Virus and the HeartBY WALTER H. ABEL-MAN-N, M.D.

SUMMARYNViral inifectionis may ox7erload the heart by alterinig pulmonary or systemic vascular

resistance, mav iniduce conigeniital malformations, or may invade the mature heartmuscle and provoke acute anid possibly chlronic myocarditis. The nature of theassociationi of myocarditis vith kniowvn viral infections anid the pathophysiologic effectsof myocardial involvenmeit are analyzed. Altlhough viral myocarditis of clinicalsigniificanice is relatively rare, recelnt advanices in diagnosis and therapy warrantgreater dissemination and application of existing knowlelge as xvell as further clinicalinivestigation.

Additional Indexing Words:Nlvocarditis

T HE NATURE OF cardiac involvementin viral diseases has been the subject of

several recent reviews.1-4 Viral infections mayaffect the heart in one of three ways:

(1) The infection may result in systemic orpulmonary hypertension (poliomyelitis) orsystemic vasodilatation, which in turn maylead to heart failure or circulatory collapse,especially in patients with underlying chroniccardiac or pulmonary disease. These circula-tory effects may account for much of thecardiovascular morbidity of viral etiology andfor most of the excess mortality of patientswith chronic cardiopulmonary disease duringinfluenza outbreaks.

(2) Infection during fetal life by xvirusesthat cross the placenta may induce congenitalmalformations. This relationship has been wvellestablished for rubella.5 About 50M of childrenexposed to maternal rubella during the firstmonth of fetal life have congenital anomalies,two thirds of which involve the heart. The risklessens subsequently but persists through the

From the Thorndike Memorial Laboratorv and theHarvard Medical Unit, Boston City Hospital, Boston,Massachusetts.

Supported in part by Grants HE 10539 and HE5244 from the N ational Heart and Lung Instittite,National Institutes of Health, U. S. Public HealthService, and from the Medical Care and EducationFoundation (Tri-State Regional Medical Programn).

950

fourth month. The most frequent anomaliesare patent ductus arteriosus and peripheralpulmonary stenosis. Efforts at wider exposureof prepubertal girls to rubella or rubellavaccination appear justified.

In addition, evidence for an associationbetween maternal Coxsackie B virus infectionand congenital heart disease has been present-ed by Brown and Evans.A Analysis of paired,maternal sera revealed a significantly higherincidence of infection with Coxsackie B virus,types 3 and 4, during pregnancy in themothers of 43 infants with congenital heartdisease than in matched controls. It is of notethat half of the infections were subclinical.Mumps virus has been assigned an etiologic

role in congenital endocardial fibroelastosis. Ina study by Shone and associates7 42 of 50cases had a positive reaction to intradermalkilled mumps virus antigen, compared to 9% of138 controls. Gersony, Katz, and Nadas,showever, were unable to confirm this in aseries of 16 cases.

(3) Viruses may invade the mature heartdirectly, inducing structural and functionalalterations.

Which Viruses Cause Myocarditis?Table 1 lists 18 of the more common viruses

or viral diseases generally accepted as poten-tial causes of myocarditis. Yet, we maylegitimately ask how many of these are

Circ ulation. Volumnc XLIV, November 1971

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

VIRUS AND THE HEART

Table 1

Viral Diseases Associated with Myocarditis

Rubeola Atypical pneumoniaRubella CoxsackieVariola Echo virusVaccinia Infectious hepatitisVaricella Infectious mononucleosisHerpes zoster PoliomyelitisMlumps Epidemic encephalitisInfluenza Yellow feverPsittacosis Rabies

established causes. Only influenza, Coxsackie,and poliomyelitis viruses have been isolatedfrom heart tissue with any regularity. Myo-carditis in animals infected experimentally hasbeen reported only for Coxsackie, vaccinia,pseudorabies, and encephalomyocarditis vi-ruses.

What are the Structural and Functional Effectsof Myocardial Invasion by Virus?The viruses associated with myocarditis are

blood borne and are thought to reach theheart with the more than 360 liters of bloodthat daily perfuse this organ even in inactiveman. Presumably virus leaves the capillariesand, via the perivascular interstitium, enters

NORMAL100

80 LV

tk 60 / RV

(1) 40 -,,Lu~~~~~~~~~~~~~~~~.

0 10 20 30 40 50

the myofibrils, in which it replicates. Myocyto-lysis, necrosis, and edema are thought to bethe direct effects of intracellular replication ofvirus. Autoimmune reactions have also beenpostulated but not proven.2 An inflammatoryresponse is usually-but not necessarily-pro-voked, resulting in accumulation of cellularinfiltrates, generally interstitial, often perivas-cular. These infiltrates are capable of healingwithout residua.9 Such microscopic lesionsmay be either focal or diffuse, without evidentabnormality upon gross inspection of theheart. Virus has also been isolated from heartsshowing no structural abnormalities onlight microscopy.9 On the other hand, theseverely and diffusely involved heart maydisplay pallor, flabbiness, dilatation, and evenincrease in weight.

I am not aware of any systematic hemody-namic observations in proven viral myocardi-tis-or myocarditis of any etiology. Hemody-namic observations made in this laboratory10in acute experimental Chagasic myocarditis inC3H mice due to Trypanosoma cruzi revealeda significant decrease in left ventricularsystolic pressure, no significant change in rightventricular systolic pressure, and significant

VOLUME (Micro/iters )Figure 1

Pressure-volume curves of isolated right and left ventricle of a normal CYH mouse (left) anda mouse with acute Chagasic myocarditis (right). LV = left ventricular; RV = right ventricular.Compliance of both right and left ventricles, indicated by the slope of the curves, is increasedin myocarditis.

Circulation, Volume XLIV, November 1971

951

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

A BELL\MANN

increases in both right and left ventricularend-diastolic pressures. These findings arecompatible with biventricular heart failure.The few isolated hemodynamic observationsin clinical cases of severe myocarditis thathave come to my attention are in agreementwith this hemodynamic pattern. Does thispattern represent true myocardial failure ordecreased compliance as in constrictive peri-carditis, endocardial fibroelastosis, interstitialfibrosis, or amyloidosis? To answer thisquestion, we are currently studying ventricu-lar pressure-volume characteristics at variousstages of experimental Chagasic myocarditis.Figure 1 depicts the left and right ventricularpressure-volume curves of a healthy controlmouse and a Chagasic mouse 80 days afterinoculation. The slopes of these curves reflectcompliance. The right ventricle is morecompliant than the left in the healthy as wellas the diseased mouse. In myocarditis, bothright and left ventricles appear more compli-apt. Thus, it would seem, at least in this formof myocarditis, that inflammation and necrosisincrease compliance and lead to dilatation ofthe ventricles. The increased diameter of thediseased ventricle, according to the law ofLaplace, results in an increase in wall tensionwhich may lead to further dilatation.

So far we have addressed ourselves togeneral and hemodynamic effects of diffusemyocarditis. We have already stated thatmyocarditis may be focal, without effect upongross appearance and heart weight andpresumably without hemodynamic effects.Focal myocarditis may cause atrial or ventric-ular irritability, atrial or ventricular tachyar-rhythmias, or partial or complete heart block.Focal lesions most frequently affect repolar-ization and result in S-T abnormalities of theelectrocardiogram. There is nothing specificabout any of these electrophysiologic effects.However, these changes tend to be variable,transient, and often completely reversible.

What Factors are Known to ModifyAcute Myocarditis?A number of factors have been identified as

potential modifiers of the incidence, nature,severity, and course of acute myocarditis.

Pearcell has shown that intravenous injectionlof pitressin, a powerful coronary vasoconstric-tor, as wvell as other means of inducingmyocardial hypoxia, increases the incidenceand severity of myocarditis in experimentalvaccinia and pseudorabies. The severity ofmyocarditis associated with a given infectionmay thus be determined by the extent towhich the disease and its complicationsenhance or decrease myocardial hypoxia.Hypoxia has been considered especially im-portant in the pathogenesis of myocarditisaccompanying poliomyelitis and influenza.Hypoxia may also, in part, be responsible

for the enhancing effect of exercise uponexperimental Coxsackie myocarditis first dem-onstrated in 1964 by Tilles and associates inour laboratory.!} When C3H mice infectedwith a cardiotropic strain of Coxsackie A9virus were exercised daily by swimming, viruswas isolated from 46% of the hearts of 24exercised animals but only from 8% of heartsof 24 control animals. Furthermore, virus wasisolated in higher titer from the exercisedanimals. Recently, Lerner and associates haveconfirmed the myocarditis-enhancing effect ofexercise for Coxsackie virus B3.12 When miceinfected with this more virulent strain weremade to swim, most animals died in acutecongestive failure.

In 1956, Kilbourne and collaborators13reported evidence of a synergistic effect ofcortisone and a cardiotropic virus. Their strainof Coxsackie B3 virus by itself resulted in butminimal focal lesions in mice. In the presenceof cortisone, however, disseminated myocar-dial necrosis was produced.

Peareell also reported that the incidence ofmyocarditis associated with experimental virusIII infection in rabbits was increased afterintravenous administration of Streptococcuspyogenes toxin. It is possible that respiratoryinfections of bacterial etiology, by means ofboth hypoxic and toxic effects, may precipitateor enhance myocarditis due to viral infections.It may thus be of interest to search for viraletiology of aseptic myocardial inflammatorylesions associated with bacterial infections.

Circulation, Volume XLlV, November 1971

952

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

VIRUS AND THE HEART

Table 2

Presentation of Viral Myocarditis

No clinical manifestationsUnexplained sinus tachycardiaAtrial or ventricular premature beatsAtrial or ventricular tachycardiaVentricular fibrillation/cardiac arrestPartial or complete heart blockGallop rhythmsPericardial rubHeart failureCirculatory collapse (shock)Abnormal ECG or X-rayIncidental autopsy finding

The above pathophysiologic considerationsmake it reasonable to postulate that increasedvolume or pressure loads upon either ventriclehave the potential not only of decreasingcardiac reserve, but also of enhancing the viralpathologic process and its consequences.Among possible factors that should be men-

tioned are fever, systemic and pulmonaryhypertension (e.g. in poliomyelitis), pregnan-cy, preexistent heart disease, and coexistentsystemic disease (e.g. anemia). No systematicexploration of the role of these factors has yetbeen carried out.

In What Manner Does MyocarditisPresent Clinically?The manner of clinical presentation (table

2) logically follows from the above considera-tions. A wide spectrum is evident, rangingfrom total absence of clinical manifestations tosudden unexpected death. The extent to whichthe presence of myocarditis will be suspectedis a function of the severity of the overtmanifestations, on the one hand, and thealertness of the clinician on the other. It mustalso be kept in mind that the cardiovascularmanifestations may be overshadowed by thesystemic manifestations of the viral illness. Thedetails of symptoms, signs, and laboratoryfindings in viral myocarditis have often beenreviewed.1 3 4 Myocarditis should be suspect-ed when an individual without prior heartdisease and without evidence of ischemicheart disease develops atrial or ventriculararrhythmias or conduction disturbances (es-Circulation, Volume XLIV, November 1971

pecially if transient), changing electrocardio-graphic abnormalities (especially of repolar-ization), cardiac enlargement, pericardialfriction rub or effusion, heart failure, or cardiacarrest. Tachycardia is the rule, but bradycar-dia has been observed. Gallop rhythms mayconstitute the only evidence of heart failure.In more severe failure, the pulse tends to besmall, and blood and pulse pressure low.Whereas signs and symptoms of left ventricu-lar failure may predominate, the picture isusually one of right or biventricular failure.Dilatation of atrioventricular valve rings andventricles may result in mitral or tricuspidinsufficiency. Myocarditis may, however, de-velop rapidly and progress to circulatorycollapse, before congestive heart failure hasbecome manifest.How is the Diagnosis of Viral MyocarditisEstablished for the Individual Patient?When a patient is seen early during the

course of illness, it may be possible to isolatevirus from throat washings, stool, blood, ormyocardium. This is most likely to besuccessful within the first week. Isolation of avirus establishes its presence, but does notnecessarily prove its etiologic role in the illnessunder consideration.

Detection of rising antibody titer in theserum during the second and third weeks ofconvalescence may be considered evidence ofa recent infection likely to be related to recentsymptoms. To this end, tests for complementfixation, virus neutralizing antibody, andhemagglutination inhibition are becomingincreasingly available. A fourfold increase isthe generally accepted criterion for a currentinfection. Recently, identification of antigen intissue or body fluids by immunofluorescentmethods and demonstration of virus in tissueby means of electron microscopy have becomepossible and promise to become clinicallyuseful.3

What is the True Incidence of and Mortalityfrom Myocarditis?

Careful search by Gore and Saphir14revealed an incidence of 1,402 cases ofmyocarditis among more than 40,000 autopsiesat the Armed Forces Institute of Pathology.

953

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

ABELMANN

Table 3

Thle apiy of Acute Alyocarditis

Specific therapyRestriction of activityOxygenMJonitoringAnitiarrhvthrnic drugsArtificial pacemakerD)igitalisDiuretics

Of these, 70 were found in association withviral diseases, and 84 cases of isolatedmyocarditis might have been of viral etiology.If these two groups are combined, an

incidence of 0.38% is obtained. During 1967,860 deaths or 0.4 per 100,000 population wereattributed to acute, nonrheumatic myocarditisin the United States.'5 The validity of theseestimates is open to question.

Morbidity is equally difficult to assess. Formost viral diseases, involvement of the heartappears to be rare. Although it has beenestimated that in outbreaks of Coxsackie viraldisease cardiac involvement occurred in about5% of cases,16 we really do not know the size ofthe population infected. Furthermore, reliablecriteria for cardiac involvement have not beenestablished. Thus, the validity of nonspecificelectrocardiographic abnormalities of the Twave and S-T segment in the diagnosis ofacute myocarditis has recently been ques-

tioned by Scott and collaborators,'7 who findthat while 1.49% of 737 children with acuterespiratory infection had such electrocardio-graphic abnormalities, 1.85% of a controlgroup of 108 children exhibited similarchanges. Laboratory evidence of recent viralinfection was encountered just as often inpatients with normal as in patients withabnormal electrocardiograms (49.5 vs. 42.6%).On the other hand, an interesting recentreport suggests that asymptomatic myocarditismay be quite frequent. Stevens and Ground,18on the basis of studies of the hearts of 263pilots killed in aircraft accidents, concludedthat the incidence of asymptomatic, isolated,focal myocarditis may be as high as 5% inBritish males aged 18 to 50 years, and cite

evidence that the incidence in Australia maybe even higher.

What are the Principal TherapeuticConsiderations?

Therapy is influenced by the etiology of thedisease, as well as by its manifestations. Theprincipal therapeutic modalities are presentedin table 3. In myocarditis associated withpsittacosis, lymphogranuloma venereum, orprimary atypical pneumonia, specific therapywith tetracycline is indicated. Restriction ofactivity during the acute phase of illnesswould appear appropriate on clinical groundsalone. The aim should be to keep cardiac workat a minimum. The evidence that exerciseenhances the severity of experimental Cox-sackie myocarditis9' 12 bears upon this point.The concern that hypoxia may aggravate

viral myocarditis"1 may be taken as indicationfor oxygen therapy, especially in the presenceof an irritable or failing heart. The repeatedobservation of life-threatening arrhythmiasand the risk of sudden, unexpected deathwould seem to indicate the need for electro-cardiographic monitoring. Would it not seemreasonable to extend to the patient with acutemyocarditis the potential benefits of intensivecare units? Defibrillation and resuscitationmay be lifesaving. In second- or third-degreeheart block, the insertion of a temporarypacemaker may be desirable.

Patients in congestive heart failure tend torespond well to digitalis and diuretics, espe-cially in childhood. A relatively low thresholdfor digitalis toxicity, however, has repeatedlybeen observed, although precise studies arelacking.Adrenal steroids have been used but never

proven to be effective. Some patients treatedwith steroids have recovered. There have beenno controlled trials. Inasmuch as experimentalCoxsackie myocarditis is clearly enhanced bycortisone,13 as mentioned above, this thera-peutic approach cannot be recommended.Are There Late Sequelae of Viral Myocarditis?

It has been known for some time thatrheumatic carditis may become chronic andeventually lead to residual fibrosis, and thatboth Chagas' disease and toxoplasmosis may

Circulation, Volume XLIV, November 1971

954

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

VIRUS AND THE HEART

lead to a chronic cardiomyopathy. Such apossibility has been entertained for viralmyocarditis, but never proven. The fact thatmost cases of chronic cardiomyopathy areidiopathic has fostered the speculation thatthey represent end stages of viral myocarditis.Bengtsson and Lambergerl9 followed 90patients with presumptive acute myocarditisfor 5 years and found that 20% still had cardiacsymptoms, 15-20% had abnormal electrocar-diograms, and about 30% had abnormal exer-cise electrocardiograms.

In 1969, Wilson and associates20 studied thenatural history of experimental murine infec-tion with Coxsackie virus B3 and demonstrat-ed persistent inflammation progressing tomyocardial fibrosis. These residual scars in-volved about one fifth of the myocardium. Inman, by means of fluorescent antibodytechniques, Burch and associates21 demon-strated Coxsackie B virus antigens in myocar-dium, associated with chronic, focal, intersti-tial myocarditis. In three cases, antigen wasalso demonstrated in the leaflets of the mitralvalve; one of these was a 55-year-old manwith unexplained cardiomegaly.

ConclusionsAcute viral myocarditis may be associated

with most of the common viral diseases insmall but significant proportions of cases; themyocarditis often remains unrecognized. Thecourse is usually benign, but may be high-lighted by life-threatening arrhythmias, heartfailure, or circulatory collapse. Therapy notonly holds promise of acute survival, but mayreduce later sequelae. Chronic cardiomyop-athy-still an unproven sequel in man-hasnow been documented after experimentalCoxsackie myocarditis.

Clinically evident heart disease of viraletiology is of low prevalence in any individualmedical center, but in the aggregate accountsfor an appreciable number of severely illpatients. Existing knowledge with regard todiagnosis, treatment, and prevention mightwell be more widely applied. Systematic studyof clinical and experimental forms of myocar-ditis would provide answers to many of theCirculation, Volume XLIV, November 1971

questions posed here. Because of the lowincidence, interhospital studies should beconsidered. Existing clinical and research unitsdevoted to the intensive study and care ofpatients with ischemic heart disease wouldseem eminently suited for futher clinicalinvestigation of acute myocarditis in man.

References1. LYON E: Virus Diseases and the Cardiovascular

System: A Survey. New York, Crune &Stratton, Inc., 1956, p 215

2. SANDERS V: Viral myocarditis. Amer Heart J 66:707, 1963

3. HUDSON REB: Cardiovascular Pathology. Balti-more, Williams & Wilkins Co., 1965, vol 1, p785; 1970, vol 3, p 5485

4. ABELMANN WH: Myocarditis. New Eng J Med275: 832, 944, 1966

5. DUDGEON JA: A new look at rubella. Proc RoySoc Med 60: 642, 1967

6. BROWN GC, EVANS TN: Serologic evidence ofCoxsackie virus etiology of congenital heartdisease. JAMA 199: 183, 1967

7. SHONE JD, ARMAS SM, MANNING JA, KEITH OD:The mumps antigen skin test in endocardialfibroelastosis. Pediatrics 37: 423, 1966

8. GERSONY WM, KATZ SL, NADAs AS: Endocardialfibroelastosis and the mumps virus. Pediatrics37: 430, 1966

9. TILLES JG, ELSON SH, SHAKA JA, ABELMANNWH, LERNER AM, FINLAND M: Effects ofexercise on Coxsackie A9 myocarditis in adultmice. Proc Soc Exp Biol Med 117: 777, 1964

10. ABELMANN WH, KUMAR R, WAGNER RL:Biventricular heart failure in experimentalChagasic myocarditis. Circulation 40 (supplIII): Ill-33, 1969

11. PEARCE JM: Heart disease and filtrable viruses.Circulation 21: 448, 1960

12. LERNER AM: Coxsackie virus myocardiopathy. JInfect Dis 120: 496, 1969

13. KILBOURNE ED, WILSON CB, PERRER D: Theinduction of gross myocardial lesions by acoxsackie (pleurodynia) virus and cortisone. JClin Invest 35: 362, 1956

14. GORE I, SAPHIR D: Myocarditis: A classificationof 1402 cases. Amer Heart J 34: 827, 1947

15. Vital Statistics of the United States 1967: Vol II.Mortality, Part A. Washington, D.C., U. S.Department of Health, Education, and Wel-fare, Public Health Service, 1969

16. GRIST NR: Coxsackie viruses and the heart.Amer Heart J 77: 295, 1969

17. ScoTT IP III, GUTELIUS MF, PAImOrr RH:

955

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

ABELMANN

Children with acute respiratory tract infec-tions: An electrocardiographic survey. Amer JDis Child 119: 111, 1970

18. STEVENS PJ, GROUND KEU: Occurrence andsignificance of myocarditis in trauma. Aero-space Med 41: 776, 1970

19. BENGTSSON E, LAMBERGER B: Five year follow-up study of cases suggestive of acutemyocarditis. Amer Heart J 72: 751, 1966

20. WILSON FM, MIRANDA QR, CHASON JL, LERNERAM: Residual pathologic changes followingmurine Coxsackie A and B myocarditis. Amer JPath 55: 253, 1969

21. BURcH GE, SuN SC, COLCOLOUGHiHL, SOHAL RS,DE PASQUALE NP: Coxsackie B viral myocar-ditis and valvulitis identified in routine autopsyspecimens by immunofluorescent techniques.Amer Heart J 74: 13, 1967

Circulation, Volume XLIV, November 1971

956

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

WALTER H. ABELMANNVirus and the Heart

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1971 American Heart Association, Inc. All rights reserved.

75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TXCirculation

doi: 10.1161/01.CIR.44.5.9501971;44:950-956Circulation. 

http://circ.ahajournals.org/content/44/5/950located on the World Wide Web at:

The online version of this article, along with updated information and services, is

  http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. Permissions and Rights Question and Answer

of the Web page under Services. Further information about this process is available in thewhich permission is being requested is located, click Request Permissions in the middle columnClearance Center, not the Editorial Office. Once the online version of the published article for

can be obtained via RightsLink, a service of the CopyrightCirculationoriginally published in Requests for permissions to reproduce figures, tables, or portions of articlesPermissions:

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from