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FOCUS SEMINAR: PERICARDIAL AND MYOCARDIAL DISEASE

STATE-OF-THE-ART REVIEW

Differentiation of Constrictionand Restriction
Complex Cardiovascular Hemodynamics
Jeffrey B. Geske, MD, Nandan S. Anavekar, MD, Rick A. Nishimura, MD, Jae K. Oh, MD,Bernard J. Gersh, MBCHB, DPHIL

ABSTRACT

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Differentiation of constrictive pericarditis (CP) from restrictive cardiomyopathy (RCM) is a complex and often challenging

process. Because CP is a potentially curable cause of heart failure and therapeutic options for RCM are limited, distinction

of these 2 conditions is critical. Although different in regard to etiology, prognosis, and treatment, CP and RCM share

a common clinical presentation of predominantly right-sided heart failure, in the absence of significant left ventricular

systolic dysfunction or valve disease, due to impaired ventricular diastolic filling. Fundamental to the diagnosis of

either condition is a clear understanding of the underlying hemodynamic principles and pathophysiology. We

present a contemporary review of the pathophysiology, hemodynamics, diagnostic assessment, and therapeutic

approach to patients presenting with CP and RCM. (J Am Coll Cardiol 2016;68:2329–47) © 2016 by the American College

of Cardiology Foundation.

D istinction of constrictive and restrictivehemodynamics remains one of cardiovas-cular medicine’s most complex challenges

(1–10). Both result in impaired ventricular fillingwith clinical manifestations of predominantly rightheart failure with preserved ejection fraction.Constrictive pericarditis (CP) is a potentially revers-ible cause of heart failure, whereas restrictivecardiomyopathy (RCM) has very limited therapeuticoptions. Therefore, the ability to differentiatebetween these conditions remains paramount totherapy. Herein, we present a review of hemody-namic differentiation of CP and RCM, as well asdiscussion of the underlying pathophysiology, diag-nostic assessment, and therapeutic approaches toboth entities.

m the Department of Cardiovascular Diseases, Mayo Clinic, Rochester, M

stedt Incorporated, related to wound vacuum and TEE probe covers. Dr. G

Mount Sinai St. Luke’s Hospital, Boston Scientific, Teva Pharmaceutica

velopment, Baxter Healthcare, and the Cardiovascular Research Foundatio

d Xenon Pharmaceuticals; and has been on the advisory board of Medtron

ationships relevant to the contents of this paper to disclose.

nuscript received May 2, 2016; revised manuscript received August 4, 20

CONSTRICTION AND RESTRICTION:

PATHOLOGY AND ETIOLOGY

PATHOLOGY AND ETIOLOGY OF CONSTRICTION. Iden-tification of pericardial disease dates back to Biblicaltimes, with observation of clinical signs attributableto CP harkening to the renaissance period, and mod-ern understanding arising during the 19th century(11). CP is a pathological condition with encasementof the heart by a thickened, fibrous, and sometimescalcified pericardium, with secondary abnormalitiesin chamber filling. The etiologic mechanisms of peri-cardial pathology have evolved over the past century,with an increasingly significant iatrogenic contribu-tion from post-surgical inflammation and radiationtherapy (12). There are major geographic influences

innesota. Dr. Anavekar has reviewed literature for

ersh has served on the data safety monitoring boards

l Industries, St. Jude Medical, Janssen Research &

n; has been a consultant to Janssen Scientific Affairs

ic. All other authors have reported that they have no

16, accepted August 9, 2016.

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ABBR EV I A T I ON S

AND ACRONYMS

3D = 3-dimensional

BNP = B-type natriuretic

peptide

CMR = cardiac magnetic

resonance

CP = constrictive pericarditis

CT = computed tomography

e0 = early diastolic velocity

EMB = endomyocardial biopsy

FDG = 18-fluorodeoxyglucose

LA = left atrium/atrial

LV = left ventricle/ventricular

NYHA = New York Heart

Association

PET = positron emission

tomography

RA = right atrium/atrial

RCM = restrictive

cardiomyopathy

RV = right ventricle/ventricular

Geske et al. J A C C V O L . 6 8 , N O . 2 1 , 2 0 1 6

Constriction vs. Restriction: Complex Cardiovascular Hemodynamics N O V E M B E R 2 9 , 2 0 1 6 : 2 3 2 9 – 4 7

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on etiology, with tuberculosis the mostfrequent cause of pericardial diseases indeveloping countries and in the world, oftencoupled with human immunodeficiency viruscoinfection (13). Of noninfectious etiologies,most are idiopathic, whereas the remainderstem from iatrogenic causes, connective tis-sue diseases, neoplasms, or uremia. Fibrousthickening of the pericardium forms a rigid,noncompliant encasement of the heart,resulting in progressive impairment in car-diovascular filling and low cardiac output(14). Symptoms often arise insidiously in CP,culminating in progressive signs and symp-toms of predominantly right heart failure.Complete surgical removal of the pericar-dium can result in excellent symptomaticimprovement. The prognosis is dependentupon the underlying etiology, with prior ra-diation therapy consistently associated withworse outcomes (12,15). For unclear reasons,there is male predominance of CP in mostclinical series.

PATHOLOGY AND ETIOLOGY OF RESTRICTION. RCM is aprimary disease of the myocardium. RCM is charac-terized by increased myocardial stiffness, whichresults in a rapid rise in ventricular filling pressuresreflected in both the systemic and pulmonary cir-culations. Despite marked abnormalities in diastolicfunction, left ventricular (LV) ejection fraction istypically preserved. Primary RCM is often idiopathic,although familial inheritance has been described,with desmin and troponin I mutations implicated(16,17). Idiopathic RCM has been associated withdistal skeletal myopathy (18). Amyloidosis is themost common secondary cause of RCM (18). Radia-tion heart disease and post-operative etiologiesrepresent an increasing proportion of RCM in thedeveloped countries. Non-eosinophilic endomyo-cardial disease (endomyocardial fibrosis) is animportant cause of RCM in tropical countries ofSouth America (Brazil and Venezuela) and Africa(Mozambique, Uganda, and others) (19–21).Numerous other secondary etiologies of RCM havebeen identified: eosinophilic endomyocardial dis-ease, storage diseases (e.g., hemochromatosis,glycogen storage diseases, Fabry disease), sarcoid-osis, scleroderma, carcinoid, medication-induced(serotonin, ergotamines), and chemotherapy-induced (anthracyclines) (14,22). Shared amongthese disorders are altered chamber wall mechanicalproperties with reduced compliance, resulting in arise in mean circulatory filling pressures and

associated sequelae. Unfortunately, therapeuticapproaches to RCM remain challenging. Despiteoptimal heart failure care, definitive treatment isoften limited to cardiac transplantation.

MIXED CONSTRICTION AND RESTRICTION. Consid-erable overlap of CP and RCM may be present,particularly in the setting of prior chest radiotherapy.Radiation indiscriminately affects both pericardialand myocardial tissues, in addition to the valves andcoronary vessels. Mixed constriction/restriction canalso be seen post-operatively, including post-cardiactransplantation. Although post-operative mecha-nisms remain suboptimally defined, mixed featuresmay arise as a combination of pericardial scarring andprocedure-mediated myocardial dysfunction (23).There is a paucity of data to describe this mixed pic-ture, and therefore, the true prevalence remains un-known. Yamada et al. (23) reported that 12.7% ofpatients referred for evaluation of CP or RCM werefound to have overlapping features. In that same se-ries, patients with mixed disease had significantlyworse survival compared with those with isolated CP.Mixed constrictive and restrictive hemodynamicspose a significant management dilemma, because theclinical outcome of high-risk surgical interventionsmay be uncertain.

HEMODYNAMIC CHARACTERISTICS OF

RESTRICTION AND CONSTRICTION

NORMAL CARDIAC HEMODYNAMICS. Understandingnormal hemodynamic findings is integral for recog-nition of derangements present in CP and RCM.Although frequently separated during discussions ofcardiac function, diastole and systole are intricatelylinked, with diastolic filling providing the preloadnecessary for generation of stroke volume via theFrank-Starling mechanism. This intimate relationshipis exemplified at the molecular level by the depen-dence of both cardiac contraction and relaxation oncalcium cycling (24). Diastolic filling is dependentupon factors extrinsic to the cardiac chamber (theloading conditions imposed upon the heart, pericar-dial restraint, chest geometry) and intrinsic myocar-dial properties, such as viscoelastic forces,myocardial stiffness, and stress–strain relationships.

Although ventricular diastole is a complexsequence of interrelated events, it can be divided into3 components: ventricular relaxation, passive filling,and atrial contraction. Sarcomere inactivation andcalcium cycling, the load on the LV, and nonunifor-mity of ventricular relaxation influence global ven-tricular relaxation (25). Early rapid filling occurs dueto a combination of ventricular relaxation, the driving

FIGURE 1 RA Pressure Tracings in CP and RCM

100 mm Hg

0 mm Hg

Constrictive pericarditis Restrictive cardiomyopathy

LV

LV

RARA

* x y y

50 mm Hg

(Left) Left ventricular (LV) (blue) and right atrial pressure (RA) (orange) hemodynamic pressure tracings in constrictive pericarditis (CP).

Prominent “x” and “y” descents are present with a square root sign (*). (Right) LV and RA pressure hemodynamic pressure tracings in restrictive

cardiomyopathy (RCM). A prominent “y” descent is present, but the “x” descent is blunted.

J A C C V O L . 6 8 , N O . 2 1 , 2 0 1 6 Geske et al.N O V E M B E R 2 9 , 2 0 1 6 : 2 3 2 9 – 4 7 Constriction vs. Restriction: Complex Cardiovascular Hemodynamics

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pressure across the mitral valve from elevated leftatrial (LA) pressure, pericardial restraint, andmyocardial stiffness. Passive filling occurs as theresult of continued ventricular relaxation and effec-tive operating chamber compliance, which is the sumtotal of passive filling dependent upon pericardialrestraint, ventricular interaction, and viscoelasticforces of the myocardium (25). Atrial contractionserves to “prime” the ventricle by actively distendingthe chamber via atrial mechanical emptying.

The pericardial sac encompasses both ventricles,the right atrium (RA), and most of the LA, whereas thepulmonary venous system and the majority of the su-perior and inferior vena cavae are external to thepericardium. Most of the superior and inferior venacavae are not intrathoracic, and thus are largely un-affected by swings in intrathoracic pressure. Duringinspiration, diaphragmatic descent results in adecrease in intrathoracic pressure of 5 to 10 mm Hg,which is fully transmitted to the cardiac chambers (26).Given no change in systemic venous pressure, the dropin intrathoracic pressure augments right heart filling.The pulmonary veins are entirely intrathoracic;therefore, there is a uniform decrease in pressurewithin the pulmonary veins and left-sided cardiacchambers. Thus, left-sided filling does not signifi-cantly alter during respiration. In the presence of anormal pericardium and a compliant right ventricle(RV), chamber distention caused by increased flow iseasily accommodated, and therefore does not result in

significant inspiratory rise in pressures. Althoughright- and left-sided diastolic pressures vary inde-pendent of one another during respiration, systolicpressures parallel one another, falling with inspirationand rising with expiration, mirroring intrathoracicpressures (27). During expiration, right-sided fillingdecreases relative to inspiration, whereas left-heartfilling remains relatively constant.

HEMODYNAMICS OF CONSTRICTION. The primaryhemodynamic consequence of constriction is limita-tion of the total volume of blood that can be accom-modated by the heart during diastole across therespiratory cycle, with equalization of right- and left-sided cardiac filling pressures. Accentuated earlyrapid ventricular filling occurs due to high atrialdriving pressures and unimpeded ventricular relaxa-tion, followed by a sudden rapid rise in pressure frompericardial restraint. This accounts for the rapid “y”descent on the atrial pressure waveform and “squareroot” sign on ventricular pressures. Reduced peri-cardial compliance limits myocardial stretch duringdiastole. Although diastolic pressures are high, thereis a paradoxically low stroke volume from low pre-load. Preserved atrial relaxation, as well as an exag-gerated ventricular longitudinal contraction, result inan exaggerated “x” descent on atrial pressure tracings(Figure 1).

Rigid cardiac encasement has the additional effectof isolation of the cardiac chambers from swings in

FIGURE 2 Simultaneous RV and LV Hemodynamic Assessment in CP and RCM

100 mm Hg

Constrictive pericarditis

50 mm Hg

100 mm Hg

Restrictive cardiomyopathy

50 mm Hg

Exp

Insp

LV

RV

*

Insp Exp

LV

RV

*

(Top) Left ventricular (LV) (blue) and right ventricular (RV) (orange) hemodynamic pressure tracings in constrictive pericarditis. End-diastolic

filling pressures are elevated and a “square root” sign is present on both pressure tracings (*). Enhanced ventricular interdependence is present,

demonstrated by visualization of the systolic area index; RV (gray) and LV (dark gray) areas under the curve are shown for both inspiration

(Insp) and expiration (Exp). During inspiration, there is an increase in the area of the RV pressure curve and decrease in the area of the LV

pressure curve. (Bottom) LV and RV pressure tracings in restrictive cardiomyopathy. Although end-diastolic filling pressures are elevated and

a square root sign (*) is present, there is no evidence of enhanced ventricular interdependence, with parallel changes in LV and RV pressure

curve areas.



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intrathoracic pressure. With inspiration, there is areduction in intrathoracic pressures not fully trans-mitted to the cardiac chambers. Because the pulmo-nary veins are intrathoracic, inspiratory reduction inpulmonary capillary and venous pressures reducesthe flow between the pulmonary veins and left-sidedcardiac chambers. In the setting of a noncompliantpericardium with a relatively fixed intrapericardialvolume, reduced LV filling allows increased RV

filling. This is accompanied by inspiratory interven-tricular septal motion towards the LV. Increasedinferior vena cava flow during inspiration,augmented by increased transdiaphragmatic pres-sure, competes with flow from the superior vena cavainto the high-pressure RA. The resultant increase injugular venous pressure with inspiration is termedKussmaul’s sign (28). The converse is seen in expi-ration. With expiration, there is a rise in intrathoracic


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(and therefore pulmonary venous) pressures. Thisaugments flow into the left heart. Increased left heartfilling within a fixed total intrapericardial volumepushes the interventricular septum towards the right,reducing RV filling, and creating expiratory diastolicflow reversals transmitted back to the inferior venacava and hepatic veins. This respirophasic hemody-namic augmentation is an important and specificfeature of constrictive physiology. Increased ven-tricular interdependence directly translates to analteration in ventricular systolic pressures. Althoughthese pressures rise and fall in parallel with respira-tion in normal physiology, systolic pressures becomediscordant in CP, a marker that is both sensitive andspecific (Figure 2) (29). Loss of pericardial complianceamplifies the effect of adjacent cardiac chambers,with resultant equalization of intracardiac diastolicpressures.

HEMODYNAMICS OF RESTRICTION. Unlike the com-plex interplay of pulmonary and systemic pressuresassociated with CP, RCM is the result of abnormalitiesintrinsic to the myocardium, which are unchangedduring respiration. As with CP, there is early rapidfilling of the ventricles in early diastole, due to highatrial pressures, followed by limitation in filling fromthe stiff myocardium. This results in a prominent “y”descent on the atrial pressure curves, as well as the“square root” sign on ventricular pressure curves(30,31). The stiff, noncompliant ventricles are unableto easily accept additional increments in volumeduring atrial contraction, and thus the contributionfrom atrial contraction is often minimal. Unlike CP,the “x” descent is frequently blunted, given pooratrial relaxation and a limited descent of the annulustowards the apex (Figure 1). Increased venous flowwith inspiration is unable to be accommodated by anoncompliant RV; hence, there are diastolic flow re-versals in the hepatic vein with inspiration. UnlikeCP, there is no discordance of intracavitary andintrathoracic pressures (Figure 2).

DIAGNOSTIC EVALUATION

PHYSICAL EXAMINATION. Equalization of intracar-diac pressures in CP results in predominantly sys-temic venous congestion, manifested as edema,hepatomegaly, and ascites. As previously noted,elevated jugular venous pressures that increase withinspiration (Kussmaul’s sign) are usually present.Recognition of the characteristic jugular venouscontour with prominent “x” and “y” descents is acritical portion of the physical examination (Figure 1).It should be noted that the “x” descent is lost in pa-tients with atrial fibrillation, even in the presence

of CP. Robust early ventricular filling accompanyingthe “y” descent with sudden deceleration results inan early diastolic, high-pitched pericardial knock,although this is an insensitive sign.

As with CP, RCM results in predominant findings ofsystemic venous congestion. Compared with CP,concomitant pulmonary venous congestion is morecommon in RCM, presenting as dyspnea. Kussmaul’ssign may be present in RCM and is therefore anonspecific finding (32,33). A prominent “y” descentis seen on the jugular venous contour, accompaniedby an S3, given rapid early filling of a stiffenedventricle. Unlike CP, a pronounced “x” descent is notseen (Figure 1).

ELECTROCARDIOGRAM AND LABORATORY TESTING.

Electrocardiographic findings are overall nonspecificfor differentiating CP and RCM, although differencesin P-wave morphology, QRS voltage, and presence ofconduction abnormalities may be present, depen-dent upon the underlying substrate. In CP, pericar-dial inflammation and fibrosis can extend to theatrial wall, resulting in an intra-atrial conductiondelay and a wide, notched, low-amplitude P-wave(34). Conversely, RCM is characterized by severebiatrial enlargement, which translates to electrocar-diographic findings of wide, increased amplitude Pwaves (34). Atrial fibrillation is a complication ofboth CP and RCM, and likely represents electro-physiological sequelae of atrial enlargement andperhaps inflammation. Discordance between QRSvoltage and wall thickness should trigger clinicalconcern for cardiac amyloidosis. Ventricular con-duction abnormalities (bundle branch block) arepresent in 20% to 30% of RCM, likely reflecting theinfluence of infiltrative pathologies, but are uncom-mon in CP (34).

In the setting of effusive CP, cytokine assessmentcan be additive in determining the underlying cause,with serum interleukin-10 levels significantly higherin patients with underlying tuberculosis (35). Tar-geted laboratory testing to assess for various sec-ondary causes of RCM should be performed on anindividualized basis. It is reasonable to assess formonoclonal paraproteinemia and paraproteinuria toevaluate for amyloidosis, although this test alone isnot sufficient to confirm amyloidosis (36). Additionaltesting, including evaluation for connective tissuediseases or infiltrative diseases, should be guided byclinical history and imaging assessment.

B-type natriuretic peptide (BNP) is a polypeptideneurohormone released by the myocardium inresponse to stretch. Although both CP and RCM resultin elevated filling pressures, patients with RCM

FIGURE 3 M-Mode of the Interventricular Septum in CP

M-mode of the ventricular septum demonstrates respirophasic septal shift (downward translation of the septum with inspiration, upward

translation with expiration) and septal shudder (circle, with enlarged view in upper right corner) in a patient with constrictive pericarditis (CP).



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develop massive biatrial enlargement. In keepingwith this, BNP tends to be higher in patients withRCM (>600 pg/ml) compared with CP (>200 pg/ml)(37,38). However, significant overlap is present,limiting the clinical utility of BNP in differentiatingthe 2 conditions (39). The difference in BNP betweenpatients with RCM and CP is lessened in the setting ofrenal insufficiency (37,40).

ECHOCARDIOGRAPHY. 2-dimensional echocardiography.Echocardiography is the initial imaging test of choicein patients with signs and symptoms of constrictionor restriction. Increased pericardial thickness canbe recognized on transthoracic echocardiography,although interpretation is often challenging (41).Pericardial thickness >3 mm on transesophagealechocardiography is both sensitive and specific forthe detection of a thickened pericardium (42).Adherence of the visceral and parietal pericardiumcan result in tethering, a finding often appreciatedon the RV free wall from the subcostal or apical4-chamber views (43). Identification of a calcifiedpericardium with ventricular contour distortion isinfrequent, but strongly suggests CP (43). Pericardialcalcification is much better appreciated via chestx-ray or computed tomography (CT). Presence of apericardial effusion may signify the presence ofeffusive–constrictive physiology.

Assessment of ventricular septal motion on bothM-mode and 2-dimensional echocardiography canprovide insight into ventricular interdependencewith inspiratory leftward motion of the septum andexpiratory rightward shift (Figure 3). Respirophasic

ventricular septal shifting is usually the first echo-cardiographic clue to the diagnosis of CP because it ispresent in almost all patients with CP. Beyond therespirophasic motion, a septal “bounce,” also referredto as a “shudder” or “diastolic checking,” may bepresent with each beat in patients with CP, trans-lating to a septal notch on M-mode imaging (Figure 3).The mechanism of this “bounce” is a combinationof differential timing of filling and pericardialconstraint, leading to rapid cessation of filling (44).

Systemic venous congestion is present in both RCMand CP. A plethoric inferior vena cava and engorgedhepatic veins are expected in both conditions.Absence of a dilated inferior vena cava in a patientwithout recent diuresis should call into question thediagnosis of hemodynamically significant CP or RCM.

Cavity size and ventricular wall thickness tend tobe normal in primary (idiopathic) RCM (18). Severeatrial enlargement is often present (Figure 4).Although hemodynamics are similar in primary andsecondary (infiltrative) forms of RCM, ventricularwall thickness is commonly increased in infiltrativediseases (22). Unfortunately, many infiltrative car-diomyopathies can have a similar appearance on2-dimensional echocardiography (45). Furtherassessment via serologic evaluation, strain, tissuecharacterization at cardiac magnetic resonance (CMR)imaging, or endomyocardial biopsy (EMB) may beneeded to clarify further.

Doppler echocard iography . Detailed Doppler he-modynamic evaluation is central to the diagnosis ofboth CP and RCM (46), and may be sufficient to

FIGURE 4 Echocardiographic Findings in RCM

(Upper left) Pulsed-wave Doppler of the mitral inflow shows a restrictive pattern, with early diastolic mitral inflow Doppler velocity (E) greater than late velocity (A) and

short deceleration time. (Upper right) Hepatic vein pulsed-wave Doppler shows increased inspiratory forward velocities (arrow), inspiratory diastolic flow reversals

(arrowhead), and minimal expiratory diastolic flow reversals (rounded arrow). (Lower left) Lateral mitral annulus tissue Doppler demonstrates markedly reduced early

diastolic velocity (e0). (Lower right) Apical 4-chamber 2-dimensional echocardiography reveals severe biatrial enlargement. RCM ¼ restrictive cardiomyopathy.


2335

confirm CP without hemodynamic catheterization inin many patients. Mitral (and tricuspid) Dopplerinflow patterns in both CP and RCM are early diastolicvelocity (E-wave) predominant with a short deceler-ation time, reflecting the predominance of early rapidventricular filling. A critical difference is the presenceof respiratory flow variation in CP (Figure 5), which isabsent in RCM (Figure 4) (3,4,6,47,48). Reportedly,mitral inflow in CP demonstrates a respiratory varia-tion of $25%, with increased velocities during expi-ration (49). The initial observation of mitral inflowrespiratory variation in CP was on the basis of 7 pa-tients (49), and subsequent larger studies have shownthe absence of respiratory variation in one-third ofpatients with CP (50,51). Therefore, the lack of respi-ratory variation should not exclude the diagnosis ofCP. Doppler respirophasic variation is similarly seenin the pulmonary veins, with peak diastolic flow>18% variation suggestive of CP (6). Tricuspid inflowDoppler demonstrates the reverse finding, namely a>40% increase in tricuspid velocity in the first beatafter inspiration in CP. Hepatic vein Doppler interro-gation in CP shows decreased expiratory diastolic

hepatic vein forward velocities with large expiratorydiastolic reversals. The presence of atrial fibrillationresults in variable cardiac cycle length and accom-panying alteration of mitral inflow velocities.Although this makes evaluation for CP via mitralinflow Doppler challenging, hepatic vein flow re-versals and annular tissue Doppler assessmentremain reliable metrics for assessment of CP (43).

Mitral and tricuspid inflow patterns in patientswith chronic obstructive pulmonary disease canmimic CP because of increased changes in intratho-racic pressure. Superior vena cava Doppler assess-ment is warranted in all patients with significantrespiratory disease undergoing evaluation for CP.Chronic obstructive pulmonary disease results in amarked increase in superior vena cava systolicforward flow velocity with inspiration, whereas pa-tients with CP do not demonstrate such respiratoryvariation (52).

Of all echocardiographic parameters, perhaps themost useful to distinguish CP and RCM is mitralannular tissue Doppler assessment. The early dia-stolic velocity of the mitral annulus (e0) sampled via

FIGURE 5 Doppler Findings in CP

(Upper left) Pulsed-wave Doppler of the mitral inflow shows >25% expiratory increase in velocities (arrows). (Upper right) Hepatic vein pulsed-wave Doppler shows

decreased expiratory forward velocities and large expiratory diastolic flow reversals (arrowhead). (Lower left) Medial mitral annulus tissue Doppler demonstrates

elevated early diastolic velocities (e0), despite increased filling pressures (annulus paradoxus). (Lower right) Lateral mitral annulus e0 is decreased relative to the medial

annulus (annulus reversus) due to lateral tethering. CP ¼ constrictive pericarditis.

TABLE 1

1. Ventricu

2. Change

3. Medial

4. Medial

5. Hepaticforwar

1 and 3

1 with 3 o

1 with 3 a

Values are %

CP ¼ condiastolic mipredictive v



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tissue Doppler reflects the status of LV myocardialrelaxation, with good inverse correlation with thetime constant of relaxation, tau (53). Under normalconditions, the medial e0 velocity is lower than thelateral e0 velocity, given the relative anatomic teth-ering of the ventricular septum, which is influencedby relaxation of both ventricles (54). The ratio of the

Echocardiographic Characteristics of Surgically Confirmed CP

Criterion Sensitivity Specificity PPV NPV

lar septal shift 93 69 92 74

in mitral E velocity >14.6% 84 73 92 55

e0 velocity >9 cm/s 83 81 94 57

e0/lateral e0 $0.91 75 85 95 50

vein diastolic reversal velocity/d velocity in expiration $0.79

76 88 96 49

80 92 97 56

r 5 87 91 97 65

nd 5 64 97 99 42

. Reprinted with permission from Welch et al. (43).

strictive pericarditis; E ¼ early diastolic mitral inflow Doppler velocity; e0 ¼ earlytral annular tissue Doppler velocity; NPV ¼ negative predictive value; PPV ¼ positivealue.

mitral inflow E-wave and the mitral annular e0 ve-locity is routinely used in patients with myocardialdiseases for diastolic function assessment, because itprovides better estimates of LV filling pressures thanother methods, such as pulmonary vein assessment(55,56).

As myocardial stiffening occurs and relaxation be-comes delayed, e0 velocities become reduced, a hall-mark of RCM (57) (Figure 4). In CP, the mechanism ofincreased filling pressures is not at the level of themyocardium or due to reduced myocardial relaxation.Lateral cardiac motion is limited, due to pericardialconstriction; hence, ventricular filling depends uponlongitudinal cardiac motion. Consequently, mitralannular tissue Doppler e0 velocities are normal orparadoxically increased despite increased fillingpressures, termed “annulus paradoxus” (58). In CP,tethering of the LV free wall can result in reversal ofthe relationship between medial and lateral mitralannular tissue Doppler velocities, such that themedial e0 is higher (typically >7 cm/s) than lateral e0, aphenomenon referred to as “annulus reversus”(Figure 5) (59).


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We favor a multifaceted approach to echocardio-graphic evaluation of CP, utilizing the Mayo Cliniccriteria such as interventricular septal motion, mitralinflow velocity pattern, mitral annulus e0 velocity,and hepatic vein diastolic flow reversals with expi-ration (43) (Table 1).

Newer echocard iographic techniques . Novelechocardiographic techniques of speckle-trackingstrain and 3-dimensional (3D) echocardiographyhave supplemented the collective understanding ofboth CP and RCM (60). Three-dimensional echocar-diographic imaging can provide additive information,specifically in regard to pericardial visualization (61),pericardial effusion assessment (62), and pericardialtethering (62,63). In RCM, such as amyloidosis, 3Dechocardiography allows for determination of tem-poral and regional characterization of LV dyssyn-chrony (64,65). Myocardial deformation (LV strain)may be useful in the future, because preliminarydata have shown that patients with CP have mark-edly abnormal circumferential deformation, torsion,and untwisting velocity, but relative sparing oflongitudinal mechanics, whereas RCM is associatedwith abnormal longitudinal mechanics, most pro-nounced at the base, with relative sparing of LVrotation (66). Characteristic strain “fingerprints”have been identified for various infiltrative car-diomyopathies, such as relative apical longitudinalstrain preservation in patients with cardiac amyloid-osis (67,68). Because the use of 3D strain continues toexpand, further patterns and mechanistic insightsmay emerge (69). At this juncture, these techniques,although promising, remain investigational, andrequire further validation in larger studies before be-ing incorporated into a routine diagnostic imagingstrategy.

CHEST X-RAY AND CARDIAC CT. Chest radiographymay demonstrate calcification of the pericardium,best assessed on the lateral view, but this finding isonly seen in approximately one-quarter of patientswith CP (Figure 6) (70,71). Because calcification is aresult of chronic inflammation, it is not typicallypresent in patients with subacute pericarditis, whichmay include effusive CP (34). Findings of pulmonaryvenous congestion, pleural effusions, or massivebiatrial enlargement are more suggestive of RCM (18).

Chest CT has largely replaced chest x-ray as theradiographic modality of choice for characterizingpericardial anatomy, given its excellent spatial reso-lution and 3D assessment of anatomy (Figure 7) (72).Notably, pericardial calcification not recognized onchest x-ray is frequently identified on CT (71). Normalpericardial thickness by CT is <2 mm (73). Although a

pathologically thickened pericardium (>4 mm) ishighly suggestive of CP, lack of this finding shouldnot be used in isolation to exclude the diagnosis,because pericardial thickness is normal in 20% ofpatients with CP (74). In addition to defining peri-cardial anatomy, gated cardiac CT provides excellentassessment of pericardial effusion size, cardiacchamber size, deformation of the cardiac contour,and pertinent noncardiac findings, such as hepaticcongestion, dilation of the inferior vena cava, andpulmonary vascular congestion. Reduced lateralmitral annular early diastolic tissue Doppler veloc-ities correlate well with pericardial thickness on CT inpatients with CP (75). Beyond anatomic definition,respirophasic septal motion in CP is well seen on thegated acquisition (76).

CARDIAC MAGNETIC RESONANCE. CMR providesexcellent assessment of the pericardium and cardiacchambers independent of chest geometry, andhas emerged as a powerful diagnostic study in theevaluation of pericardial and myocardial diseases(77,78). Both CP and RCM present with significantbiatrial enlargement. The relative atrial ratio (ratioof LA volume to RA volume) is greater in patientswith CP than RCM when assessed via CMR, with aratio of 1.32 providing the highest specificity andsensitivity (79). Beyond cardiac anatomy, CP hasbeen associated with increased liver stiffness, asevaluated via magnetic resonance elastography,likely secondary to chronic hepatic congestion orfibrosis (80).

CMR has excellent accuracy (93%) for detection ofpericardial thickening >4 mm (77). Fast spin-echo T2-weighted sequences, especially with fat saturation,and short-tau inversion-recovery sequences are use-ful to visualize pericardial edema and inflammation(81). CMR affords insight into the presence and extentof pericardial inflammation via delayed gadoliniumenhancement, as well as defining the size and loca-tion of pericardial effusion in effusive CP (Figure 8)(82). Interpretation of post-contrast pericardialenhancement abnormalities can be challenging inisolation, as delayed enhancement may represent aspectrum of pathologies from inflammation tofibrosis. Combination of post-contrast data withedema-sensitive sequences provides further imaginginsight into the presence of active inflammation. Thepresence of abnormal pericardial delayed enhance-ment in the setting of pericardial constriction mayidentify those patients who may benefit from atrial of aggressive anti-inflammatory therapy (83).Improvement in late gadolinium enhancement par-allels inflammatory markers in reversible CP treated

FIGURE 6 Chest Radiograph in CP

(Left) Anterior-posterior chest radiograph demonstrates pericardial calcification (arrowheads) along the right atrial border and inferior margin

of the heart. (Right) Lateral radiograph demonstrates extensive anterior pericardial calcification. CP ¼ constrictive pericarditis.



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with anti-inflammatory agents (83). Currently,follow-up recommendations to assess improvementof these imaging findings with medical therapy arebased upon anecdotal experience.

Myocardial delayed enhancement, indicative ofmyocardial inflammation or fibrosis, is classicallyabsent in CP. In myopericarditis, there is extension ofpericardial delayed enhancement to the myocardium,which has been associated with worse outcomescompared with patients without myocardial involve-ment (84). Myocardial delayed enhancement is seenin nearly one-third of cases of RCM (79). Patternsof myocardial delayed enhancement and other

FIGURE 7 Pericardial Assessment on CT

(Left) Anatomic location and extent of pericardial calcification (arrowhea

a patient with constrictive pericarditis. (Right) Thickened pericardium (>

the cardiac contour in the absence of pericardial calcification.

cine-imaging characteristics may help to identifyinfiltrative cardiomyopathies resulting in RCM (85).For example, in cardiac amyloidosis, global or sub-endocardial delayed myocardial enhancement isfrequently present, with a characteristic inability toadequately null the myocardium (86). Furthermore,delayed gadolinium enhancement provides incre-mental prognostic information over serum bio-markers in immunoglobulin light-chain cardiacamyloidosis (87).

CMR avoids the radiation exposure associated withcardiac CT. This allows real-time, free-breathing im-age acquisition with CMR, facilitating respirophasic

ds) demonstrated on axial noncontrast computed tomography (CT) in

4 mm) in a patient with constrictive pericarditis, with deformation of

FIGURE 8 CMR Imaging Delayed Gadolinium Enhancement of the Pericardium

(Left) Axial delayed enhancement images demonstrate pericardial enhancement (arrowheads) in the setting of fibrotic constrictive pericarditis. (Right) Delayed

enhancement of the visceral (arrowheads) and parietal pericardium (arrows) in a patient with effusive constrictive pericarditis and circumferential pericardial effusion.

CMR ¼ cardiac magnetic resonance.


2339

assessment of ventricular septal motion and ventric-ular coupling (Online Video 1). Ventricular septalexcursion, defined as the maximal difference inexpiratory and inspiratory position of the ventricularseptum, normalized to biventricular diameter, hasbeen found to discriminate between CP and RCM,with a cutoff value of 11.8% (88). Similarly, in patientswith CP, the ratio of biventricular end-diastolic areaat end-inspiration to biventricular end-diastolic areaat end-expiration remains close to 1 (1.03 � 0.03),whereas the ratio was greater in patients withoutpericardial constraint and ventricular interdepen-dence (1.28 � 0.10) (89).

Tagged cine CMR is a noncontrast technique formyocardial labeling and regional displacementassessment, analogous to echocardiographic mea-sures of strain. Cine CMR has been used to assess CP,as it may allow better recognition of tissue tethering,or “lack of slippage” (90,91). Adherence of thevisceral and parietal pericardium can result inpersistent concordance of tagged signals between thetissue planes throughout both systole and diastole.Tagging and cine CMR have been used to furtherunderstand myocardial mechanics in cardiomyopa-thies, such as Duchenne muscular dystrophy (92,93),and such techniques may also benefit RCM

evaluation. CMR and echocardiographic tissuetracking-derived left ventricular mechanics providecomparable diagnostic information for differentiatingCP from RCM (94).

NUCLEAR IMAGING. Positron emission tomography(PET) utilizing 18-fluorodeoxyglucose (FDG) providesunique insight into in vivo metabolism, withincreased uptake useful for identification of inflam-mation or neoplasm. Recognition of normal, physio-logical patterns of myocardial and pericardial FDGuptake is an important first step in isolating patho-physiology (95). PET imaging provides novel meta-bolic information not obtained via anatomic imaging,such as CMR or CT; however, these data are notexclusive to the modality, and can be coupled withanatomic imaging for further cardiac and pericardialtissue characterization (81,96). In combination withcardiac CT, FDG-PET has been utilized to assesspericardial inflammation in various infectious andinflammatory causes of pericarditis (96–100), andmay be helpful in differentiating between differentetiologies (101).

99mTechnetium (Tc)-pyrophosphate scintigraphyhas emerged as a clinical tool for differentiating bothfamilial and wild-type transthyretin-type cardiac

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2340

amyloidosis from other forms (102–104). Patientswith familial transthyretin-type cardiac amyloidosishave significantly higher quantitative and semi-quantitative cardiac visual scores than patients withlight-chain cardiac amyloidosis (103). The role of99mTc-pyrophosphate scintigraphy or FDG-PET inother forms of RCM remains largely unknown.

HEMODYNAMIC CATHETERIZATION. Hemodynamiccatheterization has served as the gold standard forthe diagnosis of CP and RCM. In both diseases, cath-eterization demonstrates early rapid diastolic filling,with elevation and equalization of end-diastolicpressures. In some patients who have undergoneaggressive diuresis, filling pressures can be low tonormal, but these patients will have a low cardiacoutput due to the abnormal diastolic pressure volumerelationships. Thus, for either CP or RCM to be pre-sent, there needs to be elevation of diastolic pres-sures, a low cardiac output, or both. In patients whohave low-to-normal filling pressures, a fluid challengeis required.

Differentiation of CP from RCM is a diagnosticchallenge in patients who have early rapid ventric-ular filling with elevation and near equalizationof diastolic pressures. In the past, several crite-ria have helped to differentiate between CP andRCM (1,105).

� Elevations of left-sided filling pressures are bettertolerated in CP than right-sided elevations, ac-counting for the predominance of right-sided fail-ure symptoms and less pulmonary hypertension inCP (pulmonary arterial systolic pressure<55mmHg)(29). Although the presence of pulmonary hyper-tension favors restrictive RCM, one-third of patientswith surgically proven CP have pulmonary hyper-tension (106).

� After brisk early filling, ventricular pressure risesrapidly as the pericardial constraining volume isreached, resulting in a “square root” or “dip andplateau” sign. Although this can be seen in bothCP and RCM, a LV rapid filling wave with a height>7 mm Hg favors CP (29).

� Kussmaul’s sign, quantified as <5 mm Hg decreasein inspiratory RA pressure, is often present in bothCP and RCM (29).

� Disproportionate abnormalities of diastolicdysfunction result in a ratio of RV end-diastolicpressure to systolic pressure >1:3 in CP (107).

� Equalization of diastolic filling pressures in CP(#5 mm Hg difference in LV and RV end-diastolicpressure) results from fixed pericardial volumeand increased ventricular interdependence (47).

However, these criteria have been shown to havepoor sensitivity and specificity in differentiating be-tween CP and RCM (Figure 9). In addition, any diseasein which there is an overload of the RV can result insimilar pressure abnormalities, such as severetricuspid regurgitation or RV infarction.

Respirophasic variation in pressures is the mosthelpful hemodynamic catheterization finding indifferentiating between CP and RCM. Careful hemo-dynamic assessment at catheterization allows forexquisitely detailed assessment of dissociation ofintrathoracic and intracavitary pressures, as well asdetermination of enhanced ventricular interdepen-dence. Dissociation of intrathoracic and intracardiacpressures can be analyzed utilizing simultaneous LVand pulmonary artery wedge pressure tracings. In CP,there is a decrease in the initial wedge-LV pressuregradient during the first beat of inspiration, which isnot present in RCM (48). Initial investigations ofrespirophasic ventricular interdependence in CPfocused on comparison of RV and LV peak systolicpressures as a surrogate of stroke volume (47). Sub-sequent investigations have found that area underthe systolic pressure curves is a better determinant ofbeat-to-beat stroke volume (29). Use of the systolicarea index (defined as the ratio of the RV area to LVarea in inspiration vs. expiration) yields a much morespecific and sensitive measure than use of systolicpressures (cutoff >1.1, 97% sensitive, 100% specific)(Figure 2) (29). In CP, respirophasic swings in strokevolume occur because of the fixed pericardial volume,with enhanced ventricular interdependence. Recog-nition of this finding and dissociation of intracardiacand intrathoracic pressures remains paramount toidentification of CP.

ENDOMYOCARDIAL BIOPSY. The role of EMB indifferentiating CP from RCM is poorly defined. EMBhas the potential to diagnose forms of RCM with tar-geted therapies available (cardiac sarcoidosis,amyloidosis, and Fabry disease). In some cases, EMBcan aid in prognostication, such as differentiation ofsubtypes of amyloidosis (108). EMB may be reason-able in patients with suspected RCM of uncertainetiology. A recent series by Bennett et al. (109) notedthat EMB was diagnostic in 29% of 281 patients withheart failure associated with unexplained RCM. Aconsensus document from the Association for Euro-pean Cardiovascular Pathology and the Society forCardiovascular Pathology provides further diagnosticguidance, dependent upon suspected underlying pa-thology (110). Although not proven, a completelynegative biopsy may favor constriction, particularlyin radiation heart disease.

FIGURE 9 Invasive Hemodynamic Assessments to Differentiate CP and RCM

30

20

10

0

-10CP RCM CP RCM

1.0

0.8

0.6

0.4

0.2

0.0

RVED

P/RV

ESP

LVED

P – R

VEDP

(mm

Hg)

100 mm Hg

LV

RV

0 mm Hg

RVEDP / RVESP= 0.38

LVEDP - RVEDP= 4 mm Hg

50 mm Hg

There have been a number of criteria proposed comparing left ventricular (LV) and right ventricular (RV) pressures at the time of cardiac

catheterization in order to differentiate constrictive pericarditis (CP) from restrictive cardiomyopathy (RCM). These include: 1) the difference of

left ventricular end-diastolic pressure (LVEDP) and right ventricular end-diastolic pressure (RVEDP); and 2) the ratio of RVEDP to right ven-

tricular end-systolic pressure (RVESP). Although there is a statistical difference when comparing the means of these criteria in a number of

patients, the degree of overlap makes application to an individual case difficult. Adapted with permission from Talreja et al. (29).


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SUMMATIVE APPROACH TO DIAGNOSIS

Diagnosis of CP and RCM requires a multifacetedapproach, as outlined herein in detail. Understandingthe multimodality imaging features of both entities isa crucial step (Figure 10). An organized approach torecognition of historical, examination, imaging, andhemodynamic findings of both CP and RCM shouldguide evaluation (Central Illustration).

CLINICAL IMPACT OF

DIAGNOSIS/TREATMENT

Although clinical and diagnostic features of CP andRCM often overlap, management differs significantly.CP represents a reversible cause of heart failure, withpericardiectomy potentially curative, whereasfrequently, RCM has few treatment options. Recog-nition of the primary underlying disease process iscritical, given these therapeutic differences.

Diuresis is the mainstay of pharmacotherapy in CP,and may be sufficient to control mild symptoms.

A subset of the patients with relatively recent onset(<3 months) of CP can be managed with nonsteroidalanti-inflammatory agents or steroids if there isongoing marked pericardial inflammation, as evi-denced by elevated inflammatory biomarkers andintense delayed enhancement on CMR (84). In sub-acute CP, such as effusive CP, spontaneous resolutionor resolution with anti-inflammatory agents has beendemonstrated (83,111,112). In one series, effusive CPwas present in 17% of cases, and it may be reasonableto observe or treat with anti-inflammatory agents fora period of 3 months, dependent upon the clinicalscenario (112). Anti-inflammatory agents may benonspecific or specifically targeted, such as antitu-bercular therapies. Treatment of tubercular pericar-ditis remains a challenge, with neither prednisolonenor Mycobacterium indicus pranii immunotherapydemonstrating a significant effect on a compositeendpoint of death, cardiac tamponade requiringpericardiocentesis, or progression to CP (113).Further consideration of strategies such asangiotensin-converting enzyme inhibitor therapy and

FIGURE 10 Multimodality Approach to Differentiating CP and RCM

Advanced cardiovascular imaging

Echocardiography

Medial e’velocity

Medial e’ tolateral e’ ratio

Transmitralinflow

Septalshift

Hepaticveins

Increased Decreased Increased DecreasedIncreased

respiratoryvariation

Normal

Decreasedforward velocity +

increasedexpiratory diastolic

reversals

Increasedforward velocity +

increasedinspiratory diastolic

reversals

FavorsConstriction

FavorsRestriction

FavorsConstriction

FavorsRestriction

FavorsConstriction

FavorsRestriction

FavorsConstriction

FavorsRestriction

Cardiac CT Cardiac MRI

Increasepericardialthickness

Cardiaccontour

deformation

Severe biatrialenlargement

Increasedpericardialthickness

Pericardialinflammation/

fibrosis

Increasedrespirophasicseptal shift

Septalbounce

Severebiatrial

enlargement

Abnormalwall

thickness

Abnormalmyocardial

delayedenhancement

Abnormalmyocardial

nullingamyloidosis

FavorsConstriction

FavorsConstriction

FavorsRestriction

FavorsConstriction

FavorsConstriction

FavorsConstriction

FavorsConstriction

FavorsRestriction

FavorsRestriction

FavorsRestriction

FavorsRestriction

Imaging features of echocardiography, cardiac CT, and CMR to distinguish constriction and restriction (Online Video 1). Abbreviations as in Figures 1, 7, and 8.



2342

intrapericardial fibrinolytic agents for preventingtuberculous CP has been proposed (114).

The gold standard for treatment of CP remainscomplete pericardiectomy (12,15,115). Peri-cardiectomy results in significant improvement inNew York Heart Association (NYHA) functional classand filling pressures (12,115,116). Timing of surgery istailored to the patient; however, earlier surgicalintervention may prevent ventricular dysfunction,thereby avoiding myocardial atrophy and post-operative ventricular dilation (117). Numerous oper-ative approaches have been described (118), withsome favoring median sternotomy for exposure,whereas others prefer left anterolateral thoracotomyto avoid sternal infection (115,119). Data from largeseries would suggest no clear benefit associated withspecific surgical approaches (15). Despite this, there issignificant evidence for the benefit of complete peri-cardiectomy over partial pericardiectomy or pericar-dial window, namely lower perioperative mortality,less post-operative low-output syndrome, shorterhospitalization stays, and improved long-term sur-vival (15).

Complete pericardiectomy refers to wide excisionof the pericardium anteriorly between the 2 phrenicnerves, and from the great arteries superiorly to thediaphragm inferiorly, posterior to the left phrenicnerve (which remains on a pedicle) to the left pul-monary veins, including the pericardium on the dia-phragmatic and posterior surfaces of the ventricles,with constricting layers of epicardium also removed(12,120). During surgery, the previously strangledheart can be seen to “jump” out of the constrainingpericardium. Complete surgical excision of the peri-cardium may be technically challenging, becauseinflammation can result in dense adherence of tissuelayers; therefore, it is not uncommon for areas of thepericardium to remain, especially in the vicinity ofthe epicardial coronary vessels. This may result inpersistence of abnormal hemodynamics, albeit withmilder clinical manifestations and improved patienttolerance. Further data are warranted comparingconcomitant surgical coronary artery bypass graftingduring a long, technically challenging cardiac surgeryversus percutaneous revascularization. The methodof revascularization is a decision that necessitates

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CENTRAL ILLUSTRATION CP and RCM: Approach to Diagnosis

Constrictivepericarditis

Cardiacprocedures

Geneticdisease

RadiationRadiation

Infection(eosinophilic disease)

Amyloidosis

Connective tissuedisease

Connective tissuediseasePatient history

Jugular venouspressure (JVP)

Advanced cardiacimaging

Invasivehemodynamics

Cardiac MRI

Echocardiogram

Cardiac CT

Lab/ECG/X-ray

Infection(TB)

Pericardialthickness Wall thickness

Pericardial Biatrialenlargement

Pulmonaryhypertension

Tissue characterizationabnormalities

Pericardial

Imaging correlates ofventricular interdependence

Systolic and diastolicdysfunction

Pericardial

y x y x

Kussmaul’s sign

Discordant respirophasicventricular pressure

changes

Concordant respirophasicventricular pressure

changes

Restrictivecardiomyopathy

Kussmaul’s sign

Geske, J.B. et al. J Am Coll Cardiol. 2016;68(21):2329–47.

Differentiation of constriction and restriction requires a multifaceted approach inclusive of history, physical examination, laboratory testing, and multimodality imaging.

Even with this toolset, hemodynamic catheterization remains necessary to provide definitive hemodynamic assessment for a subset of patients. CP ¼ constrictive

pericarditis; CT ¼ computed tomography; ECG ¼ electrocardiogram; JVP ¼ jugular venous pressure; MRI ¼ magnetic resonance imaging; RCM ¼ restrictive

cardiomyopathy; TB ¼ tuberculosis.


2343

cardiovascular surgery expertise and individualizedpatient decision-making. Although pericardiectomyis largely referred to as “curative” (even herein),outcomes in patients post-pericardiectomy are worse

with advanced NYHA symptom class, underlying ra-diation heart disease (with the best outcome seenwhen the etiology is idiopathic), advanced age,female sex, impaired renal function, pericardial



2344

calcification, LV systolic dysfunction, and pulmonaryhypertension (12,15,121–123). Perioperative mortalityis generally <5%, excluding patients with prior radi-ation therapy, whose perioperative mortality mayexceed 20% (15,118,123).

Unfortunately, treatment options remain limited inRCM. Diuretic agents may alleviate symptoms inthose with milder clinical phenotype. Infiltrative eti-ologies may have disease-specific therapies targetedat the underlying disease, although in many cases,cardiac dysfunction persists, despite therapies. Pedi-atric studies of primary RCM demonstrate relentlessprogression to death or transplantation (124,125).Ammash et al. (126) found a 5-year survival of 64%(expected 85%) in a predominantly adult population(mean age 64 years). Men >70 years of age withhigher NYHA functional class and LA dimension>60 mm demonstrated the worst prognosis. Priorseries have suggested that patients with primary RCMpresent earlier, but survive longer after presentationthan those with amyloidosis (127); however, intervaladvances in therapy for cardiac amyloidosis may alterthese results. In symptomatic patients who aretransplant candidates, transplant evaluation is war-ranted. Post-cardiac transplantation outcomes arecomparable to those of non-RCM patients, althoughsubgroup analysis suggests increased mortality forRCM secondary to radiation or amyloidosis (128). Inpatients who are not transplant candidates, palliativemeasures should be pursued.

Management of mixed constriction/restriction re-mains a challenging undertaking. Should hemody-namic evaluation reveal a substantial component ofconstrictive physiology in a patient unresponsive todiuretic therapy, pericardiectomy may be considered,with tempered expectations. Consistent datademonstrating worse outcomes in patients withradiation-induced CP may indeed reflect subclinicaloverlap in CP and RCM.

FUTURE DIRECTIONS

Further exploration of underlying inflammatory pro-cesses and myopericardial tissue mechanics mayprovide insight as to why certain patient cohorts havea predilection for developing CP following an in-flammatory insult, whereas others spontaneouslyresolve. Although the study of CP has been extensive,there is a distinct paucity of data on the natural his-tory and pathophysiology of primary RCM. Given themarkedly poor prognosis and lack of treatment op-tions apart from transplantation, there is potential fordevelopment of a host of novel therapeutics in RCM,spanning pharmacological therapies, biologic agents,and mechanical interventions.

Despite the multifaceted, evolving approach todifferentiating between CP and RCM, diagnosis oftenremains a clinical dilemma, with recognition anexigent need, given the life-altering impact of timelysurgery in CP. Our understanding of the role of cardiacCT and CMR in CP continues to evolve (46); however,validated refinement in diagnostic schemata, akin tothe Mayo Clinic echocardiographic criteria (43), arewarranted on a multimodality level. In cases of mixedconstrictive and restrictive hemodynamics, tools toassess the relative contribution of each component arelacking, and even complex invasive hemodynamiccatheterization in expert hands can yield un-certainties. The ability to discern the relative contri-bution of each hemodynamic insult has potential toguide therapeutic decision-making and temper oper-ative expectations. Although decades of study haveprovided a glimpse into the underpinnings of CP andRCM, there remains much to discover.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Jeffrey B. Geske, Department of Cardiovascular Dis-eases, Mayo Clinic, 200 First Street SW, Rochester,Minnesota 55905. E-mail: [email protected].

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KEY WORDS constrictive pericarditis, heartfailure, hemodynamics, restrictivecardiomyopathy

APPENDIX For a supplemental video andits legend, please see the online version of thisarticle.


































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