with left ventricular dysfunction after heart transplantion.pdf

7/21/2019 with Left Ventricular Dysfunction AFTER HEART TRANSPLANTION.pdf

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case records of themassachusetts general hospital

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 357;22 www.nejm.org november 29, 20072286

Founded byRichard C. CabotNancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d.,Associate Editor

Jo-Anne O. Shepard, m.d.,Associate Editor Alice M. Cort, m.d.,Associate EditorSally H. Ebeling,Assistant Editor Christine C. Peters,Assistant Editor

From the Cardiology Division (M.J.S.,J.J.P.) and the Department of Pathology(J.R .S.), Massachusetts General Hospital;the Cardiovascular Division, Brigham andWomens Hospital (L.W.S.); and the De-partments of Medicine (M.J.S., L.W.S.,

J.J.P.) and Pathology (J.R.S.), Harvard Medi-cal School.

N Engl J Med 2007;357:2286-97.

Copyright 2007 Massachusetts Medical Society.

PRESENTATION OF CASE

Four weeks after he received a heart transplant, a 47-year-old man was admitted tothis hospital because of ventricular dysfunction detected on echocardiography. Thepatient had been well until 19 months earlier, when congestive heart failure devel-oped, followed by several syncopal episodes. Echocardiography performed at anotherhospital revealed a speckled pattern of reflectance of the ventricular myocardium,and pathological examination of a biopsy specimen of a fat pad obtained at thathospital was positive for the presence of amyloid. Examination of a bone marrowbiopsy specimen revealed 10% plasma cells, and free lambda light chains werepresent in the serum.

One month later, 6 months before the admission under discussion, the patientwas admitted to this hospital for evaluation for serial cardiac and hematopoieticstem-cell transplantation. The patient had serologic evidence of past exposure tocytomegalovirus (CMV), toxoplasma, and varicella. Results of other laboratory testsare shown in Table 1. Pathological examination of endomyocardial-biopsy specimensrevealed lambda-light-chain amyloidosis. Echocardiography revealed left ventricu-lar hypertrophy with a speckled pattern of reflectance, left ventricular dysfunctionwith an ejection fraction of 32%, a dilated left atrium, and mitral regurgitation.Twenty-four-hour outpatient Holter monitoring revealed five premature ventricularcontractions, atrial premature contractions, and a three-beat run of atrial tachycar-

dia. Amyloid deposits were present within blood-vessel walls in biopsy specimens ofthe small intestine and colon.During the next month, paroxysmal nocturnal dyspnea and orthopnea developed,

and the patient was admitted to this hospital with a diagnosis of New York HeartAssociation class IV congestive heart failure (symptoms of heart failure at rest)to await the availability of a donor heart. Heparin, furosemide, dobutamine, nor-epinephrine, and milrinone were administered; an intraaortic balloon pump wasinserted, followed 2 weeks later by a biventricular assist device. Laboratory-testresults are shown in Table 1. The patients course was complicated by several epi-sodes of cardiac arrest requiring resuscitation and by cholecystitis, for which a

Case 37-2007: A 47-Year-Old Manwith Left Ventricular Dysfunction

after Heart Transplantation

Marc J. Semigran, M.D., Lynne Warner Stevenson, M.D., Jonathan J. Passeri, M.D.,and James R. Stone, M.D., Ph.D.

Downloaded from www.nejm.org on March 11, 2010 . Copyright 2007 Massachusetts Medical Society. All rights reserved.


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case records of the massachusetts general hospital

n engl j med 357;22 www.nejm.org november 29, 2007 2287

Table 1.Results of Laboratory Tests.*

TestReference Range,

Adults6 Mo beforeAdmission

5 Mo beforeAdmission

4.5 Mo beforeAdmission

1 Mo beforeAdmission Hospital Day 2

Hematocrit (%) 41.053.0 (in men) 42.1 38.9 30.9 33.0 37.2

Hemoglobin (g/dl) 13.517.5 (in men) 13.9 12.8 10.6 11.1 12.2

White-cell count (per mm3) 4,50011,000 6,700 6,000 10,600 7,000 5,300

Differential count (%)

Neutrophils 4070 75 94

Lymphocytes 2244 18 5

Monocytes 411 4 1

Eosinophils 08 2 0

Basophils 03 1 0

Platelet count (per mm3) 150,000350,000 160,000 159,000 183,000 402,000

Prothrombin time (sec) 11.113.1 14.3 21.5 15.1 18.4

Partial-thromboplastin time (sec) 22.135.1 32.6 52.1 89.8

International normalized ratio 1.4 3.0 1.5 1.5

Glucose (mg/dl) 70110 82 93 139 126 170Sodium (mmol/liter) 136145 139 135 129 139 131

Carbon dioxide (mmol/liter) 23.031.9 28.0 26.6 33.1 28.1 16.5

Urea nitrogen (mg/dl) 825 24 17 58 17 48

Creatinine (mg/dl) 0.61.5 1.2 1.3 1.4 0.7 1.3

Albumin (g/dl) 3.35.0 4.2 3.8 2.9

Globulin (g/dl) 2.64.5 2.7 2.9 2.4

Phosphorus (mg/dl) 2.64.5 4.1 1.8 4.9

Magnesium (mmol/liter) 0.71.0 0.85 1.35 0.75

Calcium (mg/dl) 8.510.5 9.5 8.7 9.2 8.2

Creatine kinase (U/liter) 60400 (in men) 78 430 550 54

Creatine kinase MB isoenzymes (ng/ml) 0.06.9 7.1 13.5 52.2 5.5

Troponin T (ng/ml) 0.000.09 0.06 0.06 2.05 4.47

Troponin I Negative

Alkaline phosphatase (U/liter) 45115 80 76 49

Aspartate aminotransferase (U/liter) 1040 26 55 15

Alanine aminotransferase (U/liter) 1055 18 25 31

Lipase (U/dl) 1.36.0 6.3 2.0 1.6

Amylase (U/liter) 3100 64 46 32

Triglycerides (mg/dl) 0150 116 66

Cholesterol (mg/dl) Desirable,


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cholecystectomy was performed. Amyloid waspresent in the gallbladder and in a biopsy speci-men of the liver obtained during the operation.

Four months after admission, orthotopic hearttransplantation was performed from a 47-year-oldmale donor who had a history of hypertension andserologic evidence of past CMV infection, with

testing equivocal for toxoplasma exposure. A coro-nary angiographic examination of the donor be-fore transplantation was reported to show mild,hemodynamically insignificant atherosclerosis inthe proximal left anterior descending artery. Patho-logical examination of the patients explanted heartrevealed biventricular hypertrophy and dilatation,with deposition of amyloid in the interstitium,blood-vessel walls, endocardium, and epicardialadipose tissue. Immunosuppression with cyclo-sporine, mycophenolate mofetil, and prednisonewas begun. Two days after transplantation, a

cardiac ultrasonographic examination was per-formed (Table 2). Five days later, cardiac cathe-terization was performed (Table 3). Pathologicalexamination of a biopsy specimen of the rightventricle showed no evidence of acute cellular re-jection or amyloid. The patient was discharged onthe 11th postoperative day.

Four days after discharge, a pathological ex-amination of a biopsy specimen of the right ven-tricle obtained at the time of right heart cathe-terization showed no evidence of acute cellularrejection or amyloid deposition. Eight days later,repeat right heart catheterization was performed(Table 3). Pathological examination of a third en-

domyocardial biopsy specimen revealed no evi-dence of acute cellular rejection or amyloid depo-sition; focal myocardial injury was present thatwas attributed to perioperative ischemic injury.The patient gradually increased his activity, wasable to walk up four flights of stairs, and had noorthopnea, nocturnal dyspnea, or leg edema. Threedays before admission, a routine follow-up trans-thoracic echocardiographic examination was per-formed (Table 2). Three days later, when the reportof the results of echocardiography were received,the patient was readmitted to this hospital.

The patient did not report chest pain otherthan that associated with the surgical incisions,and he did not report fever, chills, or a change inhis energy level. He had a history of a partialcomplex seizure disorder, gastroesophageal re-f lux disease, and migraine headaches; he had hadan appendectomy in childhood. Medications on

Table 2.Results of Echocardiographic Studies.

VariableNormalValues

1 Mo beforeAdmission

3 Days beforeAdmission

Left atrium (mm) 2538 34 41

Aorta (mm) 2439 36 33

Left ventricular internal end-diastolic diameter (mm) 3753 46 47

Left ventricular internal end-systolic diameter (mm) 33 41

Posterior wall thickness (mm) 711 10 9

Thickness of interventricular septum (mm) 711 11 12

Left ventricular ejection fraction (%) >50 54 24

Left ventricular function Normal Normal Severely impaired

Left ventricular wall motion Normal Normal Anterior, septal, and apicalhypokinesis to akinesis

Estimated right ventricular systolic pressure (mm Hg)


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admission included cyclosporine (150 mg everymorning and 125 mg every evening), mycophe-nolate mofetil (1250 mg twice daily), prednisone(25 mg daily), valganciclovir (900 mg daily), eso-meprazole (20 mg daily), levetiracetam (500 mgtwice daily), atovaquone (1500 mg daily), and ny-statin. He was allergic to trimethoprimsulfa-

methoxazole. He lived with his wife and childrenand received physical therapy and nursing care athome. He had lived in the midwestern UnitedStates, traveled throughout the United States andGuatemala, and worked with indigent populations.He did not smoke or drink alcohol, and he main-tained a diet low in sodium and saturated fat.

On examination, the blood pressure was130/70 mm Hg, the pulse 96 beats per minute,and the temperature 36.1C; the respirations were20 breaths per minute. The jugular venous pres-sure was 10 cm. The S1 and S2 heart sounds

were normal, and there was an S3 gallop witha systolic murmur at the apex. There were de-creased breath sounds at the left base, mild crack-les at the right base, and trace pitting edema inboth legs. Laboratory-test results are shown in

Table 1. A chest radiograph revealed subsegmen-tal atelectasis at the left base; other lung fieldswere clear. An electrocardiogram showed a sinusrate of 120 beats per minute, new Q waves acrossthe precordium, and T-wave inversions in leadsV4through V6. One gram of methylprednisolonewas infused intravenously.

Overnight, the patients systolic blood pres-sures decreased to 80 to 90 mm Hg, despite abolus of 250 ml of normal saline. The next day,a diagnostic procedure was performed.

DIFFERENTIAL DIAGNOSIS

Dr. Lynne WarnerStevenson:May we review the pre-transplantation echocardiographic studies?

Dr. Jonathan J. Passeri: An echocardiographicstudy performed before heart transplantationshows left ventricular hypertrophy. The myocar-

dium has a speckled pattern of reflectance thatis usually seen in infiltrative cardiomyopathiesand is classically described in cardiac amyloid(Fig. 1A and 1B, and Video 1 in the Supplemen-tary Appendix, available with the full text of this

Table 3.Results of Cardiac Catheterization Studies.

Variable Normal Values22 Days before

Admission14 Days before

Admission6 Days before

Admission

Thermodilution cardiac output(liters/min)

3.38 4.22 3.28

Cardiac index (liters/min/m

2

) >2.4 1.73 2.43 1.86Pulmonary vascular resistance

(dyn sec cm5)


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article at www.nejm.org). The echocardiographicstudy also shows moderately impaired left ven-tricular function, diffuse left ventricular hypoki-nesis, a restrictive mitral inflow filling pattern,moderate functional mitral regurgitation, and ele-vated right ventricular systolic pressure.

Dr. Stevenson:Before transplantation, this pa-

tient had a rapidly progressive course typical ofprimary amyloidosis, which was dominated byincreasing evidence of heart failure, with evidenceof extracardiac deposition of amyloid in adiposetissue and in the vasculature of the intestine,liver, and gallbladder. After transplantation, heappeared to be doing well clinically, with no evi-dence of transplant rejection, but echocardio-graphic examination on the 27th postoperativeday showed evidence of left ventricular dysfunc-

tion. Three days later, he was admitted to thehospital, and he had clinical evidence of heartfailure. This case raises several issues, includingthe natural history and management of cardiacamyloidosis, the evaluation of donor organs be-fore transplantation, and the differential diagno-sis of cardiac failure in the early post-transplan-

tation period.

Primary Cardiac Amyloidosis

The prognosis associated with primary amyloidlight-chain cardiac amyloidosis is very poor, witha median survival of less than 1 year after presen-tation.1The therapies usually used to stabilize anddecrease progression in other cardiomyopathiesare of little use in this disease, since the courseis characterized not only by abnormalities of the

A B

DC

l

LV

LA

E

A

Figure 1.Echocardiographic Images.

A transthoracic echocardiogram, parasternal long-axis view, 5 months before transplantation (Panel A) shows hyper-trophy of the left ventricle (LV). The interventricular septum (arrows) is 1.7 cm in thickness. The myocardium has a

speckled pattern of ref lectance suggesting an infiltrative cardiomyopathy. LA denotes left atrium. Pulsed-wave Dopplerimaging of the mitral inflow (Panel B) shows a tall E wave, a deceleration time of 120 msec, and an E-to-A wave ratio

of 3.2, indicating restrictive left ventricular filling. A transthoracic echocardiogram 27 days after transplantation

shows a dramatic change. In the parasternal long-axis (Panel C) and apical four-chamber (Panel D) views, the arrowsindicate areas of segmental dysfunction involving the interventricular septum and the apex, including both the left

and right ventricular myocardium.



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myocardium but also by the relentless accumula-tion of amyloid in the heart and other organs,particularly in the kidneys.

Treatment options for primary systemic amy-loidosis are limited. Transplantation of autolo-gous stem cells after intensive conditioning regi-mens has been associated with modest responses

in patients with amyloidosis, but patients withadvanced cardiac disease cannot tolerate this pro-cedure. Conversely, patients with amyloidosis maysurvive for 1 year after cardiac transplantation,but few patients survive for 5 years; most deathsresult from either systemic complications of amy-loidosis or from recurrence of amyloidosis in theallograft.2Therefore, sequential cardiac and he-matopoietic stem-cell transplantation has recentlybeen used for selected patients with primaryamyloid light-chain cardiac amyloidosis, with thegoal of both improving cardiac function and ar-

resting further deposition of amyloid, and thisplan was adopted for this patient.3,4

The Donor Heart

At the time of transplantation, the history of thedonor heart merges with the history of the recipi-ent. The donor was the same age and sex as thepatient. He had a history of hypertension, but apost-transplantation echocardiogram did not showleft ventricular hypertrophy of the donor heart;

this abnormality has been associated with earlygraft dysfunction due to ischemic injury. It isroutine for male donors older than 45 years ofage to undergo coronary angiographic examina-tion to ensure that the transplanted heart is freeof clinically significant coronary disease.5Thedonor angiogram in this case revealed no hemo-

dynamically significant coronary stenoses (Video 2in the Supplementary Appendix). However, severalareas did not appear to be completely normal, in-cluding focal dilatation and then narrowing ofthe left anterior descending artery. Since the se-verity of stenosis detected on angiography farunderestimates the prevalence of plaque in thecoronary arteries, vulnerable plaque may be pres-ent either at these areas or at others.

Early Decline in Cardiac Function

after Transplantation

A favorable early post-transplantation course wasparticularly important for this recipient, so that hecould undergo stem-cell transplantation beforethe progression of amyloidosis. However, he ex-perienced a sudden decline in left ventricularfunction 27 days after transplantation. At thispoint, we are faced with the differential diagno-sis of cardiac dysfunction 1 month after trans-plantation (Fig. 2).

The first question is whether cardiac dysfunc-

Cardiac dysfunction

Transplantrejection

Other cardiacdysfunction

Noncardiac conditions

Heart failure

Transplantrejection

Humoralrejection

Ischemic injuryDonor CADNew CADEmbolusCoagulopathy

Surgical or post- surgical injury

TamponadeValve diseaseSurgical mishapBiopsy mishap

AmyloidCardiac infection

CMVToxoplasmosisOther

BleedingAdrenal insuffi-

ciencySepsis

Figure 2.Differential Diagnosis of Heart Failure in the Early Post-Transplantation Period.

CAD denotes coronary artery disease, and CMV cytomegalovirus.



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tion is the primary problem or whether it is sec-ondary to a systemic illness. The patient was stillreceiving high doses of immunosuppressive drugsand was at risk for multiple complications. In-fection, the most common complication, can pri-marily involve the heart or it can be systemic.Infection with CMV can affect the heart and pre-

sents a particular risk when the donor is sero-positive and the recipient seronegative; in thiscase, both the donor and patient were seroposi-tive for CMV infection, and the patient was receiv-ing antiviral prophylaxis, making this diagnosisunlikely.

Transplant Rejection

If cardiac dysfunction is primary, the f irst ques-tion is whether it is because of transplant rejec-tion or another cardiac problem. Rejection withhemodynamic compromise 1 month after cardiac

transplantation is an uncommon, but very seriousoccurrence. A biopsy 1 week earlier showed noevidence of cellular rejection; therefore, cellularrejection would be unlikely at this time unlessthe patient had discontinued his immunosuppres-sive medications. Another form of rejection, hu-moral rejection, is antibody-mediated, and it isclinically defined as hemodynamic compromisethat is responsive to therapy in the absence oflymphocytic infi ltration.6It is characterized byglobally reduced left ventricular function, oftenwith increased wall thickness indicative of intra-myocardial edema. If this patients cardiac dys-function is due to rejection, the rejection is prob-ably humoral.

Other Causes of Cardiac Dysfunction

In the f irst month after transplantation, left ven-tricular dysfunction may be due to technical prob-lems that occur during the surgery or other relatedinvasive procedures. Pericardial tamponade maydevelop because of bloody fluid accumulation ina large pericardial cavity that contains the relative-

ly small donor heart. This development is unlike-ly in this patient because the pericardial cavity isusually small in a patient with amyloidosis, andthere was no evidence of tamponade on the echo-cardiogram. Tricuspid regurgitation and, less com-monly, mitral regurgitation can result from dis-tortion of the fibrous skeleton encircling thevalves. Tricuspid regurgitation can occur as acomplication of endomyocardial biopsy; this pa-tient had already had three such biopsies. How-

ever, this complication should be evident on theechocardiogram.

An ischemic event occurring early after trans-plantation is very uncommon, and ischemia wouldbe low on the initial differential diagnosis of adepressed ejection fraction at 1 month. My suspi-cion for ischemia would be increased if region-

al wall-motion abnormalities corresponding to acoronary-artery territory were noted on the echo-cardiogram. May we review the echocardiograph-ic studies performed after transplantation?

Dr. Passeri:A transthoracic echocardiographicexamination performed 3 days after cardiac trans-plantation shows that the left ventricular sizeand function are normal, and there are no seg-mental wall-motion abnormalities. On the trans-thoracic echocardiogram 27 days after transplan-tation, a stark difference in cardiac function isimmediately evident (Fig. 1C and 1D, and Video 3

in the Supplementary Appendix). There is severeimpairment of left ventricular function, with anejection fraction of 24%, and segmental wall-motion abnormalities involving the septum, ante-rior and anterolateral walls, and entire apex arepresent.

Myocardial Infarction

Dr. Stevenson:The marked decrease of contractilityin the anterolateral wall begins abruptly at a hingepoint in the septum and does not extend to theinferior wall. This regional abnormality suggestscompromise of the left anterior descending artery,which, as we recall from the donor angiogram,supplied a large territory. Mitral regurgitation hasalso appeared as a consequence of the affectedmitral-valve supporting apparatus.

What else do we know at this time? The pa-tient has elevated filling pressures on both theleft side, which are manifested by rales and a newthird heart sound, and the right side, which aremanifested by high jugular venous pressure andperipheral edema. He did not have chest pain,

since ischemic chest pain is not experienced inthe denervated heart. The electrocardiographicexamination performed on this admission con-firms the presence of an acute myocardial infarc-tion (Fig. 3). A right bundle-branch block is seenthat was not present in the early post-transplan-tation electrocardiogram. Right bundle-branchblock is a common, clinically insignif icant find-ing in transplanted hearts, but it is present im-mediately after implantation. Extensive ischemia



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is required to produce a new right bundle-branchblock, because of the dual coronary blood supply.ST-segment elevation is present throughout mostof the precordium, and there is loss of positiveforces in the lateral leads. The results of boththe echocardiogram and the electrocardiogramprovide support for the diagnosis of myocardialinfarction. The two questions now are: why andwhen did this occur?

Causes of Myocardial Infarction in Allografts

There are multiple unusual causes of myocardialinfarction in the early period after transplanta-tion.7-9However, the most likely cause in this caseis a thrombus in the proximal left anterior de-scending artery, which was abnormal at the time

of transplantation. A possible aggravating factorcould be abnormalities of coagulation in the re-cipient that are related to his amyloidosis.10

Timing of Myocardial Infarction in this Patient

It is not clear when the myocardial infarction oc-curred. The catheterization 6 days before admis-sion showed a decline in cardiac output despite arise in filling pressures, so there may have beenischemia or infarction at that time. However, the

patients condition was described as improvingon the basis of his ability to walk up four flightsof stairs. There was no apparent change in hisclinical status between that time and the echo-cardiographic examination 3 days later that showedthe infarction. After another 3 days, however, thepatient became hypotensive. At that time, the tro-ponin was elevated, but it probably was higherwhen such a large infarction occurred. Did thedelayed onset of symptoms reflect a progressivedecline of function in the unaffected compensat-ing myocardium? Was the sudden deteriorationafter admission caused by a mechanical compli-cation of the large infarction, for which the heartwithout collateral vessels or ischemic precondi-tioning may be at higher risk? One of the chal-

lenges in caring for persons who have undergonecardiac transplantation is that these patients oftenhave two serious problems simultaneously. It ispossible that this patient had humoral rejectioncontributing to the decline in cardiac functionafter the myocardial infarction.

My primary diagnosis is anterior myocardialinfarction due to occlusion of the proximal leftanterior descending artery, occurring at sometime within the previous 2 weeks. Humoral re-

l

I

II

III

VI

II

V5

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

Figure 3.Electrocardiogram Obtained on This Admission.

This electrocardiogram shows right bundle-branch block that was not present on early post-transplantation electro-

cardiograms. ST-segment elevation is present throughout most of the precordium, and there is a loss of positiveforces in the lateral leads. The findings indicate an anterolateral myocardial infarct.



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jection is less likely as the primary diagnosis, butit may be a complicating feature. It would behelpful to review the previous endomyocardialbiopsy specimens to determine whether ischemicinjury may have been present.

The recommended diagnostic study is coro-nary angiography, with attention to the proximal

left anterior descending artery. Right-sided car-diac catheterization will permit us to determinethe severity of the hemodynamic compromise;this determination will guide further therapy. Arepeated endomyocardial biopsy would present anadditional risk of bleeding if a definitive coro-nary intervention necessitated aggressive antico-agulation.

DR. LYNNE WARNER STEVENSONS

DIAGNOSIS

Acute myocardial infarction due to occlusion ofthe proximal left anterior descending coronaryartery.

PATHOLOGICAL DISCUSSION

Dr. Marc J. Semigran:After the results of the echo-cardiographic examination were received, Dr.Thomas J. Wang, the patients cardiologist, re-viewed the biopsy results.

Dr. James R. Stone:Amyloid was present in thepretransplantation endomyocardial-biopsy speci-men (Fig. 4A). None of the three post-transplan-tation biopsy specimens showed evidence of acutecellular rejection or amyloid deposition; the sec-ond and third biopsy specimens, obtained 2 and3 weeks after transplantation, showed focal heal-ing injury, a typical finding after transplantation.However, a retrospective analysis of the biopsyspecimen obtained 3 weeks after transplantationalso revealed the presence of extensive acute ische-mic myocardial necrosis, consistent with an in-farct 3 to 5 days old (Fig. 4B).

Dr. Semigran:We proceeded immediately to cor-onary angiography. An intraaortic balloon pumpwas placed to add to hemodynamic stability. Theleft coronary-artery angiogram reveals an abruptcutoff of the left anterior descending coronaryartery at its origin (Video 4 in the Supplemen-tary Appendix). The left coronary artery shows anextensive area in which coronary blood flow into

the anterolateral wall of the left ventricle is lack-ing. There was no collateral filling of the leftanterior descending coronary artery, either from

the other branches of the left coronary artery orfrom the right coronary artery. We performedimmediate percutaneous coronary interventionwith thrombectomy and placement of a stent(Video 5 in the Supplementary Appendix). A leftcoronary angiogram obtained 5 minutes after theintervention showed impaired blood flow, al-though the previously obstructed left anterior de-

l

A

B

Figure 4.Endomyocardial-Biopsy Specimens.

A specimen from an endomyocardial biopsy performed

before transplantation (Panel A, hematoxylin and eo-sin) shows deposition of amorphous eosinophilic ma-

terial consistent with the presence of amyloid in the

myocardium (arrows). The inset (Congo red) shows or-ange staining of the amyloid. A biopsy performed 3

weeks after transplantation (Panel B, hematoxylin andeosin) shows an area of granulation tissue indicating

focal healing injury about 3 weeks in age (bottomright) and extensive acute ischemic myocardial necro-

sis, with loss of myocyte nuclei and infiltration by neu-trophils, findings consistent with an infarct 3 to 5 days

in age (upper left).



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scending coronary artery was now patent (Video 6in the Supplementary Appendix). During the next48 hours, an attempt was made to wean the pa-tient from the intraaortic balloon pump; thisattempt was unsuccessful, even with the use ofpharmacologic inotropic support. The patient wasagain placed on the waiting list for cardiac trans-

plantation. Approximately 3 weeks later, a donorheart became available, and a second cardiactransplantation was performed.

Dr. Stone:Examination of the explanted heartrevealed an extensive recent myocardial infarc-tion, 3 to 5 weeks of age, involving the anteriorleft ventricle and interventricular septum (Fig. 5Aand 5B). The regional distribution of the trans-mural injury is consistent with thrombosis of theleft anterior descending coronary artery and isnot consistent with humoral rejection, in whichthe injury would be diffuse. The coronary arter-

ies contained moderate-to-severe atherosclerosiswith 80% stenosis of the left anterior descend-ing coronary artery distal to the stent (Fig. 5C),70% stenosis of the middle right coronary artery,and 30% stenosis of the left main coronary artery.The eccentric nature of these vascular lesionsand the presence of foam cells and extracellularlipid deposition indicate chronic atherosclerosis,which was present in the graft at the time of trans-plantation. There was no evidence of allograftvasculopathy. There was mild acute cellular rejec-tion, which would be classified as InternationalSociety for Heart and Lung Transplantation grade1R in an endomyocardial-biopsy specimen.11Inaddition, there were endocardial lymphocytic le-sions (also called Quilty lesions), which are oftenseen in transplanted hearts.12 Examination ofsome of the recipients pericardium that was ad-herent to the allograft revealed the presence ofperivascular amyloid deposits. There was no evi-dence of amyloid in the myocardium of the allo-graft.

In pathological specimens of transplanted

hearts, coronary-artery thrombi are commonlyencountered 3 months or more after transplan-tation; they are typically associated with allograftvasculopathy.13Coronary-artery thrombosis andtransmural myocardial infarction are uncommonwithin 2 months after transplantation; they oc-curred in 1.5% of transplant recipients in a re-cent series.14These conditions are attributed to

A

B

C

l

Figure 5.Explanted Cardiac Allograft.

A gross photograph of a cross-section through the ven-tricles (Panel A) shows extensive necrosis of the anteri-

or left ventricle (bottom) and interventricular septum.Histologic section of the septum (Panel B, hematoxylin

and eosin) shows extensive organizing myocardial in-

farction with delayed healing in the center of the largeinfarct (bottom right) and preservation of subendocar-dial myocytes (top). There is atherosclerosis with 80%

stenosis of the distal left anterior descending coronaryartery (Panel C, hematoxylin and eosin). The eccentric

nature of the stenosis and the presence of foamy mac-

rophages indicate a chronic condition that was presentin the donor heart before transplantation.



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preexisting atherosclerosis in the donor heart.13,14Severe preexisting atherosclerosis with stenosis ofat least 75% has been documented in approximate-ly 10% of cardiac allografts that fail within thefirst 2 months, and in these cases, the donorsare typically older than 45 years of age, as wasthe donor in this case.13

Subsequent testing of the patients serum forantibodies to donor HLA antigens was negative.

Dr. Semigran:Five months after he received thesecond transplant, autologous stem-cell trans-plantation was successfully performed after thepatient received melphalan. Two and a half yearsafter cardiac transplantation and 2 years afterstem-cell transplantation, there has been no evi-dence of recurrence of amyloid in serial biopsyspecimens of the heart. The patient has returnedto full-time work and to full physical activity.

This case illustrates a problem that may in-

crease in frequency as the average age of cardiacorgan donors increases. During the period from1994 through 2005, the number of cardiac trans-plantations performed in the United States pla-teaued at 2100 to 2500 procedures per year,15despite an increase in the number of patientswith heart failure during that period. The num-ber of available heart donors is the major factorlimiting the number of transplantations per-formed. To increase the number of availabledonors, clinicians have increased the acceptableupper age limit for donors. Between 1982 and2004, there was a marked increase in the num-ber of heart donors between the ages of 35 and59 years and occasional use of organs from do-nors who were older than 60 years of age.16

In this case, according to current guidelinesfor the evaluation of a donor who may be at in-creased risk for having coronary disease, we per-

formed coronary angiography before organ har-vesting.5Although the donors coronary angiogramwas not normal, the abnormality was thought tobe of limited hemodynamic significance. The re-cipient was desperately ill, and we wanted to pro-ceed with cardiac transplantation before his sys-temic amyloidosis became so severe that successful

cardiac and subsequent stem-cell transplantationwould be impossible.

Dr. Joren C. Madsen (Cardiac Surgery): We didnot consider this donor to be a marginal donor,since the angiogram showed only minimal dis-ease. However, angiograms are not 100% sensitiveand do not reveal unstable plaque; examinationof the coronary arteries in the explanted cardiacallograft showed severe atherosclerotic disease.Perhaps advances in computed tomography ormagnetic resonance imaging will obviate thisproblem in the future. In this case, if the donor

heart had been found to have a hemodynamicallysignificant stenosis, coronary-artery bypass graft-ing could have been performed at the same timeas the transplantation.

ANATOMICAL DIAGNOSES

Moderate-to-severe atherosclerosis of the donorheart with thrombosis of the left anterior de-scending coronary artery and extensive anteriorand septal myocardial infarction.

Mild acute cellular rejection.Pericardial amyloid deposition.

Dr. Stevenson reports receiving consulting and lecture feesfrom Medtronics and grant support from Scios and Medtronics.Dr. Semigran reports receiving consulting fees from INO Thera-peutics and lecture fees from GlaxoSmithKline. Dr. Stone reportsreceiving consulting fees from Merck, MuscleTech, GNC, andWal-Mart. No other potential conflict of interest relevant to thisarticle was reported.

References

Kyle RA, Gertz MA, Griepp PR, et al.A trial of three regimens for primary amy-loidosis. N Engl J Med 1997;336:1202-7.

Pelosi F Jr, Capehart J, Roberts WC.Effectiveness of cardiac transplantationfor primary (AL) cardiac amyloidosis. AmJ Cardiol 1997;79:532-4.

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Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences

Any reader of theJournalwho uses the Case Records of the Massachusetts General Hospital as a teaching exercise or referencematerial is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the

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