodynamics, and plasma hormones before andafter pericardiectomy. Circulation 1991;83:1880–7.

99. Senni M, Redfield MM, Ling LH, et al. Leftventricular systolic and diastolic function afterpericardiectomy in patients with constrictivepericarditis: Doppler echocardiographic findingsand correlation with clinical status. J Am CollCardiol 1999;33:1182–8.

100. Ling LH, Oh JK, Schaff HV, et al. Constrictivepericarditis in the modern era: evolving clinicalspectrum and impact on outcome after peri-cardiectomy. Circulation 1999;100:1380–6.

101. Uchida T, Bando K, Minatoya K, et al. Peri-cardiectomy for constrictive pericarditis using theharmonic scalpel. Ann Thorac Surg 2001;72:924–5.

102. DeValeria PA, Baumgartner WA, Casale AS,et al. Current indications, risks, and outcome afterpericardiectomy. Ann Thorac Surg 1991;52:219–24.

103. Haley JH, Tajik AJ, Danielson GK, et al.Transient constrictive pericarditis: causes andnatural history. J Am Coll Cardiol 2004;43:271–5.

104. Feng D, Glockner J, Kim K, et al. Cardiacmagnetic resonance imaging pericardial late gad-olinium enhancement and elevated inflammatory

markers can predict the reversibility of constrictivepericarditis after antiinflammatory medical ther-apy: a pilot study. Circulation 2011;124:1830–7.

105. Sagristà-Sauleda J, Angel J, Sánchez A, et al.Effusive-constrictive pericarditis. N Engl J Med2004;350:469–75.

106. Rajagopalan N, Garcia MJ, Rodriguez L, et al.Comparison of new Doppler echocardiographicmethods to differentiate constrictive pericardialheart disease and restrictive cardiomyopathy. AmJ Cardiol 2001;87:86–94.

107. Palka P, Lange A, Donnelly JE, et al. Differ-entiation between restrictive cardiomyopathy andconstrictive pericarditis by early diastolic Dopplermyocardial velocity gradient at the posterior wall.Circulation 2000;102:655–62.

108. Garcia MJ, Rodriguez L, Ares M, et al. Dif-ferentiation of constrictive pericarditis fromrestrictive cardiomyopathy: assessment of leftventricular diastolic velocities in longitudinal axisby Doppler tissue imaging. J Am Coll Cardiol 1996;27:108–14.

109. Hurrell DG, Nishimura RA, Higano ST, et al.Value of dynamic respiratory changes in left andright ventricular pressures for the diagnosis ofconstrictive pericarditis. Circulation 1996;93:2007–13.

110. Oh JK, Hatle LK, Seward JB, et al. Diagnosticrole of Doppler echocardiography in constrictivepericarditis. J Am Coll Cardiol 1994;23:154–62.

111. Meyer TE, Sareli P, Marcus RH, et al. Mecha-nism underlying Kussmaul’s sign in chronicconstrictive pericarditis. Am J Cardiol 1989;64:1069–72.

112. Talreja DR, Edwards WD, Danielson GK, et al.Constrictive pericarditis in 26 patients with histo-logically normal pericardial thickness. Circulation2003;108:1852–7.

113. Himelman RB, Lee E, Schiller NB. Septalbounce, vena cava plethora, and pericardialadhesion: informative two-dimensional echocar-diographic signs in the diagnosis of pericardialconstriction. J Am Soc Echocardiogr 1988;1:333–40.

114. Hatle LK, Appleton CP, Popp RL. Differentia-tion of constrictive pericarditis and restrictivecardiomyopathy by Doppler echocardiography.Circulation 1989;79:357–70.

115. Klein AL, Cohen GI, Pietrolungo JF, et al.Differentiation of constrictive pericarditis fromrestrictive cardiomyopathy by Doppler trans-esophageal echocardiographic measurements ofrespiratory variations in pulmonary venous flow.J Am Coll Cardiol 1993;22:1935–43.

116. Klein AL, Cohen GI. Doppler echocardio-graphic assessment of constrictive pericarditis,cardiac amyloidosis, and cardiac tamponade. CleveClin J Med 1992;59:278–90.

117. Reuss CS, Wilansky SM, Lester SJ, et al. Usingmitral ’annulus reversus’ to diagnose constrictivepericarditis. Eur J Echocardiogr 2009;10:372–5.

118. Vaitkus PT, Kussmaul WG. Constrictive peri-carditis versus restrictive cardiomyopathy: areappraisal and update of diagnostic criteria. AmHeart J 1991;122:1431–41.

119. Grizzard JD, Ang GB. Magnetic resonanceimaging of pericardial disease and cardiac masses.Cardiol Clin 2007;25:111–40, vi.

120. Ghersin E, Lessick J, Litmanovich D, et al.Septal bounce in constrictive pericarditis. Diag-nosis and dynamic evaluation with multidetectorCT. J Comput Assist Tomogr 2004;28:676–8.

121. Mirelis JG, Garcia-Alvarez A, Fernandez-Friera L, et al. Respiratory ventricular area changesmeasured with real-time cardiac magnetic reso-nance: a new, accurate, and reproducible approachfor the diagnosis of pericardial constriction. Int JCardiol 2013;166:267–71.

122. Schoenfeld MH, Supple EW, Dec GW Jr., et al.Restrictive cardiomyopathy versus constrictivepericarditis: role of endomyocardial biopsy inavoiding unnecessary thoracotomy. Circulation1987;75:1012–7.

KEY WORDS amyloidosis,echocardiography, endomyocardial fibrosis,heart failure, magnetic resonance imaging