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Metastatic calcification of the myocardium
Metastatic Calcification of the Myocardium
JOSHUA A . FIERER, MD BERNARD M . WAGNER, MD RALPH F . STREBEL, PhD New York, New York
From the Department of Pathology, College of Physicians and Surgeons, Columbia University, Francis Delafield Hospital Division, New York, N .Y . This study was supported in part by Grant HD-02261 •0 2 from the National Institutes of Health, Bethesda, Md . Manuscript received June 1, 1969, accepted July 31, 1969 . Address for reprints : Bernard M . Wagner, MD, Department of Pathology, College of Physicians and Surgeons, Columbia University, Francis Delafield Hospital Division, New York, N .Y . 10032 .
VOLUME 26 . OCTOBER 1970
Extensive myocardial calcification occurred in an adult woman with hypercalcemia treated with large doses of prednisone and sodium phosphate. The findings are presented and compared with similar findings in experimental calciphylaxis . Further investigation is needed to determine the relation of steroid and phosphate therapy to the production of myocardial calcification in man .
The occurrence of metastatic calcification with various types of osseous lesions' -' and with chronic renal disease' is well known . More recently, the association of overdoses of vitamin D with metastatic calcification has been established .'^ Experimentally, calcification has been produced by a variety of methods, including the administration of large doses of vitamin D,7' or dihydrotachysterol and the injection of parathyroid hormone .' Selye" has utilized sodium acetylsulfathiazole as a calcifying agent in experimental calciphylaxis . However, this compound acts as a calcifies only in the presence of the parathyroids, presumably because it causes renal lesions with resultant secondary hyperparathyroidism . Minerals have been used to produce metastatic calcification in animals) 5-2 ° Except for the work of Tanaka ; ° who produced calcification in rabbits by intraperitoneal injection of calcium lactate and in dogs by intravenous administration of calcium lactate and sodium phosphate, experiments with minerals have been based on a dietary approach . An acid diet, or less frequently an alternating acid and alkaline diet, has proved more effective in causing calcification of tissues than an alkaline or neutral diet . Adequate amounts of calcium and phosphorus, especially the latter,'" have been a necessary dietary adjunct to produce the calcific changes . Despite the widespread organ involvement found in cases of metastatic calcification, the heart is much less frequently a site of calcium deposition than either the lungs or the kidneys . Mulligan," who reviewed cases of metastatic calcification reported from 1855 to 1947, found a total of 88 cases in which the specific sites of calcification were documented . Of the 88, 57 patients had calcium deposits in the lungs, 59 showed renal calcification, and only 36 had involvement of the heart. Although the reports of calcification of the heart rarely specify the exact sites of calcium deposition and are frequently unaccompanied by photomicrographs, it appears that the calcium is deposited principally in elastic tissues and blood vessel walls rather than within the myofibrils . The following case is presented as an example of metastatic calcification with extensive calcium deposits in the myocardium . The observations in this case are similar to those seen in experimental cardiopathy induced by combinations of steroids and phosphates .
423
EIERER ET AL .
Case Report
Comment
A 43 year old Negro woman was transferred to Francis Delafield Hospital on January 30, 1967 for treatment of carcinoma of the left breast . A biopsy of a left breast mass, performed at another hospital a week earlier, revealed an invasive carcinoma . The tumor was deemed inoperable because the patient had extensive osteolytic metastases to the ribs, femurs, tibias and vertebrae . Physical examination revealed a cachectic woman experiencing severe back pain . The lower outer quadrant of the left breast contained a 10 by 5 cm firm mass with marked skin retraction . Three hard, fixed lymph nodes, each greater than 2 cm, were palpated in the left axilla . The level of serum calcium was 13 .6 mg/100 ml and that of serum phosphorus 3.5 mg/100 ml . Hydration resulted in only a slight lowering of serum calcium levels . In view of the patient's premenopausal state, hormonal therapy was instituted . A bilateral salpingo-oophorectomy was performed on February 21, 1967, and therapy with fluoxymesterone was started . She alternately received large doses of prednisone and medroxyprogesterone acetate . Her hospital course was marked by a persistent hypercalcemia, with only very brief periods of remission . Serum calcium levels ranged from 10 .0 to 17 .7 mg/ 100 ml and were generally above 12 .5 mg/100 ml. On September 20, 1967, when the serum calcium level reached a peak of 17 .7 mg/100 ml, treatment with large oral doses of dibasic sodium phosphate (Na,HPO,) was instituted . Although she received a total of 49 g of phosphate solution, equivalent to 17 .5 g of phosphate, radical calcium levels remained above 15 .6 mg/100 ml, and the patient died on October 25, 1967 . Her urinary output had been adequate at all times .
Metastatic calcification in otherwise apparently undamaged myocardium occurs with far less frequency than would be expected from the incidence of hypercalcemia. A review of autopsy findings in patients with hypercalcemia at Francis Delafield Hospital from 1947 to 1967 showed calcium deposits within the myofibrils in only 1 case . This was surprising since serum calcium levels in some of these patients exceeded the peak levels in the present case, the highest serum calcium value for the series being 20 .1 mg/100 ml. Thus, it appears that myocardial calcification is dependent on factors other than serum calcium levels. Shelling 23 found that animals fed a diet high in phosphorus and containing minimal amounts of calcium were extremely susceptible to calcification produced by the administration of viosterol . He also noted increased phosphorous retention in parathyroidectomized dogs that had metastatic calcification in the presence of hypocalcemia . Arterial calcinosis developed in parathyroidectomized female breeder rats with hyperphosphatemia and hypocalcemia. This finding demonstrates that hyperparathyroidism (hypercalcemia) is not essential for cardiovascular calcification .' In a series of experiments with viosterol poisoning Smith and Elvove' established a clear relation of calcification to phosphate levels in serum . A high serum phosphate level with only a slight increase in calcium resulted in extensive calcifications. These investigators failed to produce calcification in the presence of a low serum phosphate level . Similarly, disease states in which metastatic calcification is most prevalent reveal a common factor of hyperphosphatemia . Phosphate retention is a prominent feature in terminal nephritis . In some
Autopsy Findings Necropsy revealed an adult woman with a markedly cacheefic appearance . The left breast contained a 6 cm, rock-hard subareolar mass covered by an area of skin excoriation. A 1 .5 cm nodule of similar consistence was present in the upper outer quadrant of the right breast . Histologic examination of these masses showed a poorly differentiated adenocarcinoma with foci of calcification and ossification of the stroma. Metastases were found in axillary nodes, lungs, liver, spleen, adrenals and lymph nodes of the hilum and ports hepatic . Tumor was present in multiple ribs, vertebrae, clavicles and iliac bones . The heart weighed 240 g. All cardiac chambers were of normal dimensions, as were the valves . The myocardium was soft, pale brown, with prominent yellow-white striations giving the appearance of "tigering" (Fig . 1) . Representative sections were fixed in 10 percent formalin, embedded in paraffin and stained for calcium by the Von Kossa method.22 Other sections were stained with hematoxylin and eosin . Calcium deposits were seen in myofibrils (Fig . 2) as well as in the elastic tissue of the stroma and blood vessels (Fig . 3) . Similar calcium deposits were found in the lung (Fig . 4), kidneys (Fig. 5), arteries and arterioles . Sections stained with hematoxylin and eosin showed no evidence of primary myocardial disease (Fig . 6), and only a small zone of lymphocytes and macrophages were seen surrounding foci of calcium deposits . The 2 parathyroid glands identified at autopsy showed a slight hyperplasia, predominantly of chief cells .
424
cases of overdosage with Parathormone® or vitamin D preparations, serum phosphorus is increased in the terminal stages . Since metastatic calcification is frequently recognized only at autopsy, it seems possible that in these conditions the deposits occur late and only after the development of phosphate retention . In the present case the administration of phosphate solutions appeared to be a significant cause of the production of the metastatic calcium deposits . A somewhat parallel situation exists between this case and those of experimental cardiopathy reported by Selye . Concurrent treatment with 2a-methyl-9achlorocortisol greatly aggravated the cardiac lesions normally produced by dihydrotachysterol + NaH,P0 4 in the rat,28 as well as in the mouse, rabbit, dog and hamster ." An analogy between the experimental model and the present case would implicate the osteolytic metastases as the sensitizes (calcifies) and prednisone as the challenger . Steroid-phosphate-induced cardiac necrosis : Focal cardiac necrosis has been observed repeatedly in rats after the administration of steroids and so-
The American Journal of CARDIOLOGY
METASTATIC CALCIFICATION OF MYOCAFOIOM
Figure 1 . Gross appearance of myocardium showingwhite striations, representing calcium deposits.
Figure 2 . Section of myocardium showing calcium deposits (black) in myofibrils. (Von Kossa x 780, reduced by 41 percent .)
Figure 3. Section of myocardium showing calcium deposits (Sack) predominantly in elastics of stroma and blood vessels . (Von Kossa x 150, reduced by 49 percent .)
Figure 4 . Section of lung showing calcium deposits (black) predominantly in elastic tissue of alveolarseptae . (Von Kossa x 150, reduced by 49 percent .)
Figure 5 . Section of kidney showing calcium deposits (black) in walls of tubules, blood vessels and Bowman's capsule . (Von Kossa x 150, reduced by 49 percent.)
Figure 6 . Section of myocardium showing intact muscle fibers and minimal cellular response surrounding foci of calcium deposits (dark areas) . (Hematoxylin and eosin x 150, reduced by 49 percent .)
VOLUME 26, OCTOBER 1970
425
FIERER ET AL .
dium phosphate .2B - 27 Selye25 stated that the patho-
cent core and were presumed to represent deposits
genesis of the cardiac lesions was linked to the interaction of steroids and electrolytes, the former
of calcium .
conditioning the myocardium for the pathogenic effects of electrolyte imbalance . He also observed that administration of potassium prevented the development of necrosis . In similar studies, Nickerson et al ." found that the incidence and severity of cardiac necrosis correlated well with the degree of myocardial potassium depletion, and they concluded that
In the present case the myocardium was free of necrosis with the exception of minute foci of necrosis in sites of calcium deposition . Electron microscopic studies were not performed because of a greater than
30 hour interval between death and necropsy . These tiny foci of necrosis are still consistent with the light microscopic observations of D'Agostino ; ° who found that the smallest lesions often involved as few as
potassium deficiency and its sequelae were responsible for the myocardial lesions . In an extensive study
5 to 10 muscle fibers . Thus, it appears possible that
of steroid-phosphate-induced cardiac necrosis Lehr and Krukowski26 noted that parathyroidectomy has-
been initiated or enhanced by the concomitant ad-
tened the appearance of cardiac necrosis . D'Agostino2° studied the ultrastructural changes present in the rat myocardium after the combined administra-
the myocardial calcification in this patient may have ministration of steroids and sodium phosphate in the presence of marked hypercalcemia . This case demonstrates the need for a more critical appraisal of the therapeutic methods in hypercalcemia .
tion of 9a-fiuorocortisol and sodium phosphate and observed electron-dense particulate inclusions in mitochondria of degenerating muscle fibers . These inclusions contained either an electron-dense or lu-
Acknowledgments Photographs were taken by Mr. Edward Hajjar, Division of Medical Photography, Francis Delafield hospital .
References 1 . deSanto DA : Metastatic calcification occurring in myelogenous leukemia . Amer J Path 9 :105-112, 1933 2. Wells HB : Metastatic calcification . Arch Intern Med (Chicago) 15 :574-580, 1915 3. Wells HG, Holley SW : Metastatic calcification in osteitis deformans (Paget's disease of bone) . Arch Path (Chicago) 34:435-442, 1942 4 . Herbert FK, Miller HG, Richardson GO : Chronic renal disease, secondary parathyroid hyperplasia, decalcification of bone and metastic calcification . J Path Bact 53 :161-182, 1941 5. Bauer JM, Freyberg RH : Vitamin D intoxication with metastatic calcification . JAMA 130:1208-1215, 1946 6 . Mulligan RM : Metastatic calcification associated with hypervitaminosis D and haliphagia . Amer J Path 22 :1293-1303, 1946 7. Gough i. Duguid JD, Davies DR: Renal lesions in hypervitaminosis D : observations on urinary calcium and phosphorus excretion . Brit J Exp Path 14:137-145, 1933 8. Shohl AT, Goldblatt H, Brown HB : The pathological effects upon rats of excess irradiated ergosterol . J Clin Invest 8 :505-531, 1930 9. Smith MI, Elvove E : The action of irradiated ergosterol in the rabbit . Public Health Rep 44:1245-1256, 1929 10 . Selye H : Experimental production of cutaneous calcinosis and sclerosis with dihydrotachysterol (AT-10) . J Invest Derm 29 :9-14, 1957 11 . Selye H : Effect of various hormones upon the syndrome of dihydrotachysterol (At-10) intoxication . Acta Endocr (Kobenhaven) 25:83-90, 1957 12 . Hueber WC : Metastatic calcification produced by injections of parathyroid extract . Arch Path (Chicago) 3 :14-25, 1927 13 . JaffeHI,BodanskyA .BIairJE : Fibrous osteodystrophy (osteitis fibrosa) in experimental hyperparathyroidism of guinea pigs . Arch Path (Chicago) 11 :207-228, 1931 14 . SelyeH : Calciphylaxis . Vol . I . Chicago, The University of Chicago Press, p 8 15 . Butler M : Experimental calcification in mice . Proc NY Path Soc
426
24:79-86, 1924 16 . Dreyfuss W : Uber den Kalkstoffwechsel im Tierversuch . Beitr Path Mat 76 :254-269, 1926 17 . Kbikimau H : Untersuchungen uber die Bedingungen der Kah kablagergung in tierschen Geweben . Virchow Arch Path Anat 268:686-750, 1928 18 . Rabl CRH : Zum Problem der Verkalkung . Virchow Arch Path Anat 245 :542-563, 1923 19 . Stephens DJ, Barr DP : Influence of acid and phosphate on metastatic calcification . Proc Soc Exp Biol Med 30 :920-924, 1933 20 . Tanaka M : Ueber Kalkresorption and Verkalkung . Biochem Z 35 :113-133, 1911 21 . Mulligan RM : Metastatic calcification . Arch Path (Chicago) 43 :177-230, 1947 22 . Pearse AGE : Histochemistry, Theoretical & Applied . Second edition, Vol . I, Boston, Little, Brown and Co ., 1961, pp 931-946 23 . Shelling DH : Relation of calcium and phosphorus of diet to toxicity of viosterol . Proc Soc Exp Biol Med 28 :298-301, 1930 24 . Strebel RF, Wagner BM : Experimental tissue calcification . V . Effect of parathyroidectomy on spontaneously occurring caicific arteriosclerosis in female breeder rats . Arch Path (Chicago), in press 25 . Selye H : The Chemical Prevention of Cardiac Necrosis . Vol . I, chap 3 . New York, Ronald Press . 1958 26 . Lehr D, Krukowski M : About the mechanism of myocardial necrosis induced by sodium phosphate and adrenal corticoid overdosage. Ann NY Acad Sci 105 :137-182, 1963 27 . Nkkerson M, ken GW, Dresel PE : Pathogenesis of "electrolyte-steroid •cardiopathy ." Circ Res 9:209-217, 1961 28 . Selye H : Humoral "conditioning" for the production of a suppurative, acute myocarditis by the oral administration of sodium phosphate. Amer Heart J 55:1-7, 1958 29 . D'Agostino AN : An electron microscopic study of cardiac necrosis produced by 9a-fluorocortisol and sodium phosphate . Amer J Path 45 :633-637, 1964
The American Journal of CARDIOLOGY
JOSHUA A . FIERER, MD BERNARD M . WAGNER, MD RALPH F . STREBEL, PhD New York, New York
From the Department of Pathology, College of Physicians and Surgeons, Columbia University, Francis Delafield Hospital Division, New York, N .Y . This study was supported in part by Grant HD-02261 •0 2 from the National Institutes of Health, Bethesda, Md . Manuscript received June 1, 1969, accepted July 31, 1969 . Address for reprints : Bernard M . Wagner, MD, Department of Pathology, College of Physicians and Surgeons, Columbia University, Francis Delafield Hospital Division, New York, N .Y . 10032 .
VOLUME 26 . OCTOBER 1970
Extensive myocardial calcification occurred in an adult woman with hypercalcemia treated with large doses of prednisone and sodium phosphate. The findings are presented and compared with similar findings in experimental calciphylaxis . Further investigation is needed to determine the relation of steroid and phosphate therapy to the production of myocardial calcification in man .
The occurrence of metastatic calcification with various types of osseous lesions' -' and with chronic renal disease' is well known . More recently, the association of overdoses of vitamin D with metastatic calcification has been established .'^ Experimentally, calcification has been produced by a variety of methods, including the administration of large doses of vitamin D,7' or dihydrotachysterol and the injection of parathyroid hormone .' Selye" has utilized sodium acetylsulfathiazole as a calcifying agent in experimental calciphylaxis . However, this compound acts as a calcifies only in the presence of the parathyroids, presumably because it causes renal lesions with resultant secondary hyperparathyroidism . Minerals have been used to produce metastatic calcification in animals) 5-2 ° Except for the work of Tanaka ; ° who produced calcification in rabbits by intraperitoneal injection of calcium lactate and in dogs by intravenous administration of calcium lactate and sodium phosphate, experiments with minerals have been based on a dietary approach . An acid diet, or less frequently an alternating acid and alkaline diet, has proved more effective in causing calcification of tissues than an alkaline or neutral diet . Adequate amounts of calcium and phosphorus, especially the latter,'" have been a necessary dietary adjunct to produce the calcific changes . Despite the widespread organ involvement found in cases of metastatic calcification, the heart is much less frequently a site of calcium deposition than either the lungs or the kidneys . Mulligan," who reviewed cases of metastatic calcification reported from 1855 to 1947, found a total of 88 cases in which the specific sites of calcification were documented . Of the 88, 57 patients had calcium deposits in the lungs, 59 showed renal calcification, and only 36 had involvement of the heart. Although the reports of calcification of the heart rarely specify the exact sites of calcium deposition and are frequently unaccompanied by photomicrographs, it appears that the calcium is deposited principally in elastic tissues and blood vessel walls rather than within the myofibrils . The following case is presented as an example of metastatic calcification with extensive calcium deposits in the myocardium . The observations in this case are similar to those seen in experimental cardiopathy induced by combinations of steroids and phosphates .
423
EIERER ET AL .
Case Report
Comment
A 43 year old Negro woman was transferred to Francis Delafield Hospital on January 30, 1967 for treatment of carcinoma of the left breast . A biopsy of a left breast mass, performed at another hospital a week earlier, revealed an invasive carcinoma . The tumor was deemed inoperable because the patient had extensive osteolytic metastases to the ribs, femurs, tibias and vertebrae . Physical examination revealed a cachectic woman experiencing severe back pain . The lower outer quadrant of the left breast contained a 10 by 5 cm firm mass with marked skin retraction . Three hard, fixed lymph nodes, each greater than 2 cm, were palpated in the left axilla . The level of serum calcium was 13 .6 mg/100 ml and that of serum phosphorus 3.5 mg/100 ml . Hydration resulted in only a slight lowering of serum calcium levels . In view of the patient's premenopausal state, hormonal therapy was instituted . A bilateral salpingo-oophorectomy was performed on February 21, 1967, and therapy with fluoxymesterone was started . She alternately received large doses of prednisone and medroxyprogesterone acetate . Her hospital course was marked by a persistent hypercalcemia, with only very brief periods of remission . Serum calcium levels ranged from 10 .0 to 17 .7 mg/ 100 ml and were generally above 12 .5 mg/100 ml. On September 20, 1967, when the serum calcium level reached a peak of 17 .7 mg/100 ml, treatment with large oral doses of dibasic sodium phosphate (Na,HPO,) was instituted . Although she received a total of 49 g of phosphate solution, equivalent to 17 .5 g of phosphate, radical calcium levels remained above 15 .6 mg/100 ml, and the patient died on October 25, 1967 . Her urinary output had been adequate at all times .
Metastatic calcification in otherwise apparently undamaged myocardium occurs with far less frequency than would be expected from the incidence of hypercalcemia. A review of autopsy findings in patients with hypercalcemia at Francis Delafield Hospital from 1947 to 1967 showed calcium deposits within the myofibrils in only 1 case . This was surprising since serum calcium levels in some of these patients exceeded the peak levels in the present case, the highest serum calcium value for the series being 20 .1 mg/100 ml. Thus, it appears that myocardial calcification is dependent on factors other than serum calcium levels. Shelling 23 found that animals fed a diet high in phosphorus and containing minimal amounts of calcium were extremely susceptible to calcification produced by the administration of viosterol . He also noted increased phosphorous retention in parathyroidectomized dogs that had metastatic calcification in the presence of hypocalcemia . Arterial calcinosis developed in parathyroidectomized female breeder rats with hyperphosphatemia and hypocalcemia. This finding demonstrates that hyperparathyroidism (hypercalcemia) is not essential for cardiovascular calcification .' In a series of experiments with viosterol poisoning Smith and Elvove' established a clear relation of calcification to phosphate levels in serum . A high serum phosphate level with only a slight increase in calcium resulted in extensive calcifications. These investigators failed to produce calcification in the presence of a low serum phosphate level . Similarly, disease states in which metastatic calcification is most prevalent reveal a common factor of hyperphosphatemia . Phosphate retention is a prominent feature in terminal nephritis . In some
Autopsy Findings Necropsy revealed an adult woman with a markedly cacheefic appearance . The left breast contained a 6 cm, rock-hard subareolar mass covered by an area of skin excoriation. A 1 .5 cm nodule of similar consistence was present in the upper outer quadrant of the right breast . Histologic examination of these masses showed a poorly differentiated adenocarcinoma with foci of calcification and ossification of the stroma. Metastases were found in axillary nodes, lungs, liver, spleen, adrenals and lymph nodes of the hilum and ports hepatic . Tumor was present in multiple ribs, vertebrae, clavicles and iliac bones . The heart weighed 240 g. All cardiac chambers were of normal dimensions, as were the valves . The myocardium was soft, pale brown, with prominent yellow-white striations giving the appearance of "tigering" (Fig . 1) . Representative sections were fixed in 10 percent formalin, embedded in paraffin and stained for calcium by the Von Kossa method.22 Other sections were stained with hematoxylin and eosin . Calcium deposits were seen in myofibrils (Fig . 2) as well as in the elastic tissue of the stroma and blood vessels (Fig . 3) . Similar calcium deposits were found in the lung (Fig . 4), kidneys (Fig. 5), arteries and arterioles . Sections stained with hematoxylin and eosin showed no evidence of primary myocardial disease (Fig . 6), and only a small zone of lymphocytes and macrophages were seen surrounding foci of calcium deposits . The 2 parathyroid glands identified at autopsy showed a slight hyperplasia, predominantly of chief cells .
424
cases of overdosage with Parathormone® or vitamin D preparations, serum phosphorus is increased in the terminal stages . Since metastatic calcification is frequently recognized only at autopsy, it seems possible that in these conditions the deposits occur late and only after the development of phosphate retention . In the present case the administration of phosphate solutions appeared to be a significant cause of the production of the metastatic calcium deposits . A somewhat parallel situation exists between this case and those of experimental cardiopathy reported by Selye . Concurrent treatment with 2a-methyl-9achlorocortisol greatly aggravated the cardiac lesions normally produced by dihydrotachysterol + NaH,P0 4 in the rat,28 as well as in the mouse, rabbit, dog and hamster ." An analogy between the experimental model and the present case would implicate the osteolytic metastases as the sensitizes (calcifies) and prednisone as the challenger . Steroid-phosphate-induced cardiac necrosis : Focal cardiac necrosis has been observed repeatedly in rats after the administration of steroids and so-
The American Journal of CARDIOLOGY
METASTATIC CALCIFICATION OF MYOCAFOIOM
Figure 1 . Gross appearance of myocardium showingwhite striations, representing calcium deposits.
Figure 2 . Section of myocardium showing calcium deposits (black) in myofibrils. (Von Kossa x 780, reduced by 41 percent .)
Figure 3. Section of myocardium showing calcium deposits (Sack) predominantly in elastics of stroma and blood vessels . (Von Kossa x 150, reduced by 49 percent .)
Figure 4 . Section of lung showing calcium deposits (black) predominantly in elastic tissue of alveolarseptae . (Von Kossa x 150, reduced by 49 percent .)
Figure 5 . Section of kidney showing calcium deposits (black) in walls of tubules, blood vessels and Bowman's capsule . (Von Kossa x 150, reduced by 49 percent.)
Figure 6 . Section of myocardium showing intact muscle fibers and minimal cellular response surrounding foci of calcium deposits (dark areas) . (Hematoxylin and eosin x 150, reduced by 49 percent .)
VOLUME 26, OCTOBER 1970
425
FIERER ET AL .
dium phosphate .2B - 27 Selye25 stated that the patho-
cent core and were presumed to represent deposits
genesis of the cardiac lesions was linked to the interaction of steroids and electrolytes, the former
of calcium .
conditioning the myocardium for the pathogenic effects of electrolyte imbalance . He also observed that administration of potassium prevented the development of necrosis . In similar studies, Nickerson et al ." found that the incidence and severity of cardiac necrosis correlated well with the degree of myocardial potassium depletion, and they concluded that
In the present case the myocardium was free of necrosis with the exception of minute foci of necrosis in sites of calcium deposition . Electron microscopic studies were not performed because of a greater than
30 hour interval between death and necropsy . These tiny foci of necrosis are still consistent with the light microscopic observations of D'Agostino ; ° who found that the smallest lesions often involved as few as
potassium deficiency and its sequelae were responsible for the myocardial lesions . In an extensive study
5 to 10 muscle fibers . Thus, it appears possible that
of steroid-phosphate-induced cardiac necrosis Lehr and Krukowski26 noted that parathyroidectomy has-
been initiated or enhanced by the concomitant ad-
tened the appearance of cardiac necrosis . D'Agostino2° studied the ultrastructural changes present in the rat myocardium after the combined administra-
the myocardial calcification in this patient may have ministration of steroids and sodium phosphate in the presence of marked hypercalcemia . This case demonstrates the need for a more critical appraisal of the therapeutic methods in hypercalcemia .
tion of 9a-fiuorocortisol and sodium phosphate and observed electron-dense particulate inclusions in mitochondria of degenerating muscle fibers . These inclusions contained either an electron-dense or lu-
Acknowledgments Photographs were taken by Mr. Edward Hajjar, Division of Medical Photography, Francis Delafield hospital .
References 1 . deSanto DA : Metastatic calcification occurring in myelogenous leukemia . Amer J Path 9 :105-112, 1933 2. Wells HB : Metastatic calcification . Arch Intern Med (Chicago) 15 :574-580, 1915 3. Wells HG, Holley SW : Metastatic calcification in osteitis deformans (Paget's disease of bone) . Arch Path (Chicago) 34:435-442, 1942 4 . Herbert FK, Miller HG, Richardson GO : Chronic renal disease, secondary parathyroid hyperplasia, decalcification of bone and metastic calcification . J Path Bact 53 :161-182, 1941 5. Bauer JM, Freyberg RH : Vitamin D intoxication with metastatic calcification . JAMA 130:1208-1215, 1946 6 . Mulligan RM : Metastatic calcification associated with hypervitaminosis D and haliphagia . Amer J Path 22 :1293-1303, 1946 7. Gough i. Duguid JD, Davies DR: Renal lesions in hypervitaminosis D : observations on urinary calcium and phosphorus excretion . Brit J Exp Path 14:137-145, 1933 8. Shohl AT, Goldblatt H, Brown HB : The pathological effects upon rats of excess irradiated ergosterol . J Clin Invest 8 :505-531, 1930 9. Smith MI, Elvove E : The action of irradiated ergosterol in the rabbit . Public Health Rep 44:1245-1256, 1929 10 . Selye H : Experimental production of cutaneous calcinosis and sclerosis with dihydrotachysterol (AT-10) . J Invest Derm 29 :9-14, 1957 11 . Selye H : Effect of various hormones upon the syndrome of dihydrotachysterol (At-10) intoxication . Acta Endocr (Kobenhaven) 25:83-90, 1957 12 . Hueber WC : Metastatic calcification produced by injections of parathyroid extract . Arch Path (Chicago) 3 :14-25, 1927 13 . JaffeHI,BodanskyA .BIairJE : Fibrous osteodystrophy (osteitis fibrosa) in experimental hyperparathyroidism of guinea pigs . Arch Path (Chicago) 11 :207-228, 1931 14 . SelyeH : Calciphylaxis . Vol . I . Chicago, The University of Chicago Press, p 8 15 . Butler M : Experimental calcification in mice . Proc NY Path Soc
426
24:79-86, 1924 16 . Dreyfuss W : Uber den Kalkstoffwechsel im Tierversuch . Beitr Path Mat 76 :254-269, 1926 17 . Kbikimau H : Untersuchungen uber die Bedingungen der Kah kablagergung in tierschen Geweben . Virchow Arch Path Anat 268:686-750, 1928 18 . Rabl CRH : Zum Problem der Verkalkung . Virchow Arch Path Anat 245 :542-563, 1923 19 . Stephens DJ, Barr DP : Influence of acid and phosphate on metastatic calcification . Proc Soc Exp Biol Med 30 :920-924, 1933 20 . Tanaka M : Ueber Kalkresorption and Verkalkung . Biochem Z 35 :113-133, 1911 21 . Mulligan RM : Metastatic calcification . Arch Path (Chicago) 43 :177-230, 1947 22 . Pearse AGE : Histochemistry, Theoretical & Applied . Second edition, Vol . I, Boston, Little, Brown and Co ., 1961, pp 931-946 23 . Shelling DH : Relation of calcium and phosphorus of diet to toxicity of viosterol . Proc Soc Exp Biol Med 28 :298-301, 1930 24 . Strebel RF, Wagner BM : Experimental tissue calcification . V . Effect of parathyroidectomy on spontaneously occurring caicific arteriosclerosis in female breeder rats . Arch Path (Chicago), in press 25 . Selye H : The Chemical Prevention of Cardiac Necrosis . Vol . I, chap 3 . New York, Ronald Press . 1958 26 . Lehr D, Krukowski M : About the mechanism of myocardial necrosis induced by sodium phosphate and adrenal corticoid overdosage. Ann NY Acad Sci 105 :137-182, 1963 27 . Nkkerson M, ken GW, Dresel PE : Pathogenesis of "electrolyte-steroid •cardiopathy ." Circ Res 9:209-217, 1961 28 . Selye H : Humoral "conditioning" for the production of a suppurative, acute myocarditis by the oral administration of sodium phosphate. Amer Heart J 55:1-7, 1958 29 . D'Agostino AN : An electron microscopic study of cardiac necrosis produced by 9a-fluorocortisol and sodium phosphate . Amer J Path 45 :633-637, 1964
The American Journal of CARDIOLOGY