March 1990 7 0 0 Brief Communications American Heart Journal

rowed 26 % to 50 % ; 16 (46 % ) were narrowed 51% to 75 %, and 10 (27 % ) were narrowed 76 % to 95 % in cross-sectional area by atherosclerotic plaque. Many atherosclerotic plaques contained foam cells with cholesterol clefts (Fig. 3). Every 5 mm segment contained atherosclerotic plaque. Both ventricular cavities were of normal size, and the ven- tricular walls were free of lesions. The thyroid gland weighed <10 gm, few follicles were present, and the fibrous tissue in it was extensive. The left kidney weighed only 8 gm, consisted mainly of fibrous tissue, and the left main renal artery was totally occluded; the right kidney weighed 260 gm, about 25% of it was grossly infarcted, and many glomeruli and tubules were necrotic (Fig. 4).

Several features (round facies, short extremities, and ju- venile external genitalia) strongly suggest that the afore- mentioned pat ient had hypothyroidism from birth. The pericardial changes in congenital hypothyroidism (cre- tinism) have not been described previously. Similar patho- logic findings, however, were described in a 54-year-old woman with untreated hypothyroidism. 5 Most pericardial effusions resolve after the initiation of thyroid hormone supplementation.2, 3 At least two reported patients had persistent effusion with tamponade despite thyroid re- placement hormone. 7,14 The lipid deposits on the epicar- dium in our pat ient were similar to portions of the coronary atberosclerotic plaques and appear to be the consequence of the severe hypercholesterolemia. The pericardial lipid deposits, such as present in our pat ient and as reported by others 12 in hypothyroidism, have not been observed to our knowledge in patients with hypercholesterolemia not asso- ciated with hypothyroidism, such as homozygous or het- erozygous familial hypercholesterolemia.

REFERENCES

1. Watanakunakom C, Hodges RE, Evans TC. Myxedema, a study of 400 cases. Arch Intern Med 1965;116:183-90.

2. Hardisty CA, Naik DR, Munro DS. Pericardial effusion in hy- pothyroidism. Clin Endocrinol 1980;13:349-54.

3. Kerber RE, Sherman B. Echocardiographic evaluation of pericardial effusion in myxedema, incidence and biochemical and clinical correlation. Circulation 1975;52:823-7.

4. Manolis AS, Varriale P, Ostrowski RM. Hypothyroid cardiac tamponade. Arch Intern Med 1987;147:1167-9.

5. Kelly JK, Butt JC. Fatal myxedema pericarditis in a Christian Scientist. Am J Clin Pathol 1986;86:113-6.

6. King BF, Kreipke DL, Holden RW, Jackson VP, Tarver RD. Cardiac tamponade from chronic pericardial effusion in hy- pothyroidism. Indiana Med 1989;79:32-4.

7. Arvan S. Pericardial tamponade in a patient with treated myxedema. Arch Intern Med 1983;143:1983-4.

8. Smolar EN, Rubin JE, Avramides A, Carter AC. Cardiac tam- ponade in primary myxedema and review of the literature. Am J Med Sci 1976;272:345-52.

9. Alsever RN, Stjernholm MR. Cardiac tamponade in myxede- ma. Am J Med Sci 1976;269:117-21.

10. Agarwal BL, Mital VN, Misra DN. Cardiac tamponade in myXoedema. J Indian Med 1974;63:25-8.

11. Sharma SK, Bordia A. Cardiac tamponade due to pericardial effusion in myxoedema. Indian Heart J 1969;10:210-6.

12. Davis PJ, Sheldon J. Myxedema with cardiac tamponade and pericardial effusion of "gold paint" appearance. Arch Intern Med 1967;120:615-9.

13. Martin L, Spathis GS. Case of myxoedema with a huge peri- cardial effusion and cardiac tamponade. Br Med J 1965;2: 83-5.

14. Silverstone FA. Recurrent heart failure with tamponade due to pericardial effusion; improvement following pleural-peri- cardial fenestration. Ann Intern Med 1955;42:937.41.

15. Brawley RK, Vasko JS, Morrow AG. Cholesterol pericarditis; considerations of its pathogenesis and treatment. Am J Med 1966;41:235-48.

Coadministration of flecainide acetate and sotalol during pregnancy: Lack of teratogenic effects, passage across the placenta, and excretion in human breast milk

Xavier Wagner, MD, a Jacqueline Jouglard, MD, b Maurice Moulin, MD, c Aldora M. Miller, PhD, d Jo~l Petitjean, MD, e and Andr~ Pisapia, MD. f Malakoff, Marseille, and Caen, France and St. Paul, Minn.

Drugs should be prescribed no more than is necessary dur- ing pregnancy because of a potential risk of teratogenesis in the fetus. On the other hand, some diseases involve a life-threatening risk for the pat ient and entail continuous t rea tment even if pregnancy occurs, for example, in the case of severe or malignant cardiac arrhythmias. We present the first report of flecainide acetate (class Ic anti- arrhythmic agent) 1 being given during the entire duration of a pregnancy. There has been one previous report of flecainide acetate being given to the mother for the purpose of suppressing tachycardia in the fetus, but the initial dose was given at 30 weeks' gestation only. 2

A 23-year-old woman was being treated for bursts of ventricular tachycardia and polymorphous ventricular pre- mature complexes (associated with an aneurysm of the left ventricle) with flecainide acetate (100 mg twice daily) and sotalol (80 mg twice daily). She became pregnant during therapy. Antiarrhythmic drug therapy was continued throughout the pregnancy with no changes in the dosage (oral route). Clinical efficacy was maintained with no adverse reactions to the drugs. The pat ient was delivered of a normal baby by cesarean section 3 weeks before full term. There were no morphologic anomalies, the placenta was normal histologically. During labor the baby's heart

From the ADRs Monitoring Department, 3M Sent6 Laboratories (Mala- koff)a; the Regional Center of Pharmacovigilance, Department of Toxicol- ogy, Salvator University Hospital (Marseille)b; the Regional Center of Pharmacovigilance, Department of Pharmacology, University Hospital (Caen)C; the Department of Drug Metabolism, Riker Laboratories, 3M Center (St. Paul, Minn.)d; and the Departments of Obstetrics e and Cardi- ology, f St. Joseph Hospital (Marseille). Reprint requests: X. Wagner, MD, ADRs Monitoring Department, Labora- tories 3M Sent6, 3 rue Denton, 92245 Malakoff, France. 4/4/18118

V o l u m e 119

N u m b e r 3, Part 1 Brief Communications 7 0 1

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Fig. 1. Flecainide acetate and sotalol titrations (umbilical cord, mother's plasma, and milk).

T a b l e I. Measurements of drug levels and concentration ratios at delivery and during the postpartum period

Flecainide Sotalol

Post partum Post partum

Delivery* Day 5~ Day 7y- Delivery* Day 5~ Day 7"r

0.500 0.95 1.40 1.60 - - 1.35 - - - -

1.093 --- 5 4.4 - - 1.42 - - - -

2.18 - - 3.57 2.75

Mother's plasma (ttg/ml) 0.455 0.567 Umbilical cord (ttg/ml) 0.394 - - Mother's milk (ttg/ml) - - 0.891 Ratio umbilical cord/mother's plasma 0.86 - - Ratio mother's milk/mother's plasma - - 1.57

*Eleven hours after last intake of flecainide acetate and sotalol. CThree hours after second daily dose of flecainide acetate and sotalol.

rate was regular (130 to 140 beats/min). Auscultation of the heart showed no bradycardia after delivery, and results of clinical and laboratory tests in the infant were normal. An ECG was recorded in the maternity hospital 29 hours after the birth, and normal parameters related to age were ob- served (sinus rhythm, heart rate 140 beats/min, PR inter- val 120 msec, QRS duration 60 msec with a frontal QRS axis

+100 degrees, QT interval 300 msec, and corrected QT in- terval 270 msec). One year later the infant has developed appropriately for age; results of auscultation of the heart were regarded as normal during the clinical examination and no new ECG was necessary. First, flecainide and sotalol assays were performed on samples of the mother's plasma and umbil ical cord plasma; these were drawn simulta-

March "1990

7 0 2 Brief Communications American Heart Journal

neously at delivery (11 hours after the mother's last dose). The patient then resumed normal therapy twice daily af- ter delivery. Second, samples of the mother's plasma and milk were drawn simultaneously (3 hours after the second daily dose) on the fifth and seventh days post partum and assayed (Fig. 1). The baby was not breast fed. Levels of flecainide were measured by high-performance liquid chro- matography with fluorescence detection. 3

From a clinical standpoint, the lack of any teratogenic effect in this case is very reassuring, but it should not be considered to have any epidemiologic value. It provides physicians with new information concerning the possible antiarrhythmic drugs that may be used during pregnancy, but it should not stop them from following the precautions mentioned by the Food and Drug Administration in its labeling of flecainide acetate. ("Because there are no ade- quate and well-controlled studies in pregnant women, flecainide acetate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.") Analysis of the biological results (Table I) estab- lishes the following points: (1) Flecainide plasma levels in the mother were steady and fell within the therapeutic range (0.2 to 1 izg/ml) at delivery and during the postpar- tum period; (2) a ratio of 0.86:1 of umbilical cord: maternal plasma showed placental transfer of flecainide; (3) ratios from 1.57:1 to 2.18:1 of mother's milk: mother's plasma in- dicated excretion of flecainide in human breast milk. The observed changes in flecainide levels in milk are possibly the result of the different times during which the drug was ingested.

REFERENCES

1. Holmes B, Heel RC. Focus on flecainide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1985;29:1-33.

2. Wren C, Hunter S. Maternal administration of flecainide to terminate and suppress fetal tachycardia. Br Med J 1988; 296:249.

3. Chang SF, Miller AM, Fox JM, Welscher TM. Determination of flecainide in human plasma by high performance liquid chromatography with fluorescence detection. J Liq Chro- matogr 1984;7:167-76.

The effects of exercise during viremia on the signal-averaged electrocardiogram

James L. Vacek, MD, and G. Scott Smith, MD. Kansas City, Kan.

From the Section of Cardiovascular Diseases, University of Kansas Medi- cal Center.

Reprint requests: James L. Vacek, MD, Section of Cardiovascular Diseases, University of Kansas Medical Center, 39th and Rainbow Blvd., Kansas City, KS 66103.

4/4/18124

Sudden cardiac death is a major cause of mortality in the United States, including younger segments of the population. 13 Sudden death during exercise is an often dramatic event that usually occurs in the setting of under- lying coronary artery or primary myocardial disease. 39 Several recent reports 35' 10 have studied the occurrence of sudden cardiac death that happened during exercise and have noted the occasional appearance of myocarditis in pathologic specimens. Sudden death in these patients is felt to be due to inflammatory alterations in the cardiac conduction system or myocardium that promote the oc- currence of sustained ventricular arrhythmias. This report describes the occurrence of congestive heart failure and di- lated cardiomyopathy in a patient who completed a mar- athon race while suffering symptoms of a viral infection. Signal-averaged electrocardiogram parameters worsened from baseline values while he demonstrated evidence of myocardial dysfunction and subsequently improved as his clinical status stabilized.

A 35-year-old white man who had run one previous mar- athon participated in a 26.2-mile race. As a participant in a study examining the effects of endurance exercise on sig- nal-averaged electrocardiogram parameters, he underwent signal-averaged electrocardiography on the day prior, im- mediately after finishing, and at selected intervals after the race. He had no cardiac history, and physical examination as well as 12-lead electrocardiogram were normal. On the morning of the race he developed symptoms consistent with a viral upper respiratory tract infection with consti- tutional symptoms that included nasal congestion, malaise, myalgia, nonproductive cough, and a feeling of feverish- ness. The patient nevertheless successfully completed the race, although his race completion time was slower than that of the previous year. Within a week of completing the race, he developed progressive dyspnea on exertion, short- ness of breath at rest, and fatigue. Upon presentation to his regular physician, he was found to have evidence of biven- tricular congestive heart failure and on echocardiography he demonstrated diffuse chamber enlargement with left ventricular global hypocontractility. No significant valvu~ lar or regional myocardial abnormalities were noted. Serum electrolytes and creatinine were normal. Erythrocyte sed- imentation rate 9 days after the race was 76, and 2 days later was 58. His signal-averaged electrocardiogram pa- rameters (all three standard time domain variables, i.e., total duration of the filtered QRS, the root mean square voltage of the last 40 msec of the filtered QRS, and the du- ration of low-amplitude signals less than 40 ~V) showed deterioration when compared with his pre-race values. This pattern was distinctly different from that of 29 other mar- athon participants who showed no change in any signal- averaged electrocardiogram parameter when pre- and 1- to 2-week post-race studies were compared. His standard 12- lead electrocardiogram remained within normal limits throughout the period of observation. The patient refused endomyocardial biopsy and was treated conservatively with bed rest and salt restriction; 2 months later he had