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Takotsubo cardiomyopathy caused by hypoglycemia
International Journal of Cardiology 147 (2011) e21 – e23 www.elsevier.com/locate/ijcard
Letter to the Editor
Takotsubo cardiomyopathy caused by hypoglycemia A unique association with coronary arterial calcification Muhammad J. Ansari ⁎, Abhiram Prasad, Patricia A. Pellikka, Kyle W. Klarich The Division of Cardiology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, United States Received 8 January 2009; accepted 10 January 2009
Abstract Several factors attributable to the onset of Takotsubo type of cardiomyopathy are known. We report a case of a postmenopausal female, who represented with syncope and was found to be hypoglycemic and had elevated cardiac biomakers. Later found to have Takotsubo type of cardiomyopathy after a negative coronary angiogram. The left ventricular function improved over a week. She had unusual combination of hypoglycemia and cortisol excess; this is not reported in the literature. The urine catecholamines were normal. We also report a unique occurrence of coronary artery calcification as one of the associations with Takotsubo syndrome. This feature may help in risk assessment and reccurence of this syndrome. Further studies are needed to confirm this association and its prognostic significance. © 2009 Elsevier Ireland Ltd. All rights reserved. Keywords: Takotsubo cardiomyopathy; Hypoglycemia; Coronary artery calcification
1. Case description We report a case of 69 year old African American female who presented to emergency room with “loss of consciousness”. She was found unresponsive lying on the floor, by her sister who called for ambulance. The blood glucose found by the paramedics was 32 mg/dl. There was no history of lack of appetite or poor intake. She had no diabetes and there was no history of accidental ingestion of oral hypoglycemics. On examination she had Glasgow coma scale of 5/15, tachycardia with S3 gallop rhythm and crackles on lung bases. Cardiac biomarkers were elevated i.e. troponin of 0.65 ng/ml (peak) with ECG showing sinus tachycardia. First 2D echocardiograph showed severe LV dysfunction with an ejection fraction (EF) of 16%. (Fig. 1a,b). The coronary angiogram showed non-obstructing coronary
⁎ Corresponding author. Tel.: +1 507 284 1226; fax: +1 507 284 3968. E-mail address: [email protected] (M.J. Ansari). 0167-5273/$ - see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.01.016
arteries with coronary calcification. The left ventriculogram showed ballooning of the apex consistent with Takotsubo cardiomyopathy. (Fig. 2). The plasma venous glucose remained low in the range of 60–80 mg/dl initially despite IV dextrose infusion. The work up for hypoglycemia was negative as she had normal C-peptide levels 3.9, pro-insulin 6.9 pmol/L (N 2.1–26.8), and sulfonylurea screen was negative. The cortisol (am) was elevated to 107.0 mcg/dl (normal 7.0–25) and cortisol (pm) of 103.7 mcg/dl (normal 0.0–5.9). 24-hour urine free cortisol to be elevated 139.7 µg/ day (normal b 45), dopamine of 119 mcg/24 h (normal 80– 440), and normal urine norepinephrine/epinephrine levels. ACTH was 26 pg/ml (normal b46) and thyroid functions were normal. The heart rate and blood pressure were controlled on a combination of β-blockade (metoprolol) and centrally acting α-agonist (clonidine). On day 5 she improved with supportive treatment and the repeat echocardiography showed markedly improved LV function with EF 45%.(Fig. 1c) Concurrently the cortisol (am) has dropped to 57.5 mcg/dl and cortisol (pm) to 5.5 mcg/dl normalized.
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M.J. Ansari et al. / International Journal of Cardiology 147 (2009) e21–e23
Fig. 1. (a) Apical 4 chamber view showing ballooning of LV apex. (b) Parasternal long axis view. (c) Parasternal long axis view 5 days later.
LV function remained preserved along with normal blood pressure. 2. Discussion Our case depicts two unique features; the presence of hypoglycemia and the coronary arterial calcification with Takotsubo cardiomyopathy. Coronary calcification may be used as a prognostic marker or a predictor of recurrence in patients at risk. Further studies and registry for the Takotsubo may help to answer this association. This syndrome occurs typically in postmenopausal women. It is commonly referred to as Takotsubo cardiomyopathy, as first reported by Satoh et al. [8]. The name “Takotsubo” refers to a trap used to catch octopus in Japan. The ventricular ballooning at the apex with a narrow base mimics the shape of above mentioned trap. It is mentioned in the literature as “apical ballooning syndrome” or “stressinduced cardiomyopathy” both in pigs [9] with stress induced by restraint and in humans [10]. It was initially reported as “left ventricular apical ballooning, but recent studies have shown that there is right ventricular involvement as well, thus now referred to as “apical ballooning syndrome”
(ABS). An entity called “inverted takotsubo" is seen with pheochromocytoma and acute pancreatitis [5]. The base of heart is hypokinetic with apex hyperkinetic in this variant [14]. There are few case reports suggesting hypoglycemia as a trigger to develop Takotsubo type of cardiomyopathy [1,4]. Most of the literature on the association of Takotsubo syndrome to hypoglycemia is related to anorexia nervosa [4]. There is one case report suggesting adrenal insufficiency in ACTH deficiency as a cause of this type of cardiomyopathy [2]. In the largest series from Japan, 1 out of 88 cases onset of the syndrome was associated with a hypoglycemic episode [3]. The atypical presentations with syndrome have been reported in African American women [13].Our patient was unique as she had hypoglycemia, but no emotional stressor to account for the development of this syndrome. The work up for the hypoglycemia was negative. She had cortisol surplus possibly related to sympathomimetic excess. The ACTH was normal and CT scan of abdomen failed to demonstrate adrenal adenoma or hyperplasia. Various mechanisms of pathophysiology are proposed such as catecholamine excess causing neurogenic stunning, that may result in transient apical systolic asynergy, the other
Fig. 2. Left ventriculogram showing ballooning of the apex in diastole and transapical ballooning in systole.
M.J. Ansari et al. / International Journal of Cardiology 147 (2009) e21–e23
possibilities include coronary microvascular dysfunction, epicardial vessel spasm, abnormal coronary flow without obstruction and abnormal glucose metabolism at the cardiac apex due to increased number of adrenergic receptors at the apex [6,7]. The mechanism of “perfusion–metabolism mismatch” is also one of the accepted theories, with selective reduction of glucose uptake predominantly from the apex of the heart. This phenomenon has been demonstrated with the help of positron emission tomography with 13N-ammonia and 18F-fluorodeoxyglucose within 72 hours of presentation [15]. The protective role of Estrogen hormone has also been confirmed with animal (rat) experiments by supplemental estrogen on the rats with oophorectomy on the development of this type of cardiomyopathy. It was suggested that estrogen supplementation partially prevents emotional stress-induced cardiovascular responses both by indirect action on the nervous system and by direct action on the heart [16]. ABS is attributable to psychological, emotional insults and following stress due to a loss of beloved or loss of job etc. The stress related to certain metabolic disorders such as adrenal insufficiency, thyroid dysfunction, pheochromocytoma and hypoglycemia can be the initial trigger to the excessive sympathetic activity related to this disorder. The other well known triggers are postoperative states, cerebrovascular accidents, and sepsis related to infection or severe pancreatitis. Checking the cortisol levels may be helpful in the diagnostic workup as there is a correlation of cardiac improvement with the normalization of cortisol levels. Therefore we suggest the pathophysiology of this cardiomyopathy as more complex than just catecholamine excess. The mechanism of cortisol excess due to emotional or organic disease related stress may also be significant player in the pathogenesis along with dysregulation of glucose metabolism. There may be genetic predisposition which triggers cardiomyopathy with the excess of catecholamines in susceptible individuals. Understanding the pathophysiology is important as it may help to decide on treatment options. These patients may benefit from using beta-blockers with centrally acting α-agonists. There is up to 8% reported mortality rate [3,12] and 95% excellent recovery [11], but can recur on reproduction of the stress. The recurrence rate has been reported in up to 10– 11% of the cases. The association or coronary calcification may be an important predictor for recurrence or severity; we propose further studies on the same. Acknowledgement The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [17].
e23
References [1] Saito Y. Hypoglycemic attack: a rare triggering factor for takotsubo cardiomyopathy. Intern Med Mar 2005;44(3):171–2. [2] Sakihara S, Kageyama K, Nigawara T, Kidani Y, Suda T. Ampulla (Takotsubo) cardiomyopathy caused by secondary adrenal insufficiency in ACTH isolated deficiency. Endocr J Aug 2007;54(4):631–6. [3] Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris– Myocardial Infarction Investigations in Japan. J Am Coll Cardiol 2001;38(1):11–8. [4] Ohwada R, Hotta M, Kimura H, et al. Ampulla cardiomyopathy after hypoglycemia in three young female patients with anorexia nervosa. Intern Med 2005;44(3):228–33. [5] Van de Walle SO, Gevaert SA, Gheeraert PJ, De Pauw M, Gillebert TC. Transient stress-induced cardiomyopathy with an “inverted takotsubo” contractile pattern. Mayo Clin Proc Nov 2006;81 (11):1499–502. [6] Spieker L, Hurlimann D, Ruschitzka F, et al. Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors. Circulation 2002;105:2817–20. [7] Ghiadoni L, Donald AE, Cropley M, et al. Mental stress induces transient endothelial dysfunction in humans. Circulation 2000;102:2473–8. [8] Satoh H, Tateishi H, Uchida T, et al. Takotsubo-type cardiomyopathy due to multivessel spasm. In: Kodoma K, Haze K, Hon M, editors. Clinical Aspect of Myocardial injury: From Ischemia to Heart Failure, Kagakuhyouronsya Co, Tokyo; 1990. p. 56–64. (in Japanese). [9] Bergmann V. Changes of cardiac and skeletal muscle in pigs following transport stress. An electron microscopic study. Exp Pathol (Jena) 1979;17(5):243–8. [10] Selve H. The pluricausal cardiopathies. Ann N Y Acad Sci Jan 31 1969;156(1):195–206. [11] Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: a systematic review. Int J Cardiol 2009;126:283–92. [12] Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation Feb 1 2005;111(4):472–9. [13] Patel HM, Kantharia BK, Morris DL, Yazdanfar S. Takotsubo syndrome in African-American women with atypical presentations: a single-center experience. Clin Cardiol Jan 2007;30(1):14–8. [14] Nanda S, Bhatt SP, Dale TH. Takotsubo cardiomyopathy — A new variant and widening disease spectrum. “Inverted takotsubo” pattern related to catecholamine toxicity. Int J Cardiol 2009;132:438–9. [15] Bybee KA, Murphy J, Prasad A, et al. Acute impairment of regional myocardial glucose uptake in the apical ballooning (takotsubo) syndrome. J Nucl Cardiol Mar–Apr 2006;13(2):244–50. [16] Ueyama T, Ishikura F, Matsuda A, et al. Chronic estrogen supplementation following ovariectomy improves the emotional stress-induced cardiovascular responses by indirect action on the nervous system and by direct action on the heart. Circ J Apr 2007;71 (4):565–73. [17] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131: 149–50.
Letter to the Editor
Takotsubo cardiomyopathy caused by hypoglycemia A unique association with coronary arterial calcification Muhammad J. Ansari ⁎, Abhiram Prasad, Patricia A. Pellikka, Kyle W. Klarich The Division of Cardiology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, United States Received 8 January 2009; accepted 10 January 2009
Abstract Several factors attributable to the onset of Takotsubo type of cardiomyopathy are known. We report a case of a postmenopausal female, who represented with syncope and was found to be hypoglycemic and had elevated cardiac biomakers. Later found to have Takotsubo type of cardiomyopathy after a negative coronary angiogram. The left ventricular function improved over a week. She had unusual combination of hypoglycemia and cortisol excess; this is not reported in the literature. The urine catecholamines were normal. We also report a unique occurrence of coronary artery calcification as one of the associations with Takotsubo syndrome. This feature may help in risk assessment and reccurence of this syndrome. Further studies are needed to confirm this association and its prognostic significance. © 2009 Elsevier Ireland Ltd. All rights reserved. Keywords: Takotsubo cardiomyopathy; Hypoglycemia; Coronary artery calcification
1. Case description We report a case of 69 year old African American female who presented to emergency room with “loss of consciousness”. She was found unresponsive lying on the floor, by her sister who called for ambulance. The blood glucose found by the paramedics was 32 mg/dl. There was no history of lack of appetite or poor intake. She had no diabetes and there was no history of accidental ingestion of oral hypoglycemics. On examination she had Glasgow coma scale of 5/15, tachycardia with S3 gallop rhythm and crackles on lung bases. Cardiac biomarkers were elevated i.e. troponin of 0.65 ng/ml (peak) with ECG showing sinus tachycardia. First 2D echocardiograph showed severe LV dysfunction with an ejection fraction (EF) of 16%. (Fig. 1a,b). The coronary angiogram showed non-obstructing coronary
⁎ Corresponding author. Tel.: +1 507 284 1226; fax: +1 507 284 3968. E-mail address: [email protected] (M.J. Ansari). 0167-5273/$ - see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.01.016
arteries with coronary calcification. The left ventriculogram showed ballooning of the apex consistent with Takotsubo cardiomyopathy. (Fig. 2). The plasma venous glucose remained low in the range of 60–80 mg/dl initially despite IV dextrose infusion. The work up for hypoglycemia was negative as she had normal C-peptide levels 3.9, pro-insulin 6.9 pmol/L (N 2.1–26.8), and sulfonylurea screen was negative. The cortisol (am) was elevated to 107.0 mcg/dl (normal 7.0–25) and cortisol (pm) of 103.7 mcg/dl (normal 0.0–5.9). 24-hour urine free cortisol to be elevated 139.7 µg/ day (normal b 45), dopamine of 119 mcg/24 h (normal 80– 440), and normal urine norepinephrine/epinephrine levels. ACTH was 26 pg/ml (normal b46) and thyroid functions were normal. The heart rate and blood pressure were controlled on a combination of β-blockade (metoprolol) and centrally acting α-agonist (clonidine). On day 5 she improved with supportive treatment and the repeat echocardiography showed markedly improved LV function with EF 45%.(Fig. 1c) Concurrently the cortisol (am) has dropped to 57.5 mcg/dl and cortisol (pm) to 5.5 mcg/dl normalized.
e22
M.J. Ansari et al. / International Journal of Cardiology 147 (2009) e21–e23
Fig. 1. (a) Apical 4 chamber view showing ballooning of LV apex. (b) Parasternal long axis view. (c) Parasternal long axis view 5 days later.
LV function remained preserved along with normal blood pressure. 2. Discussion Our case depicts two unique features; the presence of hypoglycemia and the coronary arterial calcification with Takotsubo cardiomyopathy. Coronary calcification may be used as a prognostic marker or a predictor of recurrence in patients at risk. Further studies and registry for the Takotsubo may help to answer this association. This syndrome occurs typically in postmenopausal women. It is commonly referred to as Takotsubo cardiomyopathy, as first reported by Satoh et al. [8]. The name “Takotsubo” refers to a trap used to catch octopus in Japan. The ventricular ballooning at the apex with a narrow base mimics the shape of above mentioned trap. It is mentioned in the literature as “apical ballooning syndrome” or “stressinduced cardiomyopathy” both in pigs [9] with stress induced by restraint and in humans [10]. It was initially reported as “left ventricular apical ballooning, but recent studies have shown that there is right ventricular involvement as well, thus now referred to as “apical ballooning syndrome”
(ABS). An entity called “inverted takotsubo" is seen with pheochromocytoma and acute pancreatitis [5]. The base of heart is hypokinetic with apex hyperkinetic in this variant [14]. There are few case reports suggesting hypoglycemia as a trigger to develop Takotsubo type of cardiomyopathy [1,4]. Most of the literature on the association of Takotsubo syndrome to hypoglycemia is related to anorexia nervosa [4]. There is one case report suggesting adrenal insufficiency in ACTH deficiency as a cause of this type of cardiomyopathy [2]. In the largest series from Japan, 1 out of 88 cases onset of the syndrome was associated with a hypoglycemic episode [3]. The atypical presentations with syndrome have been reported in African American women [13].Our patient was unique as she had hypoglycemia, but no emotional stressor to account for the development of this syndrome. The work up for the hypoglycemia was negative. She had cortisol surplus possibly related to sympathomimetic excess. The ACTH was normal and CT scan of abdomen failed to demonstrate adrenal adenoma or hyperplasia. Various mechanisms of pathophysiology are proposed such as catecholamine excess causing neurogenic stunning, that may result in transient apical systolic asynergy, the other
Fig. 2. Left ventriculogram showing ballooning of the apex in diastole and transapical ballooning in systole.
M.J. Ansari et al. / International Journal of Cardiology 147 (2009) e21–e23
possibilities include coronary microvascular dysfunction, epicardial vessel spasm, abnormal coronary flow without obstruction and abnormal glucose metabolism at the cardiac apex due to increased number of adrenergic receptors at the apex [6,7]. The mechanism of “perfusion–metabolism mismatch” is also one of the accepted theories, with selective reduction of glucose uptake predominantly from the apex of the heart. This phenomenon has been demonstrated with the help of positron emission tomography with 13N-ammonia and 18F-fluorodeoxyglucose within 72 hours of presentation [15]. The protective role of Estrogen hormone has also been confirmed with animal (rat) experiments by supplemental estrogen on the rats with oophorectomy on the development of this type of cardiomyopathy. It was suggested that estrogen supplementation partially prevents emotional stress-induced cardiovascular responses both by indirect action on the nervous system and by direct action on the heart [16]. ABS is attributable to psychological, emotional insults and following stress due to a loss of beloved or loss of job etc. The stress related to certain metabolic disorders such as adrenal insufficiency, thyroid dysfunction, pheochromocytoma and hypoglycemia can be the initial trigger to the excessive sympathetic activity related to this disorder. The other well known triggers are postoperative states, cerebrovascular accidents, and sepsis related to infection or severe pancreatitis. Checking the cortisol levels may be helpful in the diagnostic workup as there is a correlation of cardiac improvement with the normalization of cortisol levels. Therefore we suggest the pathophysiology of this cardiomyopathy as more complex than just catecholamine excess. The mechanism of cortisol excess due to emotional or organic disease related stress may also be significant player in the pathogenesis along with dysregulation of glucose metabolism. There may be genetic predisposition which triggers cardiomyopathy with the excess of catecholamines in susceptible individuals. Understanding the pathophysiology is important as it may help to decide on treatment options. These patients may benefit from using beta-blockers with centrally acting α-agonists. There is up to 8% reported mortality rate [3,12] and 95% excellent recovery [11], but can recur on reproduction of the stress. The recurrence rate has been reported in up to 10– 11% of the cases. The association or coronary calcification may be an important predictor for recurrence or severity; we propose further studies on the same. Acknowledgement The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [17].
e23
References [1] Saito Y. Hypoglycemic attack: a rare triggering factor for takotsubo cardiomyopathy. Intern Med Mar 2005;44(3):171–2. [2] Sakihara S, Kageyama K, Nigawara T, Kidani Y, Suda T. Ampulla (Takotsubo) cardiomyopathy caused by secondary adrenal insufficiency in ACTH isolated deficiency. Endocr J Aug 2007;54(4):631–6. [3] Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris– Myocardial Infarction Investigations in Japan. J Am Coll Cardiol 2001;38(1):11–8. [4] Ohwada R, Hotta M, Kimura H, et al. Ampulla cardiomyopathy after hypoglycemia in three young female patients with anorexia nervosa. Intern Med 2005;44(3):228–33. [5] Van de Walle SO, Gevaert SA, Gheeraert PJ, De Pauw M, Gillebert TC. Transient stress-induced cardiomyopathy with an “inverted takotsubo” contractile pattern. Mayo Clin Proc Nov 2006;81 (11):1499–502. [6] Spieker L, Hurlimann D, Ruschitzka F, et al. Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors. Circulation 2002;105:2817–20. [7] Ghiadoni L, Donald AE, Cropley M, et al. Mental stress induces transient endothelial dysfunction in humans. Circulation 2000;102:2473–8. [8] Satoh H, Tateishi H, Uchida T, et al. Takotsubo-type cardiomyopathy due to multivessel spasm. In: Kodoma K, Haze K, Hon M, editors. Clinical Aspect of Myocardial injury: From Ischemia to Heart Failure, Kagakuhyouronsya Co, Tokyo; 1990. p. 56–64. (in Japanese). [9] Bergmann V. Changes of cardiac and skeletal muscle in pigs following transport stress. An electron microscopic study. Exp Pathol (Jena) 1979;17(5):243–8. [10] Selve H. The pluricausal cardiopathies. Ann N Y Acad Sci Jan 31 1969;156(1):195–206. [11] Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: a systematic review. Int J Cardiol 2009;126:283–92. [12] Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation Feb 1 2005;111(4):472–9. [13] Patel HM, Kantharia BK, Morris DL, Yazdanfar S. Takotsubo syndrome in African-American women with atypical presentations: a single-center experience. Clin Cardiol Jan 2007;30(1):14–8. [14] Nanda S, Bhatt SP, Dale TH. Takotsubo cardiomyopathy — A new variant and widening disease spectrum. “Inverted takotsubo” pattern related to catecholamine toxicity. Int J Cardiol 2009;132:438–9. [15] Bybee KA, Murphy J, Prasad A, et al. Acute impairment of regional myocardial glucose uptake in the apical ballooning (takotsubo) syndrome. J Nucl Cardiol Mar–Apr 2006;13(2):244–50. [16] Ueyama T, Ishikura F, Matsuda A, et al. Chronic estrogen supplementation following ovariectomy improves the emotional stress-induced cardiovascular responses by indirect action on the nervous system and by direct action on the heart. Circ J Apr 2007;71 (4):565–73. [17] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131: 149–50.