- Email: [email protected]
Left ventricular function in patients with type 2 diabetes mellitus
Left Ventricular Function in Patients With Type 2 Diabetes Mellitus Thein Htay,
MD,
Deval Mehta,
MD,
Jaekyeong Heo,
This study showed that the mean left ventricular ejection fraction, end-diastolic volume, end-systolic volume, and muscle mass are comparable in patients with type 2 diabetes mellitus to gender-matched patients who do not have diabetes mellitus, but abnormal ejection fraction is more common in men, although not in women, with diabetes mellitus than without. The ejection fraction was higher and the volumes and muscle mass were lower in women than men in the presence or absence of diabetes mellitus. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:798 – 801)
I
n 1972, Rubler et al1 described a specific type of cardiomyopathy related to diabetes mellitus (DM). Since then, multiple studies have examined left ventricular (LV) function in patients with type 2 DM.2,3 Abnormalities in diastolic function have been well confirmed, but abnormalities in systolic function are controversial and inconsistent.2,3 Part of the inconsistency may be related to concomitant myocardial ischemia and/or scar due to either macrovascular or microvascular coronary artery disease (CAD).2,4 The purpose of this study was to assess LV function in patients with type 2 DM and compare results in gender-matched patients without DM in whom myocardial ischemia and scar were excluded by stress and resting gated single-photon emission computed tomography (SPECT). •••
We studied 70 patients with type 2 DM (30 men, aged 52 ⫾10 years and 40 women, aged 58 ⫾ 15 years) and 168 control patients without DM (78 men, aged 50 ⫾ 13 years and 90 women, aged 53 ⫾ 13 years). These consecutive patients were being evaluated at the emergency department for nonspecific symptoms, such as nonanginal chest pain or shortness of breath; they had a normal physical examination, no evidence of myocardial necrosis by serial electrocardiograms or biomarkers, and were in sinus rhythm. They were considered to have a low-to-intermediate pretest likelihood of CAD and were referred for initial SPECT perfusion imaging at rest, which was followed a few days later by stress SPECT imaging. None of the patients had a previous myocardial infarction, coronary intervention, coronary artery bypass grafting, or known CAD. The diagnosis of DM was based on the From the Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. Dr. Iskandrian’s address is: Division of Cardiovascular Disease, University of Alabama at Birmingham, 318 LHRB, 1900 University Boulevard, Birmingham, Alabama 35294-0006. E-mail: aiskand@ uab.edu. Manuscript received August 24, 2004; revised manuscript received and accepted November 15, 2004.
798
©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 March 15, 2005
MD,
and Ami E. Iskandrian,
MD
requirement for treatment with insulin and/or hypoglycemic agents. All patients underwent resting and stress SPECT imaging with technetium-99m tetrofosmin (25 to 40 mCi each) on separate days. The SPECT images were acquired with an elliptic 180° acquisition protocol using a dual-head gamma camera. Gating was done at 8 frames/RR cycle. The images were acquired with attenuation correction using a dual-line source, but attenuation correction was not incorporated in the interpretation of the LV volumes, the ejection fraction, and mass. The Auto-Quant software (Cedar-Sinai, Los Angeles, California) was used to measure the LV ejection fraction, end-diastolic volume, end-systolic volume, and mass. The LV mass was assessed by measuring the total LV volume (end-diastolic volume plus muscle volume and then subtracting the enddiastolic volume from the total and multiplying it by specific gravity of myocardium, which is assumed to be 1.04). In a previous study in women, we showed a good correlation in measuring muscle mass by gated SPECT compared with magnetic resonance imaging.5 We, and many other groups, have validated the gated SPECT method for measuring the ejection fraction and volumes. All these measurements are fully automated. We obtained all these measurements in the post-stress and resting images but used the data at rest for comparing the men and women with and without DM. The volumes and mass were indexed by dividing the measurements by body surface area (square meters). All values are expressed as percentages or as mean ⫾ 1 SD. The continuous variables were compared by Student’s t test and the categorical variables by the chi-square test. Linear correlations and Bland-Altman plots were used to examine the correlation between resting and post-stress measurements. Data were analyzed using statistical analytical software (SAS, version 8.2, Cary, North Carolina). A p value ⬍0.05 was considered statistically significant. The pertinent data are listed in Table 1. The mean LV ejection fraction, volumes, mass (Table 2), and mass index were comparable in men with and without DM. Similarly, these measurements were comparable in women with and without DM (Figure 1). There were, however, more men with DM (5 of 30, 16.6%) than without (3 of 78, 3.8%; p ⫽ 0.02) with an ejection fraction of ⬍45%, which is the lower limit of normal. This difference was not seen in women, where 1 of 40 women with DM and 3 of 90 women without DM (2.5% vs 3.3%, p ⫽ NS) had an ejection fraction ⬍45%. The ejection fraction and end-diastolic volume in men and women with and without DM (Figure 2) 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.11.043
TABLE 1 Pertinent Data for the Study Patients Women ⫹ DM
Women ⫺ DM
p Value
Men ⫹ DM
Men ⫺ DM
p Value
Men vs Women*
79 ⫾ 12 136 ⫾ 21 77 ⫾ 12 190 ⫾ 40 32 ⫾ 6 14/26 63 ⫾ 10 78 ⫾ 28 40 ⫾ 13 31 ⫾ 20 16 ⫾ 9 130 ⫾ 31
74 ⫾ 15 125 ⫾ 27 74 ⫾ 17 180 ⫾ 49 30 ⫾ 7 56/34 67 ⫾ 10 76 ⫾ 22 41 ⫾ 12 27 ⫾ 17 15 ⫾ 9 128 ⫾ 29
0.10 0.02 0.37 0.28 0.21 — 0.04 0.65 0.87 0.27 0.49 0.59
76 ⫾ 15 127 ⫾ 24 70 ⫾ 25 198 ⫾ 44 27 ⫾ 5 15/15 54 ⫾ 10 109 ⫾ 29 52 ⫾ 15 51 ⫾ 23 25 ⫾ 11 154 ⫾ 17
72 ⫾ 12 124 ⫾ 18 76 ⫾ 14 200 ⫾ 41 29 ⫾ 6 63/15 57 ⫾ 8 107 ⫾ 29 51 ⫾ 13 48 ⫾ 19 23 ⫾ 9 154 ⫾ 26
0.20 0.44 0.14 0.76 0.39 — 0.16 0.75 0.66 0.44 0.40 0.96
0.10 0.30 0.68 0.005 0.01 — 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001
Heart rate at rest (beats/min) Systolic BP at rest (mm Hg) Diastolic BP at rest (mm Hg) Weight (lbs) Body mass index (kg/m2) Exercise/adenosine Ejection fraction (%) End-diastolic volume (ml) End-diastolic volume index (ml/m2) End-systolic volume (ml) End-systolic volume index (ml/m2) LV muscle mass (gm)
*p Value for comparison between men and women in the study. BP ⫽ blood pressure.
TABLE 2 The Reproducibility of Gated SPECT-derived Ejection Fraction, End-diastolic Volume, End-systolic Volume, and LV Mass in 258 Patients Study Post-stress Rest
Ejection Fraction (%)
End-diastolic Volume (ml)
End-systolic Volume (ml)
LV mass (g)
62 ⫾ 10 61 ⫾ 10
88 ⫾ 30 91 ⫾ 31
35 ⫾ 20 37 ⫾ 22
140 ⫾ 25 141 ⫾ 28
p ⫽ NS.
FIGURE 1. The mean LV ejection fraction (LVEF), end-diastolic volume index (EDVI) in men with DM, men without DM, women with DM, and women without DM.
were inversely related. Women without and with DM had a higher ejection fraction and lower volumes and mass than men without and with DM, respectively (Figure 1 and Table 1). The correlation between the post-stress and rest tests in the ejection fraction is shown in Figure 3. The measurements were fairly well reproducible. •••
The major conclusion of this study is that in patients with type 2 DM, the mean ejection fraction, volumes, and mass (absolute and indexed to body surface area) are comparable to gender-matched patients without DM in the absence of ischemia or infarction. However, an abnormal ejection fraction
(⬍45%) is ⬃4-fold more common in men with DM than without. This difference was not seen in women. The reason for the gender differences may be real or might be methodologic, as gated SPECT overestimates the ejection fraction in small-sized hearts, as was the case in women. To our knowledge, this is the first study that specifically examined this issue of LV function in patients with DM with documentation of lack of ischemia or infarction. The study also showed gender differences in the ejection fraction, volumes, and mass, regardless of DM. Many epidemiologic studies indicate that patients with DM are at an increased risk of cardiovascular morbidity and mortality.6,7 A leading cause of death in patients with DM is heart failure, and patients with DM have a worse prognosis after myocardial infarction.8 The presence of other risk factors, including hyperlipidemia and hypertension, certainly contribute to the high incidence of cardiovascular disease in the population with DM.9,10 However, the increased risk of diabetic heart failure in the Framingham Heart Study could not be explained by DM-associated risk factors alone.11 Diabetic cardiomyopathy, manifested by diastolic dysfunction followed by abnormalities in systolic function, is common in patients with DM and has been reported to be independent of hypertension and CAD.1,12 The pathogenesis of diabetic cardiomyopathy is still poorly understood. Microangiopathy, increased extracellular collagen deposition, hyperglycemia-induced oxidative stress, or abnormalities in calcium transport, alone or in combination, are considered to be associated with this dysfunction.12,13 In addition, recent evidence implicates perturbations in cardiac energy metabolism. Mitochondrial fatty acid oxidation is the chief energy source for the normal heart, but the contribution of glucose utilization is also important to achieve steady energy production in the context of diverse physiologic and dietary conditions, such as exercise and fasting states.14 Because of the role of insulin in the regulation of myocardial metabolism, long-term insulin deficiency or resistance leads to a marked reduction in cardiac glucose utilization and an almost exclusive BRIEF REPORTS
799
FIGURE 2. The correlation between LV ejection fraction (LVEF) and end-diastolic volume (EDV) in subjects with and without DM. (A) EF at rest versus EDV in men with DM. (B) EF at rest versus EDV in men without DM. (C) EF at rest versus EDV in women with DM. (D) EF at rest versus EDV in women without DM. The regression lines within a 95% confidence interval are shown for those without DM.
FIGURE 3. The Bland-Altman plots of average LV ejection fraction (average of poststress and rest) versus difference in mass between poststress and rest measurements (delta) in the entire study population.
shift to fatty acids as an energy source.10,11 The high rate of fatty acid utilization in the diabetic heart could lead to an accumulation of lipid intermediates in the myocytes, which could cause changes in cardiac gross 800 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 95
structure, myocyte ultrastructure, and finally, a maladaptive functional derangement called lipotoxicity.15 Many studies have reported diastolic dysfunction, with normal or only mildly reduced systolic function3,16 and increased LV mass and concentric LV hypertrophy in the hearts of patients with DM.17 Concomitant CAD or previous myocardial infarction complicates the interpretation of some of these studies.16,17 Romanens et al2 reported evidence of systolic and diastolic LV dysfunction in patients with chronic type 1 DM. Mustonen et al and others3,4 showed a normal LV ejection fraction at rest in the early stage of diabetic heart disease. Harrower et al18 reported supernormal LV function during stress in their patients with DM. A recent dobutamine stress echocardiographic study demonstrated normal response to stress in patients with type 2 DM.19 The patients in that study were of comparable age to our patients. In the Framingham population, the average LV mass was 22% greater in women with DM than in those without the disease.16 Struthers et al20 observed that among patients with DM, 32% had LV hypertrophy, independent of blood pressure or use of angiotensinconverting enzyme inhibitors. LV hypertrophy may MARCH 15, 2005
develop in patients with DM as a result of insulin resistance, which independently stimulates LV growth. The LV mass was not greater in our patients with DM. Our method of gated SPECT does not allow the assessment of diastolic LV function or systolic LV function during stress. These were not the objectives of our study, which specifically evaluated systolic LV function, volume, and mass in gender-matched patients with and without DM in the absence of ischemia or infarction. Our results therefore do not apply to patients with DM who have ischemia or infarction. The SPECT imaging method does not have the same degree of resolution as other imaging methods, such as 2-dimensional echocardiography or magnetic resonance imaging. These modalities are superior for measuring the muscle mass, especially when the heart size is small, as is the case in women. However, our method is automated and was used in an identical fashion in consecutive patients separated by their gender and DM. We did not require coronary angiography to exclude ischemia or scar and relied on the results of stress perfusion imaging, because luminography has limitations in assessing the physiology of coronary circulation in patients with DM. 1. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30:595– 602. 2. Romanens M, Fankhauser S, Saner B, Michaud L, Saner H. No evidence for systolic or diastolic left ventricular function at rest in selected patients with long-term type I diabetes mellitus. Eur J Heart Fail 1999;1:169 –175. 3. Cosson S, Kevorkian JP. Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy? Diabetes Metab 2003;29:455– 466.
4. Mustonen JN, Uusitupa MI, Laakso M, Vanninen E, Lansimies E, Kuikka JT, Pyorala K. Left ventricular systolic function in middle-aged patients with diabetes mellitus. Am J Cardiol 1994;73:1202–1208. 5. Manchikalapudi P, Biederman R, Dayle M, Fuisz A, Pohost GM, Howard G, Paine T, Rogers WJ, Iskandrian AE. Validation of left ventricular mass by SPECT sestamibi imaging (abstr). J Nucl Cardiol 2000;7:185. 6. Butler RA, MacDonald TM, Struthers AD, Morris AD. The clinical implications of diabetic heart disease. Eur Heart J 1998;19:1617–1627. 7. Aronow WS, Ahn C. Incidence of heart failure in 2,737 older persons with and without diabetes mellitus. Chest 1999;115:867– 868. 8. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: Framingham study. Am J Cardiol 1974;34:29 –34. 9. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 2001;161:996 –1002. 10. Forsblom CM, Sane T, Groop PH, Totterman KJ, Kallio M, Saloranta C, Laasonen L, Summanen P, Lepantalo M, Laatikainen L, et al. Risk factors for mortality in type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 1998;41:1253– 1262. 11. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979;241:2035–2038. 12. Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Cardiovasc Drugs Ther 1994;8:65–73. 13. Bell DS. Diabetic cardiomyopathy. A unique entity or a complication of coronary artery disease? Diabetes Care 1995;18:708 –714. 14. Neely JR, Rovetto MJ, Oram JF. Myocardial utilization of carbohydrate and lipid. Prog Cardiovasc Dis 1972;15:289 –329. 15. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Saffitz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 2001;107:813– 822. 16. Galderisi M, Anderson KM, Wilson PF, Levy D. Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy (the Framingham Heart Study). Am J Cardiol 1991;68:85– 89. 17. Raev DC. Which left ventricular function is impaired earlier in the evolution of diabetic cardiomyopathy? An echocardiographic study of young type I diabetic patients. Diabetes Care 1994;17:633– 639. 18. Harrower AD, Railton R, Small D. Comparison by nuclear angiography of resting left ventricular function on insulin-dependent diabetic patients and normal subjects and the effect of diabetic control. Diabetes Res 1984;1:227–229. 19. Fang ZY, Najos-Valencia O, Leano R, Marwick TH. Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine. J Am Coll Cardiol 2003;42:446 – 453. 20. Struthers AD, Morris AD. Screening for and treating left ventricular abnormalities in diabetes mellitus: a new way of reducing cardiac deaths. Lancet 2002;359:1430 –1432.
Left Ventricular Function in Children With SleepDisordered Breathing Raouf S. Amin, MD, Thomas R. Kimball, MD, Maninder Kalra, MD, Jenny L. Jeffries, RN, John L. Carroll, MD, Judy A. Bean, PhD, Sandra A. Witt, RDCS Betty J. Glascock, RDCS, and Stephen R. Daniels, MD, PhD Severe obstructive sleep apnea in children leads to congestive heart failure. We studied the early changes in left ventricular function across a range of severity of the disorder. A dose-dependent decrease From the Departments of Pulmonary Medicine, Cardiology,and Biostatistics, Cincinnati Children’s Hospital Medical Center, Sleep Disorder Center, Cincinnati, Ohio; and the Department of Pediatric Pulmonary Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas. This study was supported by a grant-in-aid from the American Heart Association, Dallas, Texas, and Grant RO1HL70907-02A1 from the National Institutes of Health, Bethesda, Maryland. Dr. Amin’s address is: Cincinnati Children’s Hospital Medical Center, Division of Pulmonary Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 45229. E-mail: [email protected]. Manuscript received July 14, 2004; revised manuscript received and accepted November 12, 2004. ©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 March 15, 2005
in diastolic function with increased severity of obstructive apnea was demonstrated. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:801– 804)
lthough early reports of obstructive sleep apnea (OSA) in children have shown that severe upper A airway obstruction during sleep is associated with congestive heart failure,1,2 the subclinical forms of cardiac dysfunction in children with OSA have not been well characterized. There are reasons to expect that OSA has a negative impact on left ventricular (LV) function in children, because the geometry and structure of the left ventricle are altered in children with this disorder.3 The objectives of this study were to describe LV diastolic and systolic function in children with varying severity of 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.11.044
801
MD,
Deval Mehta,
MD,
Jaekyeong Heo,
This study showed that the mean left ventricular ejection fraction, end-diastolic volume, end-systolic volume, and muscle mass are comparable in patients with type 2 diabetes mellitus to gender-matched patients who do not have diabetes mellitus, but abnormal ejection fraction is more common in men, although not in women, with diabetes mellitus than without. The ejection fraction was higher and the volumes and muscle mass were lower in women than men in the presence or absence of diabetes mellitus. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:798 – 801)
I
n 1972, Rubler et al1 described a specific type of cardiomyopathy related to diabetes mellitus (DM). Since then, multiple studies have examined left ventricular (LV) function in patients with type 2 DM.2,3 Abnormalities in diastolic function have been well confirmed, but abnormalities in systolic function are controversial and inconsistent.2,3 Part of the inconsistency may be related to concomitant myocardial ischemia and/or scar due to either macrovascular or microvascular coronary artery disease (CAD).2,4 The purpose of this study was to assess LV function in patients with type 2 DM and compare results in gender-matched patients without DM in whom myocardial ischemia and scar were excluded by stress and resting gated single-photon emission computed tomography (SPECT). •••
We studied 70 patients with type 2 DM (30 men, aged 52 ⫾10 years and 40 women, aged 58 ⫾ 15 years) and 168 control patients without DM (78 men, aged 50 ⫾ 13 years and 90 women, aged 53 ⫾ 13 years). These consecutive patients were being evaluated at the emergency department for nonspecific symptoms, such as nonanginal chest pain or shortness of breath; they had a normal physical examination, no evidence of myocardial necrosis by serial electrocardiograms or biomarkers, and were in sinus rhythm. They were considered to have a low-to-intermediate pretest likelihood of CAD and were referred for initial SPECT perfusion imaging at rest, which was followed a few days later by stress SPECT imaging. None of the patients had a previous myocardial infarction, coronary intervention, coronary artery bypass grafting, or known CAD. The diagnosis of DM was based on the From the Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. Dr. Iskandrian’s address is: Division of Cardiovascular Disease, University of Alabama at Birmingham, 318 LHRB, 1900 University Boulevard, Birmingham, Alabama 35294-0006. E-mail: aiskand@ uab.edu. Manuscript received August 24, 2004; revised manuscript received and accepted November 15, 2004.
798
©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 March 15, 2005
MD,
and Ami E. Iskandrian,
MD
requirement for treatment with insulin and/or hypoglycemic agents. All patients underwent resting and stress SPECT imaging with technetium-99m tetrofosmin (25 to 40 mCi each) on separate days. The SPECT images were acquired with an elliptic 180° acquisition protocol using a dual-head gamma camera. Gating was done at 8 frames/RR cycle. The images were acquired with attenuation correction using a dual-line source, but attenuation correction was not incorporated in the interpretation of the LV volumes, the ejection fraction, and mass. The Auto-Quant software (Cedar-Sinai, Los Angeles, California) was used to measure the LV ejection fraction, end-diastolic volume, end-systolic volume, and mass. The LV mass was assessed by measuring the total LV volume (end-diastolic volume plus muscle volume and then subtracting the enddiastolic volume from the total and multiplying it by specific gravity of myocardium, which is assumed to be 1.04). In a previous study in women, we showed a good correlation in measuring muscle mass by gated SPECT compared with magnetic resonance imaging.5 We, and many other groups, have validated the gated SPECT method for measuring the ejection fraction and volumes. All these measurements are fully automated. We obtained all these measurements in the post-stress and resting images but used the data at rest for comparing the men and women with and without DM. The volumes and mass were indexed by dividing the measurements by body surface area (square meters). All values are expressed as percentages or as mean ⫾ 1 SD. The continuous variables were compared by Student’s t test and the categorical variables by the chi-square test. Linear correlations and Bland-Altman plots were used to examine the correlation between resting and post-stress measurements. Data were analyzed using statistical analytical software (SAS, version 8.2, Cary, North Carolina). A p value ⬍0.05 was considered statistically significant. The pertinent data are listed in Table 1. The mean LV ejection fraction, volumes, mass (Table 2), and mass index were comparable in men with and without DM. Similarly, these measurements were comparable in women with and without DM (Figure 1). There were, however, more men with DM (5 of 30, 16.6%) than without (3 of 78, 3.8%; p ⫽ 0.02) with an ejection fraction of ⬍45%, which is the lower limit of normal. This difference was not seen in women, where 1 of 40 women with DM and 3 of 90 women without DM (2.5% vs 3.3%, p ⫽ NS) had an ejection fraction ⬍45%. The ejection fraction and end-diastolic volume in men and women with and without DM (Figure 2) 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.11.043
TABLE 1 Pertinent Data for the Study Patients Women ⫹ DM
Women ⫺ DM
p Value
Men ⫹ DM
Men ⫺ DM
p Value
Men vs Women*
79 ⫾ 12 136 ⫾ 21 77 ⫾ 12 190 ⫾ 40 32 ⫾ 6 14/26 63 ⫾ 10 78 ⫾ 28 40 ⫾ 13 31 ⫾ 20 16 ⫾ 9 130 ⫾ 31
74 ⫾ 15 125 ⫾ 27 74 ⫾ 17 180 ⫾ 49 30 ⫾ 7 56/34 67 ⫾ 10 76 ⫾ 22 41 ⫾ 12 27 ⫾ 17 15 ⫾ 9 128 ⫾ 29
0.10 0.02 0.37 0.28 0.21 — 0.04 0.65 0.87 0.27 0.49 0.59
76 ⫾ 15 127 ⫾ 24 70 ⫾ 25 198 ⫾ 44 27 ⫾ 5 15/15 54 ⫾ 10 109 ⫾ 29 52 ⫾ 15 51 ⫾ 23 25 ⫾ 11 154 ⫾ 17
72 ⫾ 12 124 ⫾ 18 76 ⫾ 14 200 ⫾ 41 29 ⫾ 6 63/15 57 ⫾ 8 107 ⫾ 29 51 ⫾ 13 48 ⫾ 19 23 ⫾ 9 154 ⫾ 26
0.20 0.44 0.14 0.76 0.39 — 0.16 0.75 0.66 0.44 0.40 0.96
0.10 0.30 0.68 0.005 0.01 — 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001
Heart rate at rest (beats/min) Systolic BP at rest (mm Hg) Diastolic BP at rest (mm Hg) Weight (lbs) Body mass index (kg/m2) Exercise/adenosine Ejection fraction (%) End-diastolic volume (ml) End-diastolic volume index (ml/m2) End-systolic volume (ml) End-systolic volume index (ml/m2) LV muscle mass (gm)
*p Value for comparison between men and women in the study. BP ⫽ blood pressure.
TABLE 2 The Reproducibility of Gated SPECT-derived Ejection Fraction, End-diastolic Volume, End-systolic Volume, and LV Mass in 258 Patients Study Post-stress Rest
Ejection Fraction (%)
End-diastolic Volume (ml)
End-systolic Volume (ml)
LV mass (g)
62 ⫾ 10 61 ⫾ 10
88 ⫾ 30 91 ⫾ 31
35 ⫾ 20 37 ⫾ 22
140 ⫾ 25 141 ⫾ 28
p ⫽ NS.
FIGURE 1. The mean LV ejection fraction (LVEF), end-diastolic volume index (EDVI) in men with DM, men without DM, women with DM, and women without DM.
were inversely related. Women without and with DM had a higher ejection fraction and lower volumes and mass than men without and with DM, respectively (Figure 1 and Table 1). The correlation between the post-stress and rest tests in the ejection fraction is shown in Figure 3. The measurements were fairly well reproducible. •••
The major conclusion of this study is that in patients with type 2 DM, the mean ejection fraction, volumes, and mass (absolute and indexed to body surface area) are comparable to gender-matched patients without DM in the absence of ischemia or infarction. However, an abnormal ejection fraction
(⬍45%) is ⬃4-fold more common in men with DM than without. This difference was not seen in women. The reason for the gender differences may be real or might be methodologic, as gated SPECT overestimates the ejection fraction in small-sized hearts, as was the case in women. To our knowledge, this is the first study that specifically examined this issue of LV function in patients with DM with documentation of lack of ischemia or infarction. The study also showed gender differences in the ejection fraction, volumes, and mass, regardless of DM. Many epidemiologic studies indicate that patients with DM are at an increased risk of cardiovascular morbidity and mortality.6,7 A leading cause of death in patients with DM is heart failure, and patients with DM have a worse prognosis after myocardial infarction.8 The presence of other risk factors, including hyperlipidemia and hypertension, certainly contribute to the high incidence of cardiovascular disease in the population with DM.9,10 However, the increased risk of diabetic heart failure in the Framingham Heart Study could not be explained by DM-associated risk factors alone.11 Diabetic cardiomyopathy, manifested by diastolic dysfunction followed by abnormalities in systolic function, is common in patients with DM and has been reported to be independent of hypertension and CAD.1,12 The pathogenesis of diabetic cardiomyopathy is still poorly understood. Microangiopathy, increased extracellular collagen deposition, hyperglycemia-induced oxidative stress, or abnormalities in calcium transport, alone or in combination, are considered to be associated with this dysfunction.12,13 In addition, recent evidence implicates perturbations in cardiac energy metabolism. Mitochondrial fatty acid oxidation is the chief energy source for the normal heart, but the contribution of glucose utilization is also important to achieve steady energy production in the context of diverse physiologic and dietary conditions, such as exercise and fasting states.14 Because of the role of insulin in the regulation of myocardial metabolism, long-term insulin deficiency or resistance leads to a marked reduction in cardiac glucose utilization and an almost exclusive BRIEF REPORTS
799
FIGURE 2. The correlation between LV ejection fraction (LVEF) and end-diastolic volume (EDV) in subjects with and without DM. (A) EF at rest versus EDV in men with DM. (B) EF at rest versus EDV in men without DM. (C) EF at rest versus EDV in women with DM. (D) EF at rest versus EDV in women without DM. The regression lines within a 95% confidence interval are shown for those without DM.
FIGURE 3. The Bland-Altman plots of average LV ejection fraction (average of poststress and rest) versus difference in mass between poststress and rest measurements (delta) in the entire study population.
shift to fatty acids as an energy source.10,11 The high rate of fatty acid utilization in the diabetic heart could lead to an accumulation of lipid intermediates in the myocytes, which could cause changes in cardiac gross 800 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 95
structure, myocyte ultrastructure, and finally, a maladaptive functional derangement called lipotoxicity.15 Many studies have reported diastolic dysfunction, with normal or only mildly reduced systolic function3,16 and increased LV mass and concentric LV hypertrophy in the hearts of patients with DM.17 Concomitant CAD or previous myocardial infarction complicates the interpretation of some of these studies.16,17 Romanens et al2 reported evidence of systolic and diastolic LV dysfunction in patients with chronic type 1 DM. Mustonen et al and others3,4 showed a normal LV ejection fraction at rest in the early stage of diabetic heart disease. Harrower et al18 reported supernormal LV function during stress in their patients with DM. A recent dobutamine stress echocardiographic study demonstrated normal response to stress in patients with type 2 DM.19 The patients in that study were of comparable age to our patients. In the Framingham population, the average LV mass was 22% greater in women with DM than in those without the disease.16 Struthers et al20 observed that among patients with DM, 32% had LV hypertrophy, independent of blood pressure or use of angiotensinconverting enzyme inhibitors. LV hypertrophy may MARCH 15, 2005
develop in patients with DM as a result of insulin resistance, which independently stimulates LV growth. The LV mass was not greater in our patients with DM. Our method of gated SPECT does not allow the assessment of diastolic LV function or systolic LV function during stress. These were not the objectives of our study, which specifically evaluated systolic LV function, volume, and mass in gender-matched patients with and without DM in the absence of ischemia or infarction. Our results therefore do not apply to patients with DM who have ischemia or infarction. The SPECT imaging method does not have the same degree of resolution as other imaging methods, such as 2-dimensional echocardiography or magnetic resonance imaging. These modalities are superior for measuring the muscle mass, especially when the heart size is small, as is the case in women. However, our method is automated and was used in an identical fashion in consecutive patients separated by their gender and DM. We did not require coronary angiography to exclude ischemia or scar and relied on the results of stress perfusion imaging, because luminography has limitations in assessing the physiology of coronary circulation in patients with DM. 1. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30:595– 602. 2. Romanens M, Fankhauser S, Saner B, Michaud L, Saner H. No evidence for systolic or diastolic left ventricular function at rest in selected patients with long-term type I diabetes mellitus. Eur J Heart Fail 1999;1:169 –175. 3. Cosson S, Kevorkian JP. Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy? Diabetes Metab 2003;29:455– 466.
4. Mustonen JN, Uusitupa MI, Laakso M, Vanninen E, Lansimies E, Kuikka JT, Pyorala K. Left ventricular systolic function in middle-aged patients with diabetes mellitus. Am J Cardiol 1994;73:1202–1208. 5. Manchikalapudi P, Biederman R, Dayle M, Fuisz A, Pohost GM, Howard G, Paine T, Rogers WJ, Iskandrian AE. Validation of left ventricular mass by SPECT sestamibi imaging (abstr). J Nucl Cardiol 2000;7:185. 6. Butler RA, MacDonald TM, Struthers AD, Morris AD. The clinical implications of diabetic heart disease. Eur Heart J 1998;19:1617–1627. 7. Aronow WS, Ahn C. Incidence of heart failure in 2,737 older persons with and without diabetes mellitus. Chest 1999;115:867– 868. 8. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: Framingham study. Am J Cardiol 1974;34:29 –34. 9. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 2001;161:996 –1002. 10. Forsblom CM, Sane T, Groop PH, Totterman KJ, Kallio M, Saloranta C, Laasonen L, Summanen P, Lepantalo M, Laatikainen L, et al. Risk factors for mortality in type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 1998;41:1253– 1262. 11. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979;241:2035–2038. 12. Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Cardiovasc Drugs Ther 1994;8:65–73. 13. Bell DS. Diabetic cardiomyopathy. A unique entity or a complication of coronary artery disease? Diabetes Care 1995;18:708 –714. 14. Neely JR, Rovetto MJ, Oram JF. Myocardial utilization of carbohydrate and lipid. Prog Cardiovasc Dis 1972;15:289 –329. 15. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Saffitz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 2001;107:813– 822. 16. Galderisi M, Anderson KM, Wilson PF, Levy D. Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy (the Framingham Heart Study). Am J Cardiol 1991;68:85– 89. 17. Raev DC. Which left ventricular function is impaired earlier in the evolution of diabetic cardiomyopathy? An echocardiographic study of young type I diabetic patients. Diabetes Care 1994;17:633– 639. 18. Harrower AD, Railton R, Small D. Comparison by nuclear angiography of resting left ventricular function on insulin-dependent diabetic patients and normal subjects and the effect of diabetic control. Diabetes Res 1984;1:227–229. 19. Fang ZY, Najos-Valencia O, Leano R, Marwick TH. Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine. J Am Coll Cardiol 2003;42:446 – 453. 20. Struthers AD, Morris AD. Screening for and treating left ventricular abnormalities in diabetes mellitus: a new way of reducing cardiac deaths. Lancet 2002;359:1430 –1432.
Left Ventricular Function in Children With SleepDisordered Breathing Raouf S. Amin, MD, Thomas R. Kimball, MD, Maninder Kalra, MD, Jenny L. Jeffries, RN, John L. Carroll, MD, Judy A. Bean, PhD, Sandra A. Witt, RDCS Betty J. Glascock, RDCS, and Stephen R. Daniels, MD, PhD Severe obstructive sleep apnea in children leads to congestive heart failure. We studied the early changes in left ventricular function across a range of severity of the disorder. A dose-dependent decrease From the Departments of Pulmonary Medicine, Cardiology,and Biostatistics, Cincinnati Children’s Hospital Medical Center, Sleep Disorder Center, Cincinnati, Ohio; and the Department of Pediatric Pulmonary Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas. This study was supported by a grant-in-aid from the American Heart Association, Dallas, Texas, and Grant RO1HL70907-02A1 from the National Institutes of Health, Bethesda, Maryland. Dr. Amin’s address is: Cincinnati Children’s Hospital Medical Center, Division of Pulmonary Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 45229. E-mail: [email protected]. Manuscript received July 14, 2004; revised manuscript received and accepted November 12, 2004. ©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 March 15, 2005
in diastolic function with increased severity of obstructive apnea was demonstrated. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:801– 804)
lthough early reports of obstructive sleep apnea (OSA) in children have shown that severe upper A airway obstruction during sleep is associated with congestive heart failure,1,2 the subclinical forms of cardiac dysfunction in children with OSA have not been well characterized. There are reasons to expect that OSA has a negative impact on left ventricular (LV) function in children, because the geometry and structure of the left ventricle are altered in children with this disorder.3 The objectives of this study were to describe LV diastolic and systolic function in children with varying severity of 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.11.044
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