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Dilated Cardiomyopathy in Identical Twins
Dilated Cardiomyopathy in Identical Twins· Hershel Dzick, M.D .; Gerald Hollander; M.D .; Alvin Greengart, M.D. ; Jacob Shani, M.D.; and Edgar Lichstein, M.D., EC .C.P.
Identical twins had dilated cardiomyopathy and evidence of an autoimmune process involving both the heart and thyroid
gland. An inherited abnormality of immune regulation is suggested as a possible basis for these unwual findings.
The specific etiology of dilated congestive cardiomyopathy remains obscure in many patients. 'Ireatment is usually directed at controlling the symptoms of congestive heart failure rather than at any specific cause of the disease. The role of autoimmune mechanisms in the pathogenesis of dilated cardiomyopathy is unclear. While hypertrophic cardiomyopathy is often a familial disease, the presentation of dilated cardiomyopathy is generally sporadic. In this case report, monozygotic twins had dilated cardiomyopathy of unknown etiology and evidence of an autoimmune process involving both the heart and thyroid gland.
dilated cardiomyopathy with bivenbicular failure was made . After a stormy course, the patient eventually became well enough to be discharged. Subsequent left- and right-sided heart catheterization and coronary arteriography confirmed the diagnosis ofdilated cardiomyopathy. The patient refused myocardial biopsy. Regimens of digoxin, furosemide, coumadin, and synthroid were maintained. Six months after discharge, she remained dyspneic on minimal exertion . Repeat echocardiogram showed no improvement in ventricular function.
CASE REPORrS
CASE 1
A 35-YeaMlldwhite woman presented with Increasing dyspnea on exertion, orthopnea, edema, lethargy, and deepening of her voice of two months' duration. Six months previously, she delivered her second child via repeat caesarian section . The patient felt well previously with good exercise tolerance until her recent symptoms. Preliminary work-up revealed low serum T., and cardiomegaly on chest film. Synthroid, .025 mg per day, was started. Three days late!; the patient complained of palpitations. Electrocardiogram showed multifOrmpremature ventricular heats and ventricular couplets, and the patient was referred to the hospital with the diagnosis of "myxedema heart disease." There was no history of diabetes, hypertension, rheumatic heart disease, myocardial infarction, family history of heart disease, or recent viral Infection. The patient did not drink alcohol. Physical examination on admission revealed blood pressure of 95/60 mm Hg : heart rate, 90 heats per minute; and a respiratory rate of 18 per minute. The patient was In no distress. Thyroid enlargement or nodularity was not found. Lung fields were clear. An S. gallop and 1/6systolic murmur were heard over the apex. There was slight pretibial pitting edema. The admission chest x-ray fUm is seen In Figure L Oral procainamide therapy was begun for control of ventricular ectopy. 1Welvehours after admission, the patient became confused, hypotensive, and acidotic, leading to cardiac arrest. She was successfully resuscitated. Right-sided heart catheterization and echocardiography were performed. Bedside M-mode echoeardiagram (Fig 2b) showed a markedly dilated left ventricle with poor function . The left abium and right ventricle were also dilated. There was no pericardial effusion or evidence of valvular disease. Rightsided heart catheterization showed elevated right ventricular enddiastolic and pulmonary capillary wedge pressure. The diagnosis of ·From the Department of Medicine, Division of Cardiology, Maimonides Medical Center, State University of New York, Downstate Medical Center, Brooklyn. Manuscript received May_ 23; accepted June 11. Reprint requem: Dr: Hollander, MaimonldesMedicalCenter, 4802
Thnth Aoenue, Brooklyn ll219
878
CASE 2 The patients identical twin sister, who was asymptomatic, was evaluated for evidence of thyroid disease or cardiomyopathy. She was not recently post-partum, did not drink alcohol, and had not had a recent viral Infection. Physical examination was unremarkable. M-mode echocardiography revealed elevated left ventricular diastolic diameter and reduced function, consistent with the diagnosis of dilated cardiomyopathy (Fig 2&). The echocardiographic and lab data from both patients are summarized In Thble 1.
Serologic Studies In patient 1, the elevated TSH, reduced T., and elevated
FIGURE 1. Admission chest x-ray fUm of patient 1 shows marked cardiomegaly. DIl8IIld C8nIIom)'opldhy In identical 1Wt1ll (Ozick fit aI)
..
..
".:
.,'.- ,;.:..':.•- : ~ .> 7- j ~ .:. ;.: : ~; :. ' : -: ~ : -"' ~ ~ i ~ ':':;: " ~ :' .'.. .
. . :.-.
<~
. ; ~: > "
::. -, ... -~ ... ",-.: .:..:."_ -' .:. . '
-
' ;"
a
:' :" ' :'~
'
b
!: 11 1 1 11111 111 1 11~ 1I 11 1 1 1 111 1 1 1 1 1111 ~ 1 11I 1 111 111 111 1 1~ 1 111 1 1 11 1I 111 1I ~ lI l l l l1 l l l l1 l l n l l l FIGURE 2. M-mode echocardiogram of patient 2 (a) and patient 1 (b) showing reduced left ventricular function as evidenced by dilated left ventricle, reduced ejection fraction and increased E point-septal separation.
antithyroid microsomal antibodies are consistent with autoimmune thyroid disease of the Hashimoto's type. The elevated levels of antithyroid antibodies and borderline elevated TSH in patient 2 are consistent with a subclinicalHashimoto's thyroiditis. 1 Serum titers of anticardiac myollemmal antibodies were elevated in both patients. These are organ-speciflc antibodies which bind to specific myocardial substructures and can be detected by immunoftuorescence. They are also capable of complement-mediated cytolysis of C3l'diocytes In vitro. These antibodies have been shown to be fairly specific fOridentifying myocarditis and postmyocarditis syndromes confirmed by biopsy.1,3 Circulating immune complexes, measured
Table I-Summary oflAboratory Finding.· Echocardiogram LV end-diastolic diameter Ejection fraction
% Fractional
shortening TSH
Patient 1 Patient 2
Normal Values
68 mm
62 mm
35-57 mm
18% 50 2.4
24% 7.1 10
28-41% 0-6,5 micro IU/ml 5.5-11.5 .,.g1dl
1:6400
1:100
1:80 152
0 12 meg AHG eqIml
36%
T. RIA Antithyroid microsomal antibodies 1:6400 Cytolytic anti-heart myolemmal antibodies 1:80 Raji cell assay 193
47%
>65%
-LV is left ventricle; TSH, thyroid stimulating hormone; and RIA, radioimmunoassay,
by the Raji cell assay,· were elevated in both patients. Complement levels were normal in both patients. The HLA typing in patient 1 revealed a DRS locus. DISCUSSION
Although cases of apparent familial dilated cardiomyopathy have been reported, this disease most often seems to occur in a sporadic pattern. This is in contrast to hypertrophic cardiomyopathy which often presents as a genetically transmitted disease .5 The finding of dilated cardiomyopathy in monozygotic twins has not been previously reported. Both patients demonstrated elevated levels of antithyroid microsomal antibodies. Patient 1 was overtly hypothyroid, consistent with the diagnosis of Hashimotos thyroiditis. This disease is often familial and has been associated with HLA locus DRS, as in our patient. 1 Relatives of patients with Hashimoto's thyroiditis frequently are found to have antithyroid antibodies, though they may not be overtly hypothyroid. An association with other diseases of presumed autoimmune origin such as pernicious anemia has been found, e but the presence of anticardiac antibodies in patients with Hashimotos thyroiditis has not been previously reported. Although some decrease in myocardial contractility may be seen in patients with long standing myxedema," there is no known association CHEST I 88 I 8 I DECEMBER, 1984
m
between autoimmune thyroid disease and dilated cardiomyopathy. Autoimmune disease has been implicated in the pathogenesis of dilated cardiomyopathy, especially dilated cardiomyopathy following viral myocarditis.I Both humoral and cellular immune dysfunction have been reported. This includes the presence of specific circulating anticardiac antibodies, defects in suppressor T-cell function, lymphocyte-mediated cytotoxicity against cardiocytes, and the presence of inflammation on myocardial biopsy.2,8 In fact, preliminary evidence suggests that immunosuppressive therapy may be bene6cial in patients with evidence of myocardial inflammation.9.10 We speculate that the two patients described inherited a common genetic abnormality of immune regulation which rendered them susceptible to the development of both autoimmune thyroid disease and autoimmune cardiomyopathy. The trigger for the development of overt clinical thyroid disease and cardiomyopathy in the first patient may have been related to the postpartum period, a time of presumed altered immune surveillance when both cardiomyopathy" and autoimmune thyroid disease" may become clinically apparent. Our data emphasize the need for further research into immunologic mechanisms in patients with dilated cardiomyopathy and for controlled clinical trials of immunosuppressive therapy for dilated cardiomyopathy where an autoimmune process is suspected. REFERENCES
1 Strakosch DR, Wenzel BE, Row vv, Volpe R. Immunology of
880
autoimmune thyroid disease. N Eng} J Med 1982;307:1499-1507
2 MaischB, 'Uostel-Soeder R, Stechemesser E, BergPA, Kochsiek IC. Diagnostic relevance of humoral and cell-mediated immune reactions in patients with acute viral myocarditis. Clio Exp Immunol 1982; 48:533-45 3 Maisch B, Kochsiek K. Humoral and cellular immune reactions in hypertrophic and congestive cardiomyopathy (abstract). Circulation 1981; 64:26
4 Theo61opoulos AM, WIlson CB, Dixon FJ. The Raji cell assay radioimmune assay for detecting immune complexes in human sera. J Clio Invest 1976; 57:169-82 5 Ross RS, Bulldey BH, Hutchins GM, Harshey JS, Jones RA, Kraus H. Idiopathic familial myocardiopathy in three generations: a clinical and pathologic study. Am Heart] 1978; 96:170-79
6 Beall NG, Solomon OH. Hashimoto's disease and Graves disease. In: Santer M, edt Immunologic disease. Little, Brown and Co, 1978:1762 7 Santos AD, Mathew PIC, Miller BE The cardiomyopathy of hypothyroidism revisited (editorial). Am J Dis Child 1980; 134:547-49 8 O'Connell JB, Gunan RM. Dilated-congestive cardiomyopathy: prognostic features and therapy. Heart Uansplantation 1982; 2:7-17 9 Mason ~ Billingham ME, Ricci DR. Treatment of acute inflammatory myocarditis assisted by endomyocardia1 biopsy. Am J Cardioll980; 45:1037-44 10 O'Connell JB, Robinson}A, Henkin RE, Gunnar RM. Immunosuppressive therapy in patients with congestive cardiomyopathy and myocardial uptake of gallium-67. Circulation 1981; 64: 780-86 11 Demakis JG, Rahimtoola SH, Sutton GC, Meadows WR, Szanto PB, Tobin JR, et aI. Natural course of peripartum cardiomyopathy. Circulation 1971; 44:1053-61 12 Amino N, Morl H, Iwantani Y, 'Dwituna 0, Kawashima M, Tsuge I, et aI. High prevalence of transient post-partum thyrotoxicosis and hypothyroidism. N Eng} J Med 1982; 306:849-52
DIlated C8rcIom)qMIIhy In identical 1Wtns (0zJcIc et 8/)
Identical twins had dilated cardiomyopathy and evidence of an autoimmune process involving both the heart and thyroid
gland. An inherited abnormality of immune regulation is suggested as a possible basis for these unwual findings.
The specific etiology of dilated congestive cardiomyopathy remains obscure in many patients. 'Ireatment is usually directed at controlling the symptoms of congestive heart failure rather than at any specific cause of the disease. The role of autoimmune mechanisms in the pathogenesis of dilated cardiomyopathy is unclear. While hypertrophic cardiomyopathy is often a familial disease, the presentation of dilated cardiomyopathy is generally sporadic. In this case report, monozygotic twins had dilated cardiomyopathy of unknown etiology and evidence of an autoimmune process involving both the heart and thyroid gland.
dilated cardiomyopathy with bivenbicular failure was made . After a stormy course, the patient eventually became well enough to be discharged. Subsequent left- and right-sided heart catheterization and coronary arteriography confirmed the diagnosis ofdilated cardiomyopathy. The patient refused myocardial biopsy. Regimens of digoxin, furosemide, coumadin, and synthroid were maintained. Six months after discharge, she remained dyspneic on minimal exertion . Repeat echocardiogram showed no improvement in ventricular function.
CASE REPORrS
CASE 1
A 35-YeaMlldwhite woman presented with Increasing dyspnea on exertion, orthopnea, edema, lethargy, and deepening of her voice of two months' duration. Six months previously, she delivered her second child via repeat caesarian section . The patient felt well previously with good exercise tolerance until her recent symptoms. Preliminary work-up revealed low serum T., and cardiomegaly on chest film. Synthroid, .025 mg per day, was started. Three days late!; the patient complained of palpitations. Electrocardiogram showed multifOrmpremature ventricular heats and ventricular couplets, and the patient was referred to the hospital with the diagnosis of "myxedema heart disease." There was no history of diabetes, hypertension, rheumatic heart disease, myocardial infarction, family history of heart disease, or recent viral Infection. The patient did not drink alcohol. Physical examination on admission revealed blood pressure of 95/60 mm Hg : heart rate, 90 heats per minute; and a respiratory rate of 18 per minute. The patient was In no distress. Thyroid enlargement or nodularity was not found. Lung fields were clear. An S. gallop and 1/6systolic murmur were heard over the apex. There was slight pretibial pitting edema. The admission chest x-ray fUm is seen In Figure L Oral procainamide therapy was begun for control of ventricular ectopy. 1Welvehours after admission, the patient became confused, hypotensive, and acidotic, leading to cardiac arrest. She was successfully resuscitated. Right-sided heart catheterization and echocardiography were performed. Bedside M-mode echoeardiagram (Fig 2b) showed a markedly dilated left ventricle with poor function . The left abium and right ventricle were also dilated. There was no pericardial effusion or evidence of valvular disease. Rightsided heart catheterization showed elevated right ventricular enddiastolic and pulmonary capillary wedge pressure. The diagnosis of ·From the Department of Medicine, Division of Cardiology, Maimonides Medical Center, State University of New York, Downstate Medical Center, Brooklyn. Manuscript received May_ 23; accepted June 11. Reprint requem: Dr: Hollander, MaimonldesMedicalCenter, 4802
Thnth Aoenue, Brooklyn ll219
878
CASE 2 The patients identical twin sister, who was asymptomatic, was evaluated for evidence of thyroid disease or cardiomyopathy. She was not recently post-partum, did not drink alcohol, and had not had a recent viral Infection. Physical examination was unremarkable. M-mode echocardiography revealed elevated left ventricular diastolic diameter and reduced function, consistent with the diagnosis of dilated cardiomyopathy (Fig 2&). The echocardiographic and lab data from both patients are summarized In Thble 1.
Serologic Studies In patient 1, the elevated TSH, reduced T., and elevated
FIGURE 1. Admission chest x-ray fUm of patient 1 shows marked cardiomegaly. DIl8IIld C8nIIom)'opldhy In identical 1Wt1ll (Ozick fit aI)
..
..
".:
.,'.- ,;.:..':.•- : ~ .> 7- j ~ .:. ;.: : ~; :. ' : -: ~ : -"' ~ ~ i ~ ':':;: " ~ :' .'.. .
. . :.-.
<~
. ; ~: > "
::. -, ... -~ ... ",-.: .:..:."_ -' .:. . '
-
' ;"
a
:' :" ' :'~
'
b
!: 11 1 1 11111 111 1 11~ 1I 11 1 1 1 111 1 1 1 1 1111 ~ 1 11I 1 111 111 111 1 1~ 1 111 1 1 11 1I 111 1I ~ lI l l l l1 l l l l1 l l n l l l FIGURE 2. M-mode echocardiogram of patient 2 (a) and patient 1 (b) showing reduced left ventricular function as evidenced by dilated left ventricle, reduced ejection fraction and increased E point-septal separation.
antithyroid microsomal antibodies are consistent with autoimmune thyroid disease of the Hashimoto's type. The elevated levels of antithyroid antibodies and borderline elevated TSH in patient 2 are consistent with a subclinicalHashimoto's thyroiditis. 1 Serum titers of anticardiac myollemmal antibodies were elevated in both patients. These are organ-speciflc antibodies which bind to specific myocardial substructures and can be detected by immunoftuorescence. They are also capable of complement-mediated cytolysis of C3l'diocytes In vitro. These antibodies have been shown to be fairly specific fOridentifying myocarditis and postmyocarditis syndromes confirmed by biopsy.1,3 Circulating immune complexes, measured
Table I-Summary oflAboratory Finding.· Echocardiogram LV end-diastolic diameter Ejection fraction
% Fractional
shortening TSH
Patient 1 Patient 2
Normal Values
68 mm
62 mm
35-57 mm
18% 50 2.4
24% 7.1 10
28-41% 0-6,5 micro IU/ml 5.5-11.5 .,.g1dl
1:6400
1:100
1:80 152
0 12 meg AHG eqIml
36%
T. RIA Antithyroid microsomal antibodies 1:6400 Cytolytic anti-heart myolemmal antibodies 1:80 Raji cell assay 193
47%
>65%
-LV is left ventricle; TSH, thyroid stimulating hormone; and RIA, radioimmunoassay,
by the Raji cell assay,· were elevated in both patients. Complement levels were normal in both patients. The HLA typing in patient 1 revealed a DRS locus. DISCUSSION
Although cases of apparent familial dilated cardiomyopathy have been reported, this disease most often seems to occur in a sporadic pattern. This is in contrast to hypertrophic cardiomyopathy which often presents as a genetically transmitted disease .5 The finding of dilated cardiomyopathy in monozygotic twins has not been previously reported. Both patients demonstrated elevated levels of antithyroid microsomal antibodies. Patient 1 was overtly hypothyroid, consistent with the diagnosis of Hashimotos thyroiditis. This disease is often familial and has been associated with HLA locus DRS, as in our patient. 1 Relatives of patients with Hashimoto's thyroiditis frequently are found to have antithyroid antibodies, though they may not be overtly hypothyroid. An association with other diseases of presumed autoimmune origin such as pernicious anemia has been found, e but the presence of anticardiac antibodies in patients with Hashimotos thyroiditis has not been previously reported. Although some decrease in myocardial contractility may be seen in patients with long standing myxedema," there is no known association CHEST I 88 I 8 I DECEMBER, 1984
m
between autoimmune thyroid disease and dilated cardiomyopathy. Autoimmune disease has been implicated in the pathogenesis of dilated cardiomyopathy, especially dilated cardiomyopathy following viral myocarditis.I Both humoral and cellular immune dysfunction have been reported. This includes the presence of specific circulating anticardiac antibodies, defects in suppressor T-cell function, lymphocyte-mediated cytotoxicity against cardiocytes, and the presence of inflammation on myocardial biopsy.2,8 In fact, preliminary evidence suggests that immunosuppressive therapy may be bene6cial in patients with evidence of myocardial inflammation.9.10 We speculate that the two patients described inherited a common genetic abnormality of immune regulation which rendered them susceptible to the development of both autoimmune thyroid disease and autoimmune cardiomyopathy. The trigger for the development of overt clinical thyroid disease and cardiomyopathy in the first patient may have been related to the postpartum period, a time of presumed altered immune surveillance when both cardiomyopathy" and autoimmune thyroid disease" may become clinically apparent. Our data emphasize the need for further research into immunologic mechanisms in patients with dilated cardiomyopathy and for controlled clinical trials of immunosuppressive therapy for dilated cardiomyopathy where an autoimmune process is suspected. REFERENCES
1 Strakosch DR, Wenzel BE, Row vv, Volpe R. Immunology of
880
autoimmune thyroid disease. N Eng} J Med 1982;307:1499-1507
2 MaischB, 'Uostel-Soeder R, Stechemesser E, BergPA, Kochsiek IC. Diagnostic relevance of humoral and cell-mediated immune reactions in patients with acute viral myocarditis. Clio Exp Immunol 1982; 48:533-45 3 Maisch B, Kochsiek K. Humoral and cellular immune reactions in hypertrophic and congestive cardiomyopathy (abstract). Circulation 1981; 64:26
4 Theo61opoulos AM, WIlson CB, Dixon FJ. The Raji cell assay radioimmune assay for detecting immune complexes in human sera. J Clio Invest 1976; 57:169-82 5 Ross RS, Bulldey BH, Hutchins GM, Harshey JS, Jones RA, Kraus H. Idiopathic familial myocardiopathy in three generations: a clinical and pathologic study. Am Heart] 1978; 96:170-79
6 Beall NG, Solomon OH. Hashimoto's disease and Graves disease. In: Santer M, edt Immunologic disease. Little, Brown and Co, 1978:1762 7 Santos AD, Mathew PIC, Miller BE The cardiomyopathy of hypothyroidism revisited (editorial). Am J Dis Child 1980; 134:547-49 8 O'Connell JB, Gunan RM. Dilated-congestive cardiomyopathy: prognostic features and therapy. Heart Uansplantation 1982; 2:7-17 9 Mason ~ Billingham ME, Ricci DR. Treatment of acute inflammatory myocarditis assisted by endomyocardia1 biopsy. Am J Cardioll980; 45:1037-44 10 O'Connell JB, Robinson}A, Henkin RE, Gunnar RM. Immunosuppressive therapy in patients with congestive cardiomyopathy and myocardial uptake of gallium-67. Circulation 1981; 64: 780-86 11 Demakis JG, Rahimtoola SH, Sutton GC, Meadows WR, Szanto PB, Tobin JR, et aI. Natural course of peripartum cardiomyopathy. Circulation 1971; 44:1053-61 12 Amino N, Morl H, Iwantani Y, 'Dwituna 0, Kawashima M, Tsuge I, et aI. High prevalence of transient post-partum thyrotoxicosis and hypothyroidism. N Eng} J Med 1982; 306:849-52
DIlated C8rcIom)qMIIhy In identical 1Wtns (0zJcIc et 8/)