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A man with diabetes and heart failure
Case Report
A man with diabetes and heart failure Lancet 2004; 364: 636 Departments of Cardiology (R Nijveldt MD) and Internal Medicine (E H Serné PhD) VU University Medical Center, 1081 HV Amsterdam; Departments of Internal Medicine (J M Sepers MD) and Cardiology (J H Cornel PhD, A E R Arnold PhD) Medical Center Alkmaar, Alkmaar, and Department of Molecular Cell Biology (J A Maassen PhD) Leiden University Medical Center, Leiden, the Netherlands Correspondence to: Dr Robin Nijveldt [email protected]
636
Robin Nijveldt, Erik H Serné, Jan M Sepers, J Antonie Maassen, Jan Hein Cornel, Alf E R Arnold,
A 61-year-old man with a history of diabetes mellitus presented, in January, 2003, with a slowly progressive dyspnoea during exertion, sometimes accompanied with chest discomfort, lower limb oedema, and general fatigue over the past year. His HbA1C levels had gradually increased, showing a degradation of glycaemic control. On physical examination and chest radiograph we found signs of congestive heart failure. Electrocardiography showed a trifascicular block and non-specific STsegment abnormalities. Echocardiography showed diffusely impaired left ventricular function with signs of hypertrophic, non-dilated cardiomyopathy, and an ejection fraction of 15%. Mibi-scintigraphy did not show ischaemia, however we could not rule out 3 vessel disease. We saw no stenoses during a coronary angiogram, and started treatment with an ACE-inhibitor, a platelet-aggregation-inhibitor and a beta-blocker. Because our patient had cardiomyopathy in the absence of atherosclerosis, we reviewed his medical and family history, looking for an explanation. At the age of 25 years he had developed nonketotic hyperglycaemia, and was classified as having type 2 diabetes. Remarkably, in the following years he never developed diabetic neuropathy, nephropathy or retinopathy, but he did lose visual acuity as a result of macular pattern dystrophy. He remained normotensive, non-obese, and had no diabetic dyslipidaemia. At age 35 years, he developed bilateral sensory hearing loss. Both his mother and brother suffered from hearing impairment and diabetes since adolescence. His mother died unexpectedly at the age of 63 years, and his brother was diagnosed with cardiomyopathy 2 years before his sudden death, also at age 63 years. This pattern of maternally-transmitted diabetes and sensorineural deafness made us consider mitochondrial diabetes.1 We isolated DNA from peripheral leucocytes and found an A→G 3243 mitochondrial DNA mutation, consistent with Maternally Inherited Diabetes and Deafness (MIDD; figure). When last seen in March, 2004, our patient was doing relatively well with acceptable HbA1clevels and no signs of overt heart failure. However, he had lost all ability to hear, and his vision had become worse. An estimated 1·3% of all diabetic patients have MIDD.2 The disease shows maternal inheritance, in agreement with a mitochondrial point mutation.1 Most patients develop diabetes and sensorineural deafness at a young age. Obesity is not usually a feature, and few patients develop diabetic retinopathy.3 Macular pattern dystrophy, neuromuscular disorders, myopathy, hypertrophic cardiomyopathy, and kidney disease may all be present.3 Why bother with such a diagnosis? In recent treatment guidelines, diabetes is considered a
Patient
Control
581
367
214
Figure: A3243G mutation with cleavage of DNA into fragments of 367 and 214bp
risk equivalent for coronary heart disease and treatment with statins is advocated. However, statins lower the plasma concentration of endogenous coenzyme Q10, which plays an essential part in the mitochondrial respiratory chain through oxidative phosphorylation with the concomitant production of ATP.4 Low concentrations of coenzyme Q10 may cause impaired cardiac function in some animals,5 and myopathic problems in humans.4 Metformin may also be contraindicated because it can induce lactic acidosis, and people with impaired mitochondrial function are naturally prone to developing mitochondrial lactic acidosis.1 It is important to take a careful medical history to identify diabetes and cardiomyopathy due to mitochondrial gene mutations, since such a diagnosis may influence treatment options. References 1 Maassen JA. Mitochondrial diabetes: pathophysiology, clinical presentation, and genetic analysis. Am J Med Genet 2002; 115: 66–70. 2 ‘t Hart LM, Lemkes HH, Heine RJ, et al. Prevalence of maternally inherited diabetes and deafness in diabetic populations in The Netherlands [Letter]. Diabetologia 1994; 37: 1169–70. 3 Guillausseau PJ, Massin P, Dubois-LaForgue D, et al. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med 2001; 134: 721–28. 4 Hargreaves IP, Heales S. Statins and myopathy [Letter]. Lancet 2002; 359: 711–12. 5 Satoh K, Yamato A, Nakai T, Hoshi K, Ichihara K. Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts. Br J Pharmacol 1995; 116: 1894–98.
www.thelancet.com Vol 364 August 14, 2004
A man with diabetes and heart failure Lancet 2004; 364: 636 Departments of Cardiology (R Nijveldt MD) and Internal Medicine (E H Serné PhD) VU University Medical Center, 1081 HV Amsterdam; Departments of Internal Medicine (J M Sepers MD) and Cardiology (J H Cornel PhD, A E R Arnold PhD) Medical Center Alkmaar, Alkmaar, and Department of Molecular Cell Biology (J A Maassen PhD) Leiden University Medical Center, Leiden, the Netherlands Correspondence to: Dr Robin Nijveldt [email protected]
636
Robin Nijveldt, Erik H Serné, Jan M Sepers, J Antonie Maassen, Jan Hein Cornel, Alf E R Arnold,
A 61-year-old man with a history of diabetes mellitus presented, in January, 2003, with a slowly progressive dyspnoea during exertion, sometimes accompanied with chest discomfort, lower limb oedema, and general fatigue over the past year. His HbA1C levels had gradually increased, showing a degradation of glycaemic control. On physical examination and chest radiograph we found signs of congestive heart failure. Electrocardiography showed a trifascicular block and non-specific STsegment abnormalities. Echocardiography showed diffusely impaired left ventricular function with signs of hypertrophic, non-dilated cardiomyopathy, and an ejection fraction of 15%. Mibi-scintigraphy did not show ischaemia, however we could not rule out 3 vessel disease. We saw no stenoses during a coronary angiogram, and started treatment with an ACE-inhibitor, a platelet-aggregation-inhibitor and a beta-blocker. Because our patient had cardiomyopathy in the absence of atherosclerosis, we reviewed his medical and family history, looking for an explanation. At the age of 25 years he had developed nonketotic hyperglycaemia, and was classified as having type 2 diabetes. Remarkably, in the following years he never developed diabetic neuropathy, nephropathy or retinopathy, but he did lose visual acuity as a result of macular pattern dystrophy. He remained normotensive, non-obese, and had no diabetic dyslipidaemia. At age 35 years, he developed bilateral sensory hearing loss. Both his mother and brother suffered from hearing impairment and diabetes since adolescence. His mother died unexpectedly at the age of 63 years, and his brother was diagnosed with cardiomyopathy 2 years before his sudden death, also at age 63 years. This pattern of maternally-transmitted diabetes and sensorineural deafness made us consider mitochondrial diabetes.1 We isolated DNA from peripheral leucocytes and found an A→G 3243 mitochondrial DNA mutation, consistent with Maternally Inherited Diabetes and Deafness (MIDD; figure). When last seen in March, 2004, our patient was doing relatively well with acceptable HbA1clevels and no signs of overt heart failure. However, he had lost all ability to hear, and his vision had become worse. An estimated 1·3% of all diabetic patients have MIDD.2 The disease shows maternal inheritance, in agreement with a mitochondrial point mutation.1 Most patients develop diabetes and sensorineural deafness at a young age. Obesity is not usually a feature, and few patients develop diabetic retinopathy.3 Macular pattern dystrophy, neuromuscular disorders, myopathy, hypertrophic cardiomyopathy, and kidney disease may all be present.3 Why bother with such a diagnosis? In recent treatment guidelines, diabetes is considered a
Patient
Control
581
367
214
Figure: A3243G mutation with cleavage of DNA into fragments of 367 and 214bp
risk equivalent for coronary heart disease and treatment with statins is advocated. However, statins lower the plasma concentration of endogenous coenzyme Q10, which plays an essential part in the mitochondrial respiratory chain through oxidative phosphorylation with the concomitant production of ATP.4 Low concentrations of coenzyme Q10 may cause impaired cardiac function in some animals,5 and myopathic problems in humans.4 Metformin may also be contraindicated because it can induce lactic acidosis, and people with impaired mitochondrial function are naturally prone to developing mitochondrial lactic acidosis.1 It is important to take a careful medical history to identify diabetes and cardiomyopathy due to mitochondrial gene mutations, since such a diagnosis may influence treatment options. References 1 Maassen JA. Mitochondrial diabetes: pathophysiology, clinical presentation, and genetic analysis. Am J Med Genet 2002; 115: 66–70. 2 ‘t Hart LM, Lemkes HH, Heine RJ, et al. Prevalence of maternally inherited diabetes and deafness in diabetic populations in The Netherlands [Letter]. Diabetologia 1994; 37: 1169–70. 3 Guillausseau PJ, Massin P, Dubois-LaForgue D, et al. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med 2001; 134: 721–28. 4 Hargreaves IP, Heales S. Statins and myopathy [Letter]. Lancet 2002; 359: 711–12. 5 Satoh K, Yamato A, Nakai T, Hoshi K, Ichihara K. Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts. Br J Pharmacol 1995; 116: 1894–98.
www.thelancet.com Vol 364 August 14, 2004