Myocardial Ischemia in Infants

THE ANNALS OF THORACIC SURGERY Journal of The Society of Thoracic Surgeons and the Southern Thoracic Surgical Association VOLUME 8 NUMBER 5 NOVEMBER 1969. * Myocardial Ischemia in Infants Its Role in Three Common Congenital Cardiac Anomalies Roy L. Tawes, Jr., M.D.,* Colin L. Berry, M.D.(Lond.), Eoin Aberdeen, F.R.C.S., and Gerald R. Graham, M.D. M yocardial ischemia in children is not well recognized except when relatively rare conditions exist, such as anomalous left coronary artery arising from the pulmonary artery. Reviewing our operative mortality for coarctation of the aorta in children, we noted ischemic changes in many infant hearts examined postmortem. This prompted a review of the necropsy specimens of those dying after two other extracardiac operations commonly performed in infancy, namely, operations for patent ductus arteriosus and tetralogy of Fallot. Our data suggest that myocardial ischemia is more common in these conditions than previously was suspected. The possible influence of myocardial ischemia on the survival of infants? who undergo operation for these three cardiac anomalies will be discussed. Fioiii the Cardio-thoracic Unit, Hospital for Sick Children, Great Orniond Street, London W.C.1, England. Giannini Foundation Fellow, Gepartment of Surgery, University of California Medical Center, San Francisco, Calif. This study was supported by the British Heart Foundation. Accepted for publication July 1, 1969. Address reprint requests to Dr. Aberdeen, The Hospital for Sick Children, Great Ormond Street, London W.C.l, England. tcliildren less than 1 year of age. VOL. 8, NO. 5, NOV., 1969 383

TAWES ET AL. MATERIAL AND METHODS Mortality data were extracted for the following three extracardiac operations performed at the Hospital for Sick Children, Great Ormond Street, London, from 1953 to 1967: 1. Resection and anastomosis of coarctation of the thoracic aorta. 2. Closure of patent ductus arteriosus. 3. Systemic-to-pulmonary-artery anastomosis (Blalock-Taussig) for tetralogy of Fallot. The electrocardiograms of each patient were reviewed by one of us (G. R. G.) without knowledge of which patients had ischemic changes at postmortem examination. The hearts examined were grouped into the basic congenital cardiac anomalies: Group I: Coarctation, 61 specimens. Group 11: Patent ductus arteriosus, 25 specimens. Group 111: Tetralogy of Fallot (shunts), 17 specimens. PATHOLOGY Hearts that had been visibly damaged by recent cardiac massage were excluded. One specimen with evidence of luetic cardiomyopathy was also omitted. TECHNIQUES In each case, sections were taken from the right and left ventricle and from the septum. In hearts from infants less than 6 months old, a transverse section of the midpart of the ventricular mass was made and was mounted as one section. All sections were stained by hematoxylin-van Gieson and hematoxylin and eosin, and by the fuchsinophilic technique previously reported [I]. The sections were examined without knowledge of the clinical history. HISTOLOGY Histological changes were divided into two groups for each of the three congenital cardiac defects: 1. Evidence of myocardial ischemia by conventional staining techniques. 2. Evidence of recent ischemia (fuchsinophilia). Following tabulation of the histological data, each of the three groups of cardiac anomaly were compared and the relative incidence of myocardial ischemia determined. Finally, the influence on survival was assessed. RESULTS HISTOLOGY Group I: Evidence of ischemic injury (standard methods). In a number of cases, histological studies showed loss of fibrillar structure (Fig. 1) with formation of granular hyaline fibers or vacuolation (Fig. 2). Areas of focal necrosis were seen. A number of hearts showed extensive focal and interstitial fibrosis (Fig. 3). Calcification was seen in many fibrotic areas. These changes were visible on conventional stains and were considered to be of 24 hours duration or more. No coronary artery lesions were observed. Endocardia1 lesions associated with endocardia1 fibroelastosis were seen in 5 cases of coarctation; in 4 of these 5 384 THE ANNALS OF THORACIC SURGERY

Myocardial Ischemia in Infants FIG. 1. Patchy loss of striation and edema in hypertrophied cardiac muscle fibers. (H&E; X 700.) FIG. 2. Vacuolation of muscle fibers, right ventricle. (HplrE; X 60.) FIG. 3. Interstitial fibrosis, from left ventricle. (HplrE; X 250.) VOL. 8, NO. 5, NOV., 1969 385

TAWES ET AL. TABLE 1. INCIDENCE OF MYOCARDIAL ISCHEMIA Histological Evidence Incidence of Long- Conven- Standing Cardiac No. of tional Fuchsino- Both Ap Ischemia Anomaly Specimens Methods philia proaches (%) Coarctation 61 23 22 7 38 Patent ductus arteriosus 25 3 9 1 12 Tetralogy of Fallot 17 6 7 2 35 cases there was evidence of myocardial ischemia. No case of patent ductus arteriosus or tetralogy of Fallot showed endocardia1 fibroelastosis. Table 1 summarizes the findings for these cardiac defects. Group ZZ: Evidence of recent ischemic in jury (fuchsinophilia). Positive staining with acid fuchsin results in purplish staining of the myocardial fibers. Poley et al. 151 have demonstrated the temporal relationship of this staining to experimental ischemic lesions, and they indicate that the change demonstrates recent injury. No attempt was made to grade the severity or extent of the changes; positive fuchsinophilia was simply recorded (Table 1). INCIDENCE OF MYOCARDIAL ISCHEMIA Group I: Coarctation. Changes compatible with long-standing ischemia by conventional staining techniques were present in 23 of the 61 hearts examined, an incidence of 38%. Evidence of recent ischemia by the fuchsinophilic technique was present in 15 others. In 7 of these specimens, evidence was obtained with both histological methods. Group ZZ: Patent ductus arteriosus. Conventional evidence of ischemia was present in 3 of the 25 hearts examined, an incidence of 12%. Eight others had recent ischemic changes, and 1 had ischemic changes by both techniques. Group ZZZ: Tetralogy of Fallot (shunts). Six of the 17 hearts examined had conventional evidence of myocardial ischemia, an incidence of 35%. Five other hearts had recent evidence, and 2 had ischemic changes by both techniques. CLINICAL DATA The data are too lengthy to present in tabular form for each patient; therefore, the clinical data are summarized for each of the three conditions. Coarctation. All 61 infants were in congestive heart failure. A patent ductus arteriosus was present in all but 1 infant. In 48 cases (SO%), the coarctation was preductal. In 46 cases (7873, additional cardiac defects were present, ventricular septa1 defects being the most common. In 52 cases (86%), there was evidence of pulmonary hypertension. Myocardial hypertrophy was a common finding at operation and was found at postmortem examination in all cases. Myocardial ischemia was most often seen in those cases with preductal coarctations with gross myocardial hypertrophy and small ventricular chambers. The hypertrophy was often biventricular. The hearts in these infants weighed between 70 and 110 gm., about two to three times that of normal infant hearts. Death occurred at operation in half (30) of the infants, usually as a result of cardiac arrest or ventricular fibrillation. At postmortem examination, 57% of 386 THE ANNALS OF THORACIC SURGERY

Myocardial Ischemia in Infants these hearts (17 of 30) showed evidence of long-standing myocardial ischemia, compared to the 38% incidence for the group as a whole, and to the 19% incidence for the 31 other infants dying after operation. Patent ductus arteriosus. All 25 infants had congestive heart failure and evidence of pulmonary insufficiency. None had had a coarctation of the aorta resected. Associated cardiac defects were present in 22 (88%), ventricular septal defects being the most common. Myocardial hypertrophy was marked in 11 (44%) and was predominantly right ventricular. Evidence of long-standing myocardial ischemia was present in only 1 of these, but recent ischemic changes were present in 6. Death occurred at operation in 7 infants (28%). None had evidence of longstanding myocardial ischemia, but recent ischemic changes were seen in 1. Long-standing ischemic changes were observed in only 3 hearts (12%), each of which had severe additional cardiac defects: atrioventricular canal; transposition of the great arteries plus a ventricular septal defect; and in 1, a large ventricular septal defect. Tetralogy of Fallot. The 17 infants in this group died after a palliative systemic-to-pulmonary-artery anastomosis (Blalock-Taussig). Right-ventricular hypertrophy was present in all and marked in 6. Six had thrombotic episodes in other organs associated with polycythemia (packed cell volume ranged from 50 to 69%), but there was no evidence of thrombus in the coronary arteries. Death occurred at operation in 4 of the 17 infants. Myocardial ischemia of long standing was seen in one of these. Conventional evidence of ischemia was present in 5 of the 13 other specimens examined. Two of these had evidence of recent ischemia. In 35% of this group (6 of 17 infants), evidence of myocardial injury was obtained by conventional staining techniques. ELECTROCARDIOGRAM An electrocardiogram had not been recorded in all patients. Often only one electrocardiogram had been recorded, and in several cases, this record had been made many days before death. Interpretation of the electrocardiogram in relation to coronary insufficiency was made difficult by the fact that many of the children were digitalized at the time of recording, obscuring any possible evidence of coronary insufficiency. The electrocardiograms available were interpreted without knowledge of the pathological findings. Among the cases of coarctation, electrocardiograms had been recorded in 54 cases. The tracing (or tracings) correctly indicated coronary insufficiency in 6, but there were 5 false-positives and 4 false-negatives. Among the cases of patent ductus arteriosus, only 3 false-positive and 1 false-negative interpretation were recorded out of a total of 14 infants on whom electrocardiograms had been taken. Among the cases of tetralogy of Fallot the result was similarly unhelpful: only 1 correct diagnosis of coronary insufficiency and 2 false-positives out of a total of 15 infants for whom an electrocardiogram was available. MORTALITY The mortality for these three common extracardiac operations in infants is shown in Figure 4. It is based on a 15-year operative experience. During this period, of the 333 children who underwent operation for coarctation of the aorta, 179 (54%) were less than 1 year of age (infants); similarly, of the 786 children having ligation of a patent ductus arteriosus, 179 (23%) were infants. Of the 352 systemic-to-pulmonary-artery anastomoses for tetralogy of Fallot, 107 were performed in infants. The mortality is proportionally higher in the youngerage group in all three operations. The three curves of mortality compared to age at operation show a striking similarity (Fig. 4). VOL. 8, NO. 5, NOV., 1969 387

TAWES ET AL. 90-80 - I... Patent Ductus Arteriosus - Coarctation of Aorta --- Fallot s Tetralogy COMMENT These data show that ischemic injury is not uncommon in infants with the three common cardiac anomalies studied, and suggest that myocardial ischemia may adversely influence their survival. In children, coronary artery disease is seldom a significant factor in myocardial ischemia. Inadequate perfusion of the coronary arteries or hypoxemia, as seen in cyanotic heart disease, are probably more important. The congenital cardiac anomalies in the infants in this series generally were complex. Gross myocardial hypertrophy and congestive failure were almost invariable; both these states increase the susceptibility of the myocardium to low perfusion injury. Those cases with tetralogy of Fallot had as additional factors the effects of polycythemia and hypoxemia on the myocardium. Berry [l] recently reported evidence of myocardial ischemia in a variety of conditions in severely ill infants and children in whom the cardiac reserve was compromised. Esterly and Oppenheimer [2] reviewed 450 cases of 15 common congenital cardiac defects in children under 15 years old and found myocardial necrosis, calcification, or scarring in 106 (24%). Myocardial lesions were seen in 19% of the preductal coarctations (11 of 58>, in 11% of those with tetralogy of Fallot (8 of 62), and in 14% of those with patent ductus arteriosus (1 of 7). It was not stated how many were infants, which may account for the disparity between the incidence of myocardial lesions in their study and 388 THE ANNALS OF THORACIC SURGERY

Myocardial Ischemia in Infants ours. Vlodaver and Neufeld [S] reported coronary artery lesions in 10 children between the ages of 2 and 10 years. No infants were studied. We found no coronary artery lesions in the 103 infant hearts examined. We have based our incidence of myocardial injury (Table 1) on data derived from conventional staining techniques only, representing a minimum figure. If the results of staining with acid fuchsin are included, a higher incidence is obtained. The use of the fuchsinophilic technique to demonstrate recent myocardial injury has been described before [l]. This technique, first used by Selye [6] to demonstrate myocardial injury in certain experimental forms of myocarditis, is simple and may be used on fixed paraffin-processed material. It has obvious limitations, but it is useful in surveys of this kind. It is difficult, for several reasons, to assess the possible influence of myocardial ischemia on survival following operation. The status of the myocardium is not known for those infants surviving operation. The electrocardiogram has been of little benefit in diagnosing myocardial ischemia in these children, and myocardial biopsy specimens are not taken at operation. It is assumed that those living have an adequate myocardial blood supply. Conversely, it would be logical to assume that myocardial ischemia contributed in part to the death in those with diagnostic histological changes, especially those who died at operation. Half the infants with coarctation included in this study died at operation, and 57% of their hearts examined postmortem showed long-standing myocardial ischemia, compared to the 19% incidence for the others who died several days after operation. Because of the many complex factors contributing to the infant mortality, it would be difficult to attribute death to one single factor. Congestive heart failure, pulmonary hypertension and pulmonary insufficiency, hypoxia, and acidosis were common factors in the infant deaths in this study. Multiple cardiac lesions, many of which were lethal (endocardia1 fibroelastosis), were present in 70% of the infants. The similarity of the mortality for the three conditions studied (Fig. 4) reflects the complexity of congenital heart disease seen in infancy. The multiple factors mentioned above are well recognized as significantly affecting infant survival. Myocardial ischemia rarely receives consideration, when in fact it may well be the major factor in many cases and may play a significant role in others. Survival among infants with preductal coarctation has more than doubled in the last five years as a result of intensive respiratory care (Table 2). Infants with this defect now frequently undergo tracheostomy at operation and are maintained on the Engstrom ventilator. The infant s acid-base balance is carefully maintained, and deficiencies (usually metabolic acidosis) are corrected. If it is accepted that these infants suffer from pulmonary insufficiency and poor myocardial perfusion, it VOL. 8, NO. 5, NOV., 1969 389

TAWES ET AL. TABLE 2. SURVIVAL AMONG INFANTS UNDER 1 YEAR OF AGE WITH PREDUCTAL COARCTATION AND AORTIC ARCH ATRESIA No. of No. of Years Cases Survivors Percent 1953-1962 1963-1967 35 59 7 29 20 49 is readily understandable why this form of treatment has significantly improved the operative results in a cardiac defect that had very few operative survivors in infancy until the past few years [S, 4, 71. SUMMARY Postmortem examination of 103 hearts of infants who died after undergoing a commonly performed extracardiac operation for coarctation of the aorta, patent ductus arteriosus, or tetralogy of Fallot showed a high incidence of myocardial ischemia by conventional histological methods. No coronary artery lesions were observed. The ischemic changes were attributed to inadequate coronary artery perfusion of the grossly hypertrophied hearts of those with coarctation of the aorta and, to a lesser extent, of those with patent ductus arteriosus. Inadequate coronary artery perfusion was also considered an important factor in cases of tetralogy of Fallot superimposed on chronic hypoxemia and polycythemia. The incidence of myocardial ischemia was three times greater in those with coarctation who died at operation than in those who died later in the postoperative period. Myocardial ischemia may be a more important factor in infant operative mortality of the three cardiac anomalies studied than previously was recognized. REFERENCES 1. Berry, C. L. Myocardial ischaemia in infancy and childhood. J. Clin. Path. 20:38, 1967. 2. Esterly, J. R., and Oppenheimer, E. H. Some aspects of cardiac pathology in infancy and childhood: IV. Myocardial and coronary lesions in cardiac malformations. Pediatrics 39:896, 1967. 3. Glass, I. H., Mustard, W. T., and Keith, J. D. Coarctation of the aorta in infants: A review of 12 years experience. Pediatrics 26:109, 1960. 4. Hallman, G. L., Yashar, J. J., Bloodwell, R. D., and Cooley, D. A. Surgical correction of coarctation of the aorta in the first year of life. Ann. Thorac. Surg. 4:106, 1967. 5. Poley, R. W., Fobes, C. D., and Hall, M. J. Fuchsinophilia in early myocardial infarction. Arch. Path. (Chicago) 77:325, 1964. 6. &lye, H. Chemical Prevention of Cardiac Necroses. New York: Ronald, 1958. P. 43n. 7. Tawes, R. L., Jr., Aberdeen, E., Waterston, D. J., and Bonham-Carter, R. E. Recoarctation of the aorta in children: Report of 16 cases. In preparation. 8. Vlodaver, Z., and Neufeld, H. N. The coronary arteries in coarctation of the aorta. Circulation 37:449, 1968. 390 THE ANNALS OF THORACIC SURGERY