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Amyloid heart disease
Amyloid
Heart Disease*
ALINAGHI FARROKH, M.D., THOMAS J. WALSH, St.
M.D.,
Louis,
ARDIAC amyloidosis is a disease of obscure etiology’-* that usually manifests itself by progressive signs and symptoms of congestive heart failure, which fails to respond to therapeutic measures and eventually proves fatal.‘-‘” The patients are usually in the oider age group and present no other etiologic factor for their development of heart disease. Cardiac amyloidosis has been considered one of the rarer causes of congestive heart failure and has been reported most frequently in the socalled primary type of amyloidosis.‘” vls,22 Unfortunately, antemortem diagnosis of amyloidosis of the heart has been most difficult,2~4~*~22 because of the nonspecific clinical and electroIn recent years, adcardiographic findings. vancing knowledge of electrocardiography, more careful study of the course of this illness, and correlation with postrnortem findings have made possible the recognition of certain electrocardiographic features and clinical findings strongly suggestive of this disease.4~5~7~” The purpose of this paper is to direct attention to these findings and to compare them with those of our own series.
When 21,300 postmortem examinations performed at Barnes Hospital between 1916 and 1962 were reviewed, 28 cases of cardiac amyloidosis were found. Five typical patients were selected from this series for detailed presentation. CASE REPORTS
CASE 1. This 82 year old male Negro was admitted to the hospital for the first time in 1962 with #dyspnea present for about 1 year. Two months before admission the dyspnea became worse, and he experienced pronounced orthopnea and ankle edema for which he was digitalized. Since he did not respond to medical therapy as an outpatient, he was admitted to the hospital for further evaluation and treatment. Physical examination revealed a blood pressure of of Medicine,
Washington
EDWARD
MASSIE,
KD.,
I;.A.c.c.
120/70 mm. Hg, pulse rate 98/min. with irregular rhythm and marked respiratory distress. The heart was enlarged to the left; distant heart sounds and a grade 2/6 ejection systolic murmur were heard over the precordium, with aortic and pulmonic second sounds of equal intensity. There was distension of neck veins, dullness at both lung bases and moist rales throughout both lung fields. The liver and spleen were enlarged ; moderate ascites with 4+ ankle edema was present. The venous pressure was 290 mm. of water; the arm to tongue circulation time was 59 sec. The laboratory data revealed lf proteinuria, and a blood urea nitrogen of 49 mg. 70. The chest roentgenogram showed cardiac enlargement, pulmonary congestion and bilateral pleural effusion. Death occurred three days after admission. The electrocardiogram (Fig. 1) showed atria1 fibrillation with rapid ventricular response. There was left axis deviation of the QRS, low QRS voltage in the limb leads, absent R waves in VI to Va, intraventricular conduction delay, occasional ventricular premature contractions and digitalis effect. Postmortem examination revealed an enlarged heart (590 gm.) with diffuse amyloid deposition in the myoThere was bilateral pleural effusion, cardium. moderate ascites and the lungs were very edematous and congested. The liver and spleen were enlarged. ‘This 82 year old male Negro was first CASE 2. admitted to the hospital in 1957 because of marked congestive heart failure of two months’ duration. He was treated with digitalis, diuretics and low salt diet with very little response and was discharged seven Because of increasingly severe heart days later. failure and marked dehydration, he was admitted for the second time one month later. Physical examination revealed a blood pressure of 140/83, pulse rate of 85/min., and an irregular rhythm due to ventricular premature contractions. He was well developed and somewhat obese. The heart was enlarged to the left, and had faint sounds. A grade 2/6 ejection systolic murmur was best heard at the base, and a ventricular gallop rhythm was present at the apex; the pulmonic second sound was accentuated. The neck veins were distended; moist rales were present in both lungs with dullness in both bases posteriorly. There was 3+ ankle edema and
CASE MATERIAL
* From the Department Hospital. St. Louis, MO.
nnd
Missouri
C
ILLUSTRATIVE
F.A.C.C.
University School of Medicine,
750
THE
and the Heart Station, Barnes
AMERICAN
JOURNAL
OF CARDIOLOGY
7.5I
FIG. 1. Casr 1. Llectrocardiogram showing left axis clrviation of QRS, low voltage in limb leads, atria1 fibrillation ;~nti loss of R waves in VI to VY
hepatosplenomegaly. Chest roentgenogram showed a very enlarged heart, pulmonary congestion and biDehydration and hemolateral pleural effusion. concentration were marked; the blood urea nitrogen had risen from 9 to 109 mg.$‘& from the first admission to the second. The electrocardiogram (Fig. 2) showed sinus rhythm with a normal P-R interval, low QRS voltage in the limb leads, left axis deviation of the QRS? minute R waves in VI and V?, loss of R waves in V3 and \‘r and digitalis effect. Postmortem examination revealed an enlarged heart weighing 520 gm. and extensive amyloid infiltration Bilateral in the myocardium and small vessels. pleural effusion, pulmonary congestion and ascites were also present. CASE 3. This 55 year old white woman was admitted to the hospital for the first time in 1960 and died a month later. Her main complaints included weakness, shortness of breath, increasing size of her abdomen, and ankle edema of two months’ duration. The past history was negative. Physical examination revealed a normal blood pressure. a pulse rate of 95/min., an irregular rhythm The heart was enlarged to and normal temperature. the left and had very faint heart sounds and no murmurs; the aortic second sound was louder than the pulmonic second sound. There were moist rales The liver and dullness in both lung bases posteriorly. and spleen were markedly enlarged; ankle edema was pronounced. The conjunctivae were pale. The venous pressure was 230 mm. of water and arm to Hematologic tongue circulation time was 22 sec. evaluation
demonstrated
a
marked
anemia
and
myelosclerosis. ‘I here was l+ proteinuria. and the blood urea nitrogen was 55 mg. ye. 7 he electrocardiqgram (Fig. 3A) showed prolonged P-R interval, intraventricular conduction delay, low QRS voltage in the limb leads, left axis deviation of QRS, loss of R waves in Vt to Va and digitalis effect. A subsequent electrocardiogram (Fig. 3B) taken one day before her death demonstrated an idioventricular rhythm of 38jmin. without evidence of atria1 acuvuy. d vectorcardiogram (Fig. 3C) displayed left axis h deviation of the QRSsE loop in the frontal plane, The planar QRS loops were smaller than usual. There were increased superior and posterior forces; the interpretation was peripheral intraventricular conduction delay or possibly enIargement of the right ventricular outflow tract. Postmortem examination showed evidence of generalized amyloidosis involving mainly the heart, lungs, liver, kidney and spleen. The heart was large.PBilateral pleural effusion, ascites, pulmonary congestion and edema were demonstrated. CASE 4. ‘1 his 57 year old w-hite \voman had shortness of breath and swelling of the ankles for one year. She was treated for congestive heart failure with very poor results. Because of the worsening of her symptoms, she was admitted to the hospital.l T‘hc past history was completely negative. On examination, the blood pressure was 145/85, pulse rate 86/min., and the rhythm was irregular. The heart was enlarged to the left and distant heart sounds and many ventricular premature contractions were noted. A faint ejection systolic murmur was best heard at the left sternal border: ;aortic and
752
Farrokh,
Walsh and Massie
FIG. 2. Case 2. Electrocardiogram showing sinus rhythm, left axis deviation of QRS, low voltage in limb leads, minute R waves in VI and VP and absent R waves in Vs and V+
Horizontal
_
Rt. Sagittal
Frontal
FIG. 3. Case 3. Electrocardiogram and vectorcardiogram. A, electrocardiogram taken on admission shows sinus rhythm with prolonged atrioventricular conduction (0.22 sec.), left axis deviation of QRS, low voltage in limb leads taken shortly before death shows an idioventricular rhythm of and loss of R waves in VI to VS. B, electrocardiogram 38/min. with no evidence of atria1 activity. C, vectorcardiogram (amplified 3 times ) reveals superior orientation of the QRS& loop with increased terminal forces posteriorly and to the right. pulmonic second sounds were of equal intensity. There was distension of the neck veins, hepatosplenomegaly, evidence of pulmonary congestion, and pleural effusion along with 4f ankle edema. The chest roentgenogram showed cardiac enlarge-
ment, pulmonary congestion and bilateral pleural effusion. The electrocardiogram (Fig. 4) showed left axis deviation of QRS, low QRS voltage in the limb leads, absence of R waves in Vt to Vs, prolonged atriovenTHE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Amyloid
Heart
Disease
Fro. 4. Case 4. Electrocardiogram showing left axis deviation of QRS, low voltage of limb leads and loss of R waves in VI to Vs.
tricular
conduction, and nonconducted atria1 premature contractions with nodal escape beats. In addition, digitalis effect was present. Postmortemexamination demonstrated a very large heart with amyloid deposition in the myocardium and subendocardial tissues. There was pulmonary congestion, bilateral pleural effusion and hepatosplenomegaly.
vectorcardiogram was interpreted as being eompatible with anterior and possibly diaphragmatic myocardial infarction. Postmortem examination revealed myocardial hypertrophy and diffuse amyloid deposition in the myocardium. The heart weighed 410 gm. Pulmonary congestion, mild generalized arteriosclerosis, bilateral pleural effusion and ascites were present.
CASE 5. Tbis 64 year old white woman was admitted to the hospital for the first time in 1962 because of progressive signs and symptoms of congestive heart failure of unknown etiology and received the usual treatment for heart failure with some improvement. She was re-admitted five months later because of worsening of all symptoms and a 12 pound gain in weight. Physical examination revealed a blood pressure of 175/75 mm. Hg, pulse rate of 83/min., and an irregular rhythm. The heart was markedly enlarged to the left and had distant heart sounds and no murmurs. A protodiastolic gallop was heard at the apex, and the pulmonic second sound was accentuated. The lungs showed evidence of marked pulmonary congestion and pleural effusion. The neck veins \vere distended; the liver and spleen were enlarged; and there was ascites with 4f ankJe edema. The chest x-ray film revealed a very large heart with pulmonary congestion and bilateral pleural effusion. The electrocardiogram (Fig. 5A) showed a prolonged P-R interval, left axis deviation of QRS, low QRS voltage in the limb leads, loss of R waves in II, III, a\‘F, Vr to VS, and digitalis effect. The vectorcardiogram (Fig. 5B) also showed left axis deviation of the A QRSsE loop in the frontal plane with small planar QRS loops. Because of loss of anterior forces and posterior rotation of the loop in the horizontal and sagittaf planes and the superior orientation of the ,. QRSsE loop in the sagittal and frontal planes, the
Comment: These 5 patients demonstrate interesting features which were common to all and deserve emphasis. They were elderlypatients and had congestive heart failure of obscure etiology which did not respond to medical management and finally proved fatal. The electrocardiographic interpretation also made the clinical picture more complicated because of the presence of the classic pattern of anteroseptal myocardiai infarction in 4 cases and both diaphragmatic and anteroseptal myocardial infarcts in the 1 remaining. The vectorcardiogram correlated fairly well with the electrocardiogram in Case 5, but there were some discrepancies in Case 3. Thus, arteriosclerotic or coronary heart disease was the final impression in all the 5 cases of cardiac amyloidosis before death, even though no history of angina pectoris or myocardial infarction was obtained, and the course of the heart failure differed from that usually seen in arteriosclerotic heart disease. DISCUSSION Features: The electrocardiogram was abnormal in almost all 28 patients in our series of cardiac amyloidosis, and in some instances, these abnormalities were Electrocardiographic
754
Farrokh, Walsh and Massie
‘6
Horizontal
Rt. Sagittal
Frontal
Fro. 5. Case 5. Electrocardiogram and vectorcardiogram. A, electrocardiogram shows prolongation of atrioventricular conduction (0.25 sec.), left axis deviation of QRS, low voltage in limb leads and loss of R waves in II, III, aVF, VI, V: and VS. B, vectorcardiogram shows the posterior and superior orientation of QRS& loop with marked loss of anterior forces.
considered nondiagnostic. In recent years, advancing knowledge of electrocardiography and better understanding of amyloid disease have made it possible to recognize certain electrocardiographic patterns as being suggestive of this disease.4~5,1*8,24 The combination of left axis deviation of QRS, low QRS voltage in the limb leads, a QS configuration and/or small R waves in Vr to Vs, sometimes loss of R waves in leads II, III and aVF, with or without atria1 fibrillation and rapid ventricular response, occurring in the electrocardiogram of an elderly patient usually in congestive heart failure, without a history- of heart disease, should bring to mind the possibility of cardiac amyloidosis.2,4~s,7~8 Thirteen of our series of 28 patients showed a QS configuration in Vr to
Vs, and small R waves in Vr to Va were present in 12 of the remaining 15 cases. In 5 instances the R wave was absent in leads II, III and aVF. Only 4 patients in our series of 28 gave a history compatible with myocardial infarction; 2 of them showed evidence of anteroseptal and 1 of diaphragmatic myocardial involvement at autopsy. Low QRS voltage in the limb leads was encountered in 24 cases, and left axis deviation of QRS of varying degree was found in21. Bernreiter’ reported 6 cases of cardiac amyloidosis, all in congestive heart failure. The electrocardiograms in his series showed QS configuration in V, to V,, atria1 fibrillation, left axis deviation of QRS and low voltage in the limb leads. There was no history of chest THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Amyloid
Heart
pain or known heart disease in any of his patients, and postmortem examination showed These electrocardiocardiac amyloidosis. graphic findings have been reported by other observers as we11.“,4~5,8,g Ventricular and occasionally atria1 premature systoles were observed in almost all of our patients from time to time. Other electrocardiographic findings in our series consisted of left bundle branch block, right bundle branch block, prolonged atrioventricular conduction, second degree heart block with Wenckebach phenomenon, prolonged intraventricular conduction time and atria1 fibrillation with rapid ventricular response. Nonspecific S-T segment and T wave abnormalities were present in almost all of our patients and in most instances were considered to represent digitalis effect. Table I summarizes some of the electrocardiographic findings in our series and a ,group of 15 cases obtained from the literature.2 Only 4 cases in oyr study had vectorcardiograms. The QRSsE loops tended to be small in all cases, and all showed left axis deviation of the QRSsf? loop in the frontal plane. In 3 patients, the pattern was that of antetoseptal (or anterior) and possibly inferior myocardial infarction ; in the remaining 1 (Case 3) the I-ectorcardiogram was that of left peripheral intraventricular conduction delay and possibly enlargement of the right ventricular outflow tract. Only 1 had evidence of an anteroseptal myocardial ‘infarct at postmortem examination, while the other 3 showed no significant coronary disease. A vectorcardiographic study was previously reported y in an elderly man with amyloid disease of the heart who was in congestive heart failure. The diagnosis was anteroseptal and diaphragmatic myocardial infarction with marked left axis deviation of the QRS loop. At necropsy, amyloid disease of the heart was found without evidence of coronary \‘ectorcardiographic findings also thrombosis. have been studied in 9 cases of paramyloidosis by Coehlo and Pimental; they reported that all but one of the vectorcardiograms had the configuration of left bundle branch block and,/or left ventricular enlargement. The other vectorcardiogram of their study was interpreted as showing right \-entricular enlargement and disturbance of conduction of the terminal portion of the QRS loop, similar to that seen in one of our patients (Case 3). Clinical and Postmortem Findings: Cardiac amyloidosis has been reported in both white
Ihease
75.5
and Negro subjects, male and female,“,‘” but has been more frequent in the male.‘,“--‘” There were 19 men and 9 women in our series with an over-all male to female ratio of 2.1 to 1; in contrast, Mulligan9 reported 16 men and 1 woman in his group with a 16: 1 ratio, which is unusually high.2,23 Five male Negroes and 1 woman are included in our group of cases. The average reported ratio of male to female subjects varied between 1.5: 1 and 3: 1. The average age in our series was 67 years with the youngest patient being 46 and the oldest 94 years. The average age in Mulligan’s9 group published reports indicate that 75 was 83; per cent of the patients are over 70 years of age. 2,9,11-17 Seventeen patients in our series presented signs and symptoms of congestive heart failure; 6 patients also had cardiac enlargement and exertional dyspnea without evidence of frank heart failure. Nineteen of 20 cases reported by Eliot2 had heart failure at one time or another. A faint blowing systolic murmur was present in 50 per cent of our patients. Only 1 patient in our series had a characteristic murmur of aortic stenosis, and this lesion was confirmed postmortem. A ventricular gallop was heard in 3 cases. The blood pressure wa.s either normal or slightly below normal in most of our patients ; only 4 had hypertension. Four of the entire series of 28 patients had a history of chest pain compatible with angina pectoris. Other associated diseases contributed to the patients’ deaths. Infection was the most important and common complication. There were 4 cases of bronchopneumonia and 2 of TABLE
I
Summary of Pertinent Electrocardiographic Findings in 28 Cases of Our Series and in 15 Cases Obtained from the Literature
ECG Findings Loss of R in V1-Vv3 Left axis deviation Low voltage in limb leads Atria1 fibrillation Prolonged A-V conduction R.B.B.B. L.B.B.B. Ventricular premature contractions Total
Cases from Cases in Our Literature Series No. No. % % 8 8 11
5 7 1 1
6 15
53.3 53.3 73.3 33.3 46.6 6.6 6.6 40
R.B.B.B. = Right bundle branch block. L.B.B.B. = Left bundle branch block.
13
21 24 8 11 2
I 24 28
46.4 75 85.7 28.5 39.2 7.1 3.5 85.7
Farrokh,
Walsh
septicemia. In Mulligan’s series9 there were 6 patients with bronchopneumonia. Carcinoma was the next most common associated disease; 3 patients in our series and 3 patients in Mulligan’s study9 had generalized carcinomatosis. Also, most of these patients were in a state of malnutrition. Myocardial infarction was present in 4 cases of our series and in 3 of Mulligan’s group. At auto&y the heart was large in 23 cases in our series with an average weight of 525 gm. In a group of 76 cases in the literature,2 the heart weight averaged 472 gm. Eliot and his colleagues2 reported a case of cardiac amyloidosis with a heart weight of 1,090 gm., the largest amyloid heart ever reported, whereas the average in their series of 20 cases was 442 gm. The microscopic examination revealed that amyloid deposition was present in the myocardium, interstitial tissue and blood vessels. The subendocardial areas were also diffusely infiltrated with amyloid, and in 2 patients amyloid tissue was present in the tricuspid valve. %JMM.L\RY
Twenty-eight cases of cardiac amyloidosis were observed on reviewing 21,300 postmortem examinations performed at Barnes Hospital between 1916 and 1962. Five of these have been presented in detail. electrocardiographic and in The clinical, instances vectorcardiographic findings some have been correlated with the postmortem findings of cardiac amyloidosis. Pertinent antemortem features are described which may permit a more accurate diagnosis of amyloid heart disease; particularly the combination of left axis deviation of QRS, low QRS voltage in the limb leads, a QS configuration and/or small R waves in Vi to V,, with or without atria1 fibrillation, occurring in the electrocardiogram of elderly patients in intractable congestive heart failure without a history of heart disease. ACKNOWLEDGMENT We are greatly indebted to Dr. George D. Sorenson, of the Department of Pathology of the Washington University School of Medicine, for his help in obtaining the autopsy data on the patients discussed in this paper. We gratefully acknowledge the able technical assistance of Mrs. Edna M. Comfort, Mrs. Shirley GonzalesRubio, Miss Sandra Steinhauser, and Mrs. Eileen Gerner. We are indebted to Dr. Koo-Young Chung for his help in the preparation of this article.
and
Massie
REFERENCES 1. LINDSAY, S. and KNORP, W. F. Primary systemic amyloidosis. Arch. Path., 39: 315, 1945. 2. ELIOT, R. S., MCGEE, H. J. and BLOUNT, S. G. Cardiac amyloidosis. Circulation, 23: 613, 1961. 3. WHITTLESSAY,W. N. Primarv atvoical amvloidosis. report of a’case. Arch. Znt: Mli., 86: 2i5, 1950: 4. Case records of the Massachusetts General Hospital, Case No. 7-1961. New EngLand J. .Med., 264: 190, 1961. 5. Case records of the Massachusetts General Hospital, Case No. 18-1961. Nerv England J. Med., 264: 504, 1961. 6. CASSIDY, J. T. Cardiac amyloidosis, two cases with digitalis sensitivity. Ann. Znt. Med., 55: 989, 1961. 7. BERNREITER,M. Cardiac amyloidosis, electrocardiographic findings. Am. J. Cardiol., 1: 644, 1958. 8. Case records of the Massachusetts General Hospital, Case No. 67-1961. New E&and J. Med., 265: 593, 1961. 9. MULLIGAN, R. M. Amyloidosis of the heart. Arch. Path., 65: 615, 1958. 10. HIGGINS, W. H. and HIGGINS, W. H., JR. Primary amyloidosis, a clinical and pathological study. Am. J. M. SC., 220: 610, 1950. 11. THOMASHOW,A. I., ANGLE, W. D. and MORRIONE, T. G. Primary cardiac amyloidosis. rim. Heart J., 46: 895, 1953. 12. BALLINGER,J. Amyloid heart disease. -4m. J. Med. SC., 217: 308, 1949. 13. JONES, R. S. and FRAZIER, D. B. Primary cardiovascular amyloidosis, its clinical manifestation, pathology and histogenesis. Arch. Path., 5: 366, 1950. 14. RANSTROM,S. Myocardial amyloidosis. .4cta. path. et microbial. scandinatf., 28 : 302, 195 1. 15. BUDD, T. W. Primary amyloid disease of the heart. Am. J. Path., 10: 299, 1934. 16. LEE, H. Y. and KAUFMANN,W. Cardiac amyloidosis in the aged. A.M.A. Arch. Path., 64: 494, 1957. 17. DILLON, J. A. and EVANS, L. R. Primary amyloidosis, a report of three cases. Ann. Znt. Med., 17: 722-31, 1942. 18. BINFORD, C. H. Primary amyloidosis of the myocardium and blood vessels, report of case with death from myocardial failure. Arch. Path., 29: 314,194o. 19. BUCHEM,F. S., VAN MANDEMA, E. and ARENDS, A. Amyloidosis of the heart. Acta med. scandinar .? 171: 159, 1962. 20: RANSOM, S. Amyloidosis myocardii. Acta med. scandinav., 123: 111, 1946. 21. EISEN, H. N. Primary systemic amyloidosis. Am. J. Med., 1 : 144, 1946. 22. FISHER, H. and PREUSS, F. S. Primary systemic amyloidosis with involvement of the nervous system: Report of a case. Am. J. Clin. Path., 21: 758, 1951. 23. JOSSELSON, A. J., PRUITT, R. D. and EDWARDS, J. E. Amyloid localized to the heart; analysis of 23 cases. A.M.A. Arch. Path., 54: 359, 1952. 24. GRANT, R. P. Left axis deviation, an electrocardiographic correlation study. Circulation, 14 : 593,1956. 25. COELHO, E. and PIMENTAL,J. C. Cardiac involvement in a peculiar form of paramyloidosis. Am. J. Cardiol., 8: 624, 1961. THE AMERICANTOURNALOF CARDIOLOGY
Heart Disease*
ALINAGHI FARROKH, M.D., THOMAS J. WALSH, St.
M.D.,
Louis,
ARDIAC amyloidosis is a disease of obscure etiology’-* that usually manifests itself by progressive signs and symptoms of congestive heart failure, which fails to respond to therapeutic measures and eventually proves fatal.‘-‘” The patients are usually in the oider age group and present no other etiologic factor for their development of heart disease. Cardiac amyloidosis has been considered one of the rarer causes of congestive heart failure and has been reported most frequently in the socalled primary type of amyloidosis.‘” vls,22 Unfortunately, antemortem diagnosis of amyloidosis of the heart has been most difficult,2~4~*~22 because of the nonspecific clinical and electroIn recent years, adcardiographic findings. vancing knowledge of electrocardiography, more careful study of the course of this illness, and correlation with postrnortem findings have made possible the recognition of certain electrocardiographic features and clinical findings strongly suggestive of this disease.4~5~7~” The purpose of this paper is to direct attention to these findings and to compare them with those of our own series.
When 21,300 postmortem examinations performed at Barnes Hospital between 1916 and 1962 were reviewed, 28 cases of cardiac amyloidosis were found. Five typical patients were selected from this series for detailed presentation. CASE REPORTS
CASE 1. This 82 year old male Negro was admitted to the hospital for the first time in 1962 with #dyspnea present for about 1 year. Two months before admission the dyspnea became worse, and he experienced pronounced orthopnea and ankle edema for which he was digitalized. Since he did not respond to medical therapy as an outpatient, he was admitted to the hospital for further evaluation and treatment. Physical examination revealed a blood pressure of of Medicine,
Washington
EDWARD
MASSIE,
KD.,
I;.A.c.c.
120/70 mm. Hg, pulse rate 98/min. with irregular rhythm and marked respiratory distress. The heart was enlarged to the left; distant heart sounds and a grade 2/6 ejection systolic murmur were heard over the precordium, with aortic and pulmonic second sounds of equal intensity. There was distension of neck veins, dullness at both lung bases and moist rales throughout both lung fields. The liver and spleen were enlarged ; moderate ascites with 4+ ankle edema was present. The venous pressure was 290 mm. of water; the arm to tongue circulation time was 59 sec. The laboratory data revealed lf proteinuria, and a blood urea nitrogen of 49 mg. 70. The chest roentgenogram showed cardiac enlargement, pulmonary congestion and bilateral pleural effusion. Death occurred three days after admission. The electrocardiogram (Fig. 1) showed atria1 fibrillation with rapid ventricular response. There was left axis deviation of the QRS, low QRS voltage in the limb leads, absent R waves in VI to Va, intraventricular conduction delay, occasional ventricular premature contractions and digitalis effect. Postmortem examination revealed an enlarged heart (590 gm.) with diffuse amyloid deposition in the myoThere was bilateral pleural effusion, cardium. moderate ascites and the lungs were very edematous and congested. The liver and spleen were enlarged. ‘This 82 year old male Negro was first CASE 2. admitted to the hospital in 1957 because of marked congestive heart failure of two months’ duration. He was treated with digitalis, diuretics and low salt diet with very little response and was discharged seven Because of increasingly severe heart days later. failure and marked dehydration, he was admitted for the second time one month later. Physical examination revealed a blood pressure of 140/83, pulse rate of 85/min., and an irregular rhythm due to ventricular premature contractions. He was well developed and somewhat obese. The heart was enlarged to the left, and had faint sounds. A grade 2/6 ejection systolic murmur was best heard at the base, and a ventricular gallop rhythm was present at the apex; the pulmonic second sound was accentuated. The neck veins were distended; moist rales were present in both lungs with dullness in both bases posteriorly. There was 3+ ankle edema and
CASE MATERIAL
* From the Department Hospital. St. Louis, MO.
nnd
Missouri
C
ILLUSTRATIVE
F.A.C.C.
University School of Medicine,
750
THE
and the Heart Station, Barnes
AMERICAN
JOURNAL
OF CARDIOLOGY
7.5I
FIG. 1. Casr 1. Llectrocardiogram showing left axis clrviation of QRS, low voltage in limb leads, atria1 fibrillation ;~nti loss of R waves in VI to VY
hepatosplenomegaly. Chest roentgenogram showed a very enlarged heart, pulmonary congestion and biDehydration and hemolateral pleural effusion. concentration were marked; the blood urea nitrogen had risen from 9 to 109 mg.$‘& from the first admission to the second. The electrocardiogram (Fig. 2) showed sinus rhythm with a normal P-R interval, low QRS voltage in the limb leads, left axis deviation of the QRS? minute R waves in VI and V?, loss of R waves in V3 and \‘r and digitalis effect. Postmortem examination revealed an enlarged heart weighing 520 gm. and extensive amyloid infiltration Bilateral in the myocardium and small vessels. pleural effusion, pulmonary congestion and ascites were also present. CASE 3. This 55 year old white woman was admitted to the hospital for the first time in 1960 and died a month later. Her main complaints included weakness, shortness of breath, increasing size of her abdomen, and ankle edema of two months’ duration. The past history was negative. Physical examination revealed a normal blood pressure. a pulse rate of 95/min., an irregular rhythm The heart was enlarged to and normal temperature. the left and had very faint heart sounds and no murmurs; the aortic second sound was louder than the pulmonic second sound. There were moist rales The liver and dullness in both lung bases posteriorly. and spleen were markedly enlarged; ankle edema was pronounced. The conjunctivae were pale. The venous pressure was 230 mm. of water and arm to Hematologic tongue circulation time was 22 sec. evaluation
demonstrated
a
marked
anemia
and
myelosclerosis. ‘I here was l+ proteinuria. and the blood urea nitrogen was 55 mg. ye. 7 he electrocardiqgram (Fig. 3A) showed prolonged P-R interval, intraventricular conduction delay, low QRS voltage in the limb leads, left axis deviation of QRS, loss of R waves in Vt to Va and digitalis effect. A subsequent electrocardiogram (Fig. 3B) taken one day before her death demonstrated an idioventricular rhythm of 38jmin. without evidence of atria1 acuvuy. d vectorcardiogram (Fig. 3C) displayed left axis h deviation of the QRSsE loop in the frontal plane, The planar QRS loops were smaller than usual. There were increased superior and posterior forces; the interpretation was peripheral intraventricular conduction delay or possibly enIargement of the right ventricular outflow tract. Postmortem examination showed evidence of generalized amyloidosis involving mainly the heart, lungs, liver, kidney and spleen. The heart was large.PBilateral pleural effusion, ascites, pulmonary congestion and edema were demonstrated. CASE 4. ‘1 his 57 year old w-hite \voman had shortness of breath and swelling of the ankles for one year. She was treated for congestive heart failure with very poor results. Because of the worsening of her symptoms, she was admitted to the hospital.l T‘hc past history was completely negative. On examination, the blood pressure was 145/85, pulse rate 86/min., and the rhythm was irregular. The heart was enlarged to the left and distant heart sounds and many ventricular premature contractions were noted. A faint ejection systolic murmur was best heard at the left sternal border: ;aortic and
752
Farrokh,
Walsh and Massie
FIG. 2. Case 2. Electrocardiogram showing sinus rhythm, left axis deviation of QRS, low voltage in limb leads, minute R waves in VI and VP and absent R waves in Vs and V+
Horizontal
_
Rt. Sagittal
Frontal
FIG. 3. Case 3. Electrocardiogram and vectorcardiogram. A, electrocardiogram taken on admission shows sinus rhythm with prolonged atrioventricular conduction (0.22 sec.), left axis deviation of QRS, low voltage in limb leads taken shortly before death shows an idioventricular rhythm of and loss of R waves in VI to VS. B, electrocardiogram 38/min. with no evidence of atria1 activity. C, vectorcardiogram (amplified 3 times ) reveals superior orientation of the QRS& loop with increased terminal forces posteriorly and to the right. pulmonic second sounds were of equal intensity. There was distension of the neck veins, hepatosplenomegaly, evidence of pulmonary congestion, and pleural effusion along with 4f ankle edema. The chest roentgenogram showed cardiac enlarge-
ment, pulmonary congestion and bilateral pleural effusion. The electrocardiogram (Fig. 4) showed left axis deviation of QRS, low QRS voltage in the limb leads, absence of R waves in Vt to Vs, prolonged atriovenTHE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Amyloid
Heart
Disease
Fro. 4. Case 4. Electrocardiogram showing left axis deviation of QRS, low voltage of limb leads and loss of R waves in VI to Vs.
tricular
conduction, and nonconducted atria1 premature contractions with nodal escape beats. In addition, digitalis effect was present. Postmortemexamination demonstrated a very large heart with amyloid deposition in the myocardium and subendocardial tissues. There was pulmonary congestion, bilateral pleural effusion and hepatosplenomegaly.
vectorcardiogram was interpreted as being eompatible with anterior and possibly diaphragmatic myocardial infarction. Postmortem examination revealed myocardial hypertrophy and diffuse amyloid deposition in the myocardium. The heart weighed 410 gm. Pulmonary congestion, mild generalized arteriosclerosis, bilateral pleural effusion and ascites were present.
CASE 5. Tbis 64 year old white woman was admitted to the hospital for the first time in 1962 because of progressive signs and symptoms of congestive heart failure of unknown etiology and received the usual treatment for heart failure with some improvement. She was re-admitted five months later because of worsening of all symptoms and a 12 pound gain in weight. Physical examination revealed a blood pressure of 175/75 mm. Hg, pulse rate of 83/min., and an irregular rhythm. The heart was markedly enlarged to the left and had distant heart sounds and no murmurs. A protodiastolic gallop was heard at the apex, and the pulmonic second sound was accentuated. The lungs showed evidence of marked pulmonary congestion and pleural effusion. The neck veins \vere distended; the liver and spleen were enlarged; and there was ascites with 4f ankJe edema. The chest x-ray film revealed a very large heart with pulmonary congestion and bilateral pleural effusion. The electrocardiogram (Fig. 5A) showed a prolonged P-R interval, left axis deviation of QRS, low QRS voltage in the limb leads, loss of R waves in II, III, a\‘F, Vr to VS, and digitalis effect. The vectorcardiogram (Fig. 5B) also showed left axis deviation of the A QRSsE loop in the frontal plane with small planar QRS loops. Because of loss of anterior forces and posterior rotation of the loop in the horizontal and sagittaf planes and the superior orientation of the ,. QRSsE loop in the sagittal and frontal planes, the
Comment: These 5 patients demonstrate interesting features which were common to all and deserve emphasis. They were elderlypatients and had congestive heart failure of obscure etiology which did not respond to medical management and finally proved fatal. The electrocardiographic interpretation also made the clinical picture more complicated because of the presence of the classic pattern of anteroseptal myocardiai infarction in 4 cases and both diaphragmatic and anteroseptal myocardial infarcts in the 1 remaining. The vectorcardiogram correlated fairly well with the electrocardiogram in Case 5, but there were some discrepancies in Case 3. Thus, arteriosclerotic or coronary heart disease was the final impression in all the 5 cases of cardiac amyloidosis before death, even though no history of angina pectoris or myocardial infarction was obtained, and the course of the heart failure differed from that usually seen in arteriosclerotic heart disease. DISCUSSION Features: The electrocardiogram was abnormal in almost all 28 patients in our series of cardiac amyloidosis, and in some instances, these abnormalities were Electrocardiographic
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Farrokh, Walsh and Massie
‘6
Horizontal
Rt. Sagittal
Frontal
Fro. 5. Case 5. Electrocardiogram and vectorcardiogram. A, electrocardiogram shows prolongation of atrioventricular conduction (0.25 sec.), left axis deviation of QRS, low voltage in limb leads and loss of R waves in II, III, aVF, VI, V: and VS. B, vectorcardiogram shows the posterior and superior orientation of QRS& loop with marked loss of anterior forces.
considered nondiagnostic. In recent years, advancing knowledge of electrocardiography and better understanding of amyloid disease have made it possible to recognize certain electrocardiographic patterns as being suggestive of this disease.4~5,1*8,24 The combination of left axis deviation of QRS, low QRS voltage in the limb leads, a QS configuration and/or small R waves in Vr to Vs, sometimes loss of R waves in leads II, III and aVF, with or without atria1 fibrillation and rapid ventricular response, occurring in the electrocardiogram of an elderly patient usually in congestive heart failure, without a history- of heart disease, should bring to mind the possibility of cardiac amyloidosis.2,4~s,7~8 Thirteen of our series of 28 patients showed a QS configuration in Vr to
Vs, and small R waves in Vr to Va were present in 12 of the remaining 15 cases. In 5 instances the R wave was absent in leads II, III and aVF. Only 4 patients in our series of 28 gave a history compatible with myocardial infarction; 2 of them showed evidence of anteroseptal and 1 of diaphragmatic myocardial involvement at autopsy. Low QRS voltage in the limb leads was encountered in 24 cases, and left axis deviation of QRS of varying degree was found in21. Bernreiter’ reported 6 cases of cardiac amyloidosis, all in congestive heart failure. The electrocardiograms in his series showed QS configuration in V, to V,, atria1 fibrillation, left axis deviation of QRS and low voltage in the limb leads. There was no history of chest THE
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pain or known heart disease in any of his patients, and postmortem examination showed These electrocardiocardiac amyloidosis. graphic findings have been reported by other observers as we11.“,4~5,8,g Ventricular and occasionally atria1 premature systoles were observed in almost all of our patients from time to time. Other electrocardiographic findings in our series consisted of left bundle branch block, right bundle branch block, prolonged atrioventricular conduction, second degree heart block with Wenckebach phenomenon, prolonged intraventricular conduction time and atria1 fibrillation with rapid ventricular response. Nonspecific S-T segment and T wave abnormalities were present in almost all of our patients and in most instances were considered to represent digitalis effect. Table I summarizes some of the electrocardiographic findings in our series and a ,group of 15 cases obtained from the literature.2 Only 4 cases in oyr study had vectorcardiograms. The QRSsE loops tended to be small in all cases, and all showed left axis deviation of the QRSsf? loop in the frontal plane. In 3 patients, the pattern was that of antetoseptal (or anterior) and possibly inferior myocardial infarction ; in the remaining 1 (Case 3) the I-ectorcardiogram was that of left peripheral intraventricular conduction delay and possibly enlargement of the right ventricular outflow tract. Only 1 had evidence of an anteroseptal myocardial ‘infarct at postmortem examination, while the other 3 showed no significant coronary disease. A vectorcardiographic study was previously reported y in an elderly man with amyloid disease of the heart who was in congestive heart failure. The diagnosis was anteroseptal and diaphragmatic myocardial infarction with marked left axis deviation of the QRS loop. At necropsy, amyloid disease of the heart was found without evidence of coronary \‘ectorcardiographic findings also thrombosis. have been studied in 9 cases of paramyloidosis by Coehlo and Pimental; they reported that all but one of the vectorcardiograms had the configuration of left bundle branch block and,/or left ventricular enlargement. The other vectorcardiogram of their study was interpreted as showing right \-entricular enlargement and disturbance of conduction of the terminal portion of the QRS loop, similar to that seen in one of our patients (Case 3). Clinical and Postmortem Findings: Cardiac amyloidosis has been reported in both white
Ihease
75.5
and Negro subjects, male and female,“,‘” but has been more frequent in the male.‘,“--‘” There were 19 men and 9 women in our series with an over-all male to female ratio of 2.1 to 1; in contrast, Mulligan9 reported 16 men and 1 woman in his group with a 16: 1 ratio, which is unusually high.2,23 Five male Negroes and 1 woman are included in our group of cases. The average reported ratio of male to female subjects varied between 1.5: 1 and 3: 1. The average age in our series was 67 years with the youngest patient being 46 and the oldest 94 years. The average age in Mulligan’s9 group published reports indicate that 75 was 83; per cent of the patients are over 70 years of age. 2,9,11-17 Seventeen patients in our series presented signs and symptoms of congestive heart failure; 6 patients also had cardiac enlargement and exertional dyspnea without evidence of frank heart failure. Nineteen of 20 cases reported by Eliot2 had heart failure at one time or another. A faint blowing systolic murmur was present in 50 per cent of our patients. Only 1 patient in our series had a characteristic murmur of aortic stenosis, and this lesion was confirmed postmortem. A ventricular gallop was heard in 3 cases. The blood pressure wa.s either normal or slightly below normal in most of our patients ; only 4 had hypertension. Four of the entire series of 28 patients had a history of chest pain compatible with angina pectoris. Other associated diseases contributed to the patients’ deaths. Infection was the most important and common complication. There were 4 cases of bronchopneumonia and 2 of TABLE
I
Summary of Pertinent Electrocardiographic Findings in 28 Cases of Our Series and in 15 Cases Obtained from the Literature
ECG Findings Loss of R in V1-Vv3 Left axis deviation Low voltage in limb leads Atria1 fibrillation Prolonged A-V conduction R.B.B.B. L.B.B.B. Ventricular premature contractions Total
Cases from Cases in Our Literature Series No. No. % % 8 8 11
5 7 1 1
6 15
53.3 53.3 73.3 33.3 46.6 6.6 6.6 40
R.B.B.B. = Right bundle branch block. L.B.B.B. = Left bundle branch block.
13
21 24 8 11 2
I 24 28
46.4 75 85.7 28.5 39.2 7.1 3.5 85.7
Farrokh,
Walsh
septicemia. In Mulligan’s series9 there were 6 patients with bronchopneumonia. Carcinoma was the next most common associated disease; 3 patients in our series and 3 patients in Mulligan’s study9 had generalized carcinomatosis. Also, most of these patients were in a state of malnutrition. Myocardial infarction was present in 4 cases of our series and in 3 of Mulligan’s group. At auto&y the heart was large in 23 cases in our series with an average weight of 525 gm. In a group of 76 cases in the literature,2 the heart weight averaged 472 gm. Eliot and his colleagues2 reported a case of cardiac amyloidosis with a heart weight of 1,090 gm., the largest amyloid heart ever reported, whereas the average in their series of 20 cases was 442 gm. The microscopic examination revealed that amyloid deposition was present in the myocardium, interstitial tissue and blood vessels. The subendocardial areas were also diffusely infiltrated with amyloid, and in 2 patients amyloid tissue was present in the tricuspid valve. %JMM.L\RY
Twenty-eight cases of cardiac amyloidosis were observed on reviewing 21,300 postmortem examinations performed at Barnes Hospital between 1916 and 1962. Five of these have been presented in detail. electrocardiographic and in The clinical, instances vectorcardiographic findings some have been correlated with the postmortem findings of cardiac amyloidosis. Pertinent antemortem features are described which may permit a more accurate diagnosis of amyloid heart disease; particularly the combination of left axis deviation of QRS, low QRS voltage in the limb leads, a QS configuration and/or small R waves in Vi to V,, with or without atria1 fibrillation, occurring in the electrocardiogram of elderly patients in intractable congestive heart failure without a history of heart disease. ACKNOWLEDGMENT We are greatly indebted to Dr. George D. Sorenson, of the Department of Pathology of the Washington University School of Medicine, for his help in obtaining the autopsy data on the patients discussed in this paper. We gratefully acknowledge the able technical assistance of Mrs. Edna M. Comfort, Mrs. Shirley GonzalesRubio, Miss Sandra Steinhauser, and Mrs. Eileen Gerner. We are indebted to Dr. Koo-Young Chung for his help in the preparation of this article.
and
Massie
REFERENCES 1. LINDSAY, S. and KNORP, W. F. Primary systemic amyloidosis. Arch. Path., 39: 315, 1945. 2. ELIOT, R. S., MCGEE, H. J. and BLOUNT, S. G. Cardiac amyloidosis. Circulation, 23: 613, 1961. 3. WHITTLESSAY,W. N. Primarv atvoical amvloidosis. report of a’case. Arch. Znt: Mli., 86: 2i5, 1950: 4. Case records of the Massachusetts General Hospital, Case No. 7-1961. New EngLand J. .Med., 264: 190, 1961. 5. Case records of the Massachusetts General Hospital, Case No. 18-1961. Nerv England J. Med., 264: 504, 1961. 6. CASSIDY, J. T. Cardiac amyloidosis, two cases with digitalis sensitivity. Ann. Znt. Med., 55: 989, 1961. 7. BERNREITER,M. Cardiac amyloidosis, electrocardiographic findings. Am. J. Cardiol., 1: 644, 1958. 8. Case records of the Massachusetts General Hospital, Case No. 67-1961. New E&and J. Med., 265: 593, 1961. 9. MULLIGAN, R. M. Amyloidosis of the heart. Arch. Path., 65: 615, 1958. 10. HIGGINS, W. H. and HIGGINS, W. H., JR. Primary amyloidosis, a clinical and pathological study. Am. J. M. SC., 220: 610, 1950. 11. THOMASHOW,A. I., ANGLE, W. D. and MORRIONE, T. G. Primary cardiac amyloidosis. rim. Heart J., 46: 895, 1953. 12. BALLINGER,J. Amyloid heart disease. -4m. J. Med. SC., 217: 308, 1949. 13. JONES, R. S. and FRAZIER, D. B. Primary cardiovascular amyloidosis, its clinical manifestation, pathology and histogenesis. Arch. Path., 5: 366, 1950. 14. RANSTROM,S. Myocardial amyloidosis. .4cta. path. et microbial. scandinatf., 28 : 302, 195 1. 15. BUDD, T. W. Primary amyloid disease of the heart. Am. J. Path., 10: 299, 1934. 16. LEE, H. Y. and KAUFMANN,W. Cardiac amyloidosis in the aged. A.M.A. Arch. Path., 64: 494, 1957. 17. DILLON, J. A. and EVANS, L. R. Primary amyloidosis, a report of three cases. Ann. Znt. Med., 17: 722-31, 1942. 18. BINFORD, C. H. Primary amyloidosis of the myocardium and blood vessels, report of case with death from myocardial failure. Arch. Path., 29: 314,194o. 19. BUCHEM,F. S., VAN MANDEMA, E. and ARENDS, A. Amyloidosis of the heart. Acta med. scandinar .? 171: 159, 1962. 20: RANSOM, S. Amyloidosis myocardii. Acta med. scandinav., 123: 111, 1946. 21. EISEN, H. N. Primary systemic amyloidosis. Am. J. Med., 1 : 144, 1946. 22. FISHER, H. and PREUSS, F. S. Primary systemic amyloidosis with involvement of the nervous system: Report of a case. Am. J. Clin. Path., 21: 758, 1951. 23. JOSSELSON, A. J., PRUITT, R. D. and EDWARDS, J. E. Amyloid localized to the heart; analysis of 23 cases. A.M.A. Arch. Path., 54: 359, 1952. 24. GRANT, R. P. Left axis deviation, an electrocardiographic correlation study. Circulation, 14 : 593,1956. 25. COELHO, E. and PIMENTAL,J. C. Cardiac involvement in a peculiar form of paramyloidosis. Am. J. Cardiol., 8: 624, 1961. THE AMERICANTOURNALOF CARDIOLOGY