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Bone mineral density is associated with left ventricular diastolic function in men with type 2 diabetes
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Original article
Bone mineral density is associated with left ventricular diastolic function in men with type 2 diabetes R.-T. Wang a,1 , H.-T. Liu a,1 , Y.-L. Zhao b , N. Li c , T. Liu d , X. Kong e , K.-J. Yu a,∗ a
Department of Intensive Care Unit, Harbin Medical University, the Third Affiliated Hospital, Harbin, Heilongjiang, China b Harbin Medical University (Da Qing), Harbin, Heilongjiang, China c Department of Cardiology, Harbin Medical University, the Second Affiliated Hospital, Harbin, Heilongjiang, China d Division of Hypothalamic Research, UT Southwestern Medical Center, Department of Internal Medicine, 75390 Dallas, TX, USA e Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215 Boston, MA, USA Received 9 October 2015; received in revised form 4 February 2016; accepted 15 February 2016
Abstract Aims. – Type 2 diabetes (T2DM) is associated with chronic heart failure and cardiomyopathy. Furthermore, low bone mineral density (BMD) predicts incident heart failure. Abnormal diastolic function reflects early changes in cardiac function and plays a key role in the development of heart failure. The purpose of this study was to investigate the association between BMD with left ventricular (LV) diastolic function in men with T2DM. Methods. – In all, 344 men with T2DM and 331 age-matched control subjects were enrolled. BMD measurements were performed. LV diastolic function and structure were assessed by echocardiographic evaluation. Results. – BMD was lower in men with T2DM than in controls. There were significant differences in the level of parameters reflecting cardiac structure and LV diastolic function between two groups. Moreover, LV diastolic function and structure parameters also showed significant differences as BMD reduced in T2DM group. BMD at femoral neck was correlated with LV diastolic function parameters in T2DM after adjusting for confounding factors. Multivariable logistic analysis revealed that osteopenia and osteoporosis were associated with diastolic dysfunction compared to the control in men with T2DM. However, no association between BMD and LV diastolic function was found in subjects without T2DM. Conclusion. – Osteoporosis may be an independent factor for LV diastolic dysfunction in men with T2DM. Our data suggested that early detection of abnormal BMD should warrant for early search of undetected LV diastolic dysfunction in diabetic men. © 2016 Elsevier Masson SAS. All rights reserved. Keywords: Bone mineral density; Brachial-ankle pulse wave velocity; Left ventricular diastolic function; Type 2 diabetes
1. Introduction
Abbreviations: T2DM, type 2 diabetes; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; FPG, fasting plasma glucose; eGFR, estimated glomerular filtration rate; FN, femoral neck; BMD, bone mineral density. ∗ Corresponding author at: Department of Intensive Care Unit, Harbin Medical University, the Third Affiliated Hospital, NO.150 Haping ST, Nangang District, 150081 Harbin, China. Tel.: +86 451 86298036; fax: +86 451 86298036. E-mail address: kaijiang [email protected] (K.-J. Yu). 1 R.-T. Wang and H.-T. Liu contributed equally to this work.
Type 2 diabetes (T2DM) is associated with ischemic heart disease and chronic heart failure. Moreover, individuals with T2DM may develop cardiomyopathy independent of hypertension and coronary artery disease. Abnormal diastolic function reflects early changes in cardiac function and plays a key role in the development of heart failure. Recent studies have shown that left ventricular (LV) diastolic dysfunction is associated with cardiovascular outcomes and mortality [1,2]. In parallel, osteoporosis has been suggested as an independent risk factor for cardiovascular disease [3]. Low bone mineral density (BMD) increased cardiovascular mortality [4].
http://dx.doi.org/10.1016/j.diabet.2016.02.001 1262-3636/© 2016 Elsevier Masson SAS. All rights reserved.
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Furthermore, subjects with cardiovascular disease have a higher risk of bone loss and fracture [5]. Currently, literature has emerged that shows common underlying biological processes might contribute to vascular calcification and bone mineralization [5]. The conclusions on the relationship between BMD and LV diastolic dysfunction were inconsistent. A study reported that BMD is associated with LV diastolic dysfunction in men with hypertension [6]. Another study found that BMD is not an independent determinant of left ventricular mass index in men [7]. This inconsistency may be due to small sample sizes and selected populations. Recently, a study demonstrated that low BMD predicts incident heart failure in healthy individuals [8]. On the basis of these observations, we hypothesized that low BMD might be an index for diastolic dysfunction in T2DM. However, some of above studies used ultrasound of the calcaneum as a measure of osteoporosis, yet dual energy X-ray absorptiometry (DEXA) is the standard method recommended to diagnose osteoporosis [6–8]. In this study, we aim to evaluate the association between BMD measured by DEXA and LV diastolic function in men with T2DM. 2. Methods 2.1. Participants Between January 2013 to December 2013, 344 men with T2DM were enrolled in the cross-sectional study. A total of 331 age-matched control subjects were also studied. All participants were recruited from the International Physical Examination and Healthy Center in Harbin. Male subjects with type 2 diabetes aged 50–80 y were recruited. Control subjects were randomly selected from the International Physical Examination and Healthy Center and were age matched in 5-year age groups. We combined sequential recruitment strategy and opportunistic recruitment strategy in this study. The recruited subjects were free of complications linked to diabetes (retinopathy, neuropathy, and arterial disease) except incipient nephropathy. Exclusion criteria were cancer, autoimmune diseases, chronic obstructive pulmonary disease, chronic inflammatory disease, chronic renal failure, chronic heart failure, Cushing disease, thyroid disease, hypogonadism, fractures, coronary heart disease, stroke, atrial fibrillation, and medical treatment with glucocorticoid, any sex hormones, glitazone, bisphosphonates, vitamin D or calcium. Our institutional ethics committee approved the study protocol, and all study subjects gave written informed consent. 2.2. Clinical examination Clinical data include medical history, alcohol consumption, smoking status, current use of medication, physical examination, and laboratory test. Cigarette smoking was defined as having smoked at least 100 cigarettes in one’s lifetime. Alcohol drinking was defined as the consumption of at least 30 g of alcohol per week for 1 year or more. Regular leisure-time
physical activity was defined as participation in moderate or vigorous activity for 30 minutes or more per day at least 3 days a week. Blood pressure was measured using a mercury-gravity sphygmomanometer in the sitting position after a 15-min rest. Systolic and diastolic blood pressures were determined twice with a 10-min interval and mean values were used in the analysis. Body mass index was calculated as weight/height squared (kg/m2 ). 2.3. Biochemical analyses All blood samples were drawn after subjects had fasted over-night. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), fasting plasma glucose (FPG), calcium, phosphorus, albumin, and prealbumin were determined by standard laboratory methods (Modular Analytics, Roche, Mannheim, Germany). The glycated hemoglobin (HbA1c ) level was measured using high-performance liquid chromatography method (VariantTM II; Bio-Rad, Hercules, CA, USA). All measurements were conducted within 2 h of sampling. Diagnosis of type 2 diabetes (T2DM) was based on American Diabetes Association criteria such as fasting plasma glucose ≥ 7.0 mmol/L, current treatment with a hypoglycaemic agent, or casual glucose ≥ 11.1 mmol/L. The Modification of Diet in Renal Disease (MDRD) equation was used to estimate glomerular filtration rate (eGFR). MDRD equation was: eGFR = 186.3 × (SCr)−1.154 × (age)−0.203 . 2.4. BMD measurement BMD at lumbar spine (L2–L4) and femoral neck (FN) was measured using dual-energy X-ray absorptiometry (DPX-MD; LUNAR, GE, Madison, WI, USA). BMD was expressed as g/cm2 and as T-score. Osteopenia or osteoporosis was defined according to lowest measured T-score value in either spine or femoral neck. The method was validated in a previous report [9]. Diagnostic classification was based on the World Health Organization criteria: BMD T-score ≥ −1.0 is normal; > −2.5 and < −1.0 is low bone mass (osteopenia); and ≤ −2.5 is osteoporosis. 2.5. Echocardiographic examination Echocardiography was performed by standardized procedures with Philips iE33 (Philips Ultrasound, Bothell, WA). LV linear dimensions were measured according to the American Society of Echocardiography’s recommendations [10]. LV mass was calculated with a validated formula and indexed for height2.7 [11]. LV ejection fraction was calculated by biplane modified Simpson’s rule. The peak early diastolic transmitral flow velocity (E), peak late diastolic transmitral flow velocity (A), and E/A ratio were measured using pulsed-wave Doppler imaging of the mitral valve inflow from the apical 4-chamber view. Peak early diastolic mitral annular velocity (e ) was measured in the septal position using spectral Doppler imaging. The e wave velocities from the septal and lateral walls were averaged and the E/e ratio
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was calculated as an indicator of LV filling pressure. Diastolic dysfunction was defined as: • E/A ≤ 0.7 (impaired relaxation, grade I); • or 0.7 < E/A ≤ 1.5 and e < 7 cm/s (pseudo-normalized pattern, grade II); • or E/A > 1.5 and e < 7 cm/s (restrictive pattern, grade III) [12]. Echocardiograms were analysed by an experienced echocardiographer blinded to clinical data and functional status. 2.6. Statistical analysis All data were expressed as means ± SD or medians (interquartile range) for continuous variables and percentages of the number for categorical variables. When baseline characteristics between two groups were compared, normally distributed continuous variables were compared with the Student t test and skewed-distributed with the Mann-Whitney U test. When baseline characteristics among three groups were compared, normally distributed continuous variables were compared with the one-way ANOVA and skewed-distributed with Kruskal-Wallis H test. The Chi2 test was used for categorical variables. The categories of the participants comprised the following: normal, osteopenia, and osteoporosis. Partial correlation coefficients were used to determine the relationship between BMD and LV diastolic function parameters after adjustment for several confounders. The distributions of continuous variables were evaluated. TG, HDL, and FPG were logarithmically transformed prior to analysis. Multivariable logistic regression model was used to identify the independent association between osteopenia or osteoporosis and LV diastolic dysfunction. Multiple linear regression analysis was performed to assess the correlation between E/A or E/e ratio and BMD. P-values of 0.05 or less were considered to be statistically significant. All analyses were run using the SPSS software package version 22.0 (SPSS Inc., Chicago, IL, USA). 3. Results The characteristics of participants stratified by T2DM status are shown in Table 1. The groups were well matched with respect to age. Patients with T2DM were more centrally obese, and had a greater frequency of microalbuminuria and hypertension than those without T2DM. They also had lower HDL, L2-4 BMD, FN BMD and higher SBP, DBP, TC, TG, LDL, FPG, and HbA1c than their counterparts without T2DM. However, age, heart rate, eGFR, T-score L2-4, T-score FN, albumin, prealbumin, calcium, phosphorus, and the proportion of smokers, drinking, physical activity and use of statins had no difference. The cardiac structure and LV diastolic function of the subjects stratified by T2DM status are shown in Table 2. Significant differences in cardiac structure parameters (Interventricular septal diameter, LV posterior wall thickness, LV wall thickness, LV relative wall thickness, LV mass, LV mass index, and LA diameter) were observed between the groups. In terms of LV diastolic function, A velocity and E/E ratio were increased and E and E/A
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Table 1 Characteristics of the participants according to T2DM status. Variables
With T2DM
Without T2DM
P value
Number Age (years) BMI (kg/m2 ) Smoker (n, %) Drinking (n, %) Physical activity (n, %) SBP (mmHg) DBP (mmHg) TC (mmol/L) TG (mmol/L) HDL (mmol/L) LDL (mmol/L) Albumin (g/L) Prealbumin (mg/L) Calcium (mmol/L) Phosphorus (mmol/L) FPG (mmol/L) Hemoglobin A1c (%) Hemoglobin A1c (mmol/mol) Heart rate (bpm) eGFR (mL/min/1.73 m2 ) L2-4 BMD (g/cm2 ) T-score L2-4 (SD) FN BMD (g/cm2 ) T-score FN (SD) Hypertension (n, %) Statins (n, %) Microalbuminuria (n, %)
334 66.6 (9.3) 25.3 (3.3) 115.0 (34.4) 138.0 (41.3) 67.0 (20.1) 136.3 (11.3) 77.8 (8.8) 5.03 (0.98) 4.19 (3.40–4.78) 1.31 (1.11–1.49) 2.60 (0.86) 44.5 (3.2) 310.3 (26.2) 2.40 (0.10) 1.13 (0.32) 6.66 (6.25–7.15) 6.9 (1.0) 52 (10.9) 75.8 (12.7) 72.7 (15.9) 0.955 (0.235) −1.334 (1.081) 0.688 (0.194) −1.385 (1.031) 169 (50.6) 99 (29.6) 47 (14.1)
331 67.2 (9.4) 24.5 (3.3) 131.0 (39.6) 121.0 (36.6) 62.0 (18.7) 132.4 (10.2) 75.2 (8.6) 4.85 (1.01) 3.58 (3.09–4.30) 1.36 (1.18–1.50) 2.34 (0.90) 44.1 (3.2) 310.6 (34.1) 2.39 (0.11) 1.15 (0.34) 5.39 (5.01–5.68) 5.4 (0.7) 36 (7.7) 74.0 (12.8) 74.0 (15.0) 1.021 (0.214) −1.328 (1.231) 0.770 (0.169) −1.437 (1.115) 98 (29.6) 94 (28.4) 16 (4.8)
0.451 0.002 0.169 0.208 0.665 < 0.001 < 0.001 0 016 < 0.001 0.036 < 0.001 0.099 0.888 0.218 0.372 < 0.001 < 0.001 < 0.001 0.070 0.271 < 0.001 0.949 < 0.001 0.539 0.009 0.724 < 0.001
Data are shown as means (SD) or median (inter-quartile range) or percentage. T2DM: type 2 diabetes; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglyceride; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol; FPG: fasting plasma glucose; eGFR: estimated glomerular filtration rate; FN: femoral neck; BMD: bone mineral density. P value was calculated by the student’s t-test or Mann-Whitney U test or Chi2 test.
ratio were reduced in T2DM compared with control subjects. However, E velocity was not significantly different. The characteristics of subjects with normal BMD, osteopenia, and osteoporosis in T2DM are shown in Table 3. Mean age, SBP, DBP, TC, TG, LDL, FPG, L2-4 BMD, T-score L24, FN BMD, T-score FN, T2DM duration, the percentage of hypertension increased, and eGFR reduced, as BMD decreased. However, BMI, HDL, heart rate and the percentage of smokers, drinking, physical activity, and the proportion using statins and anti-diabetic drugs had no difference. The echocardiographic parameters of the subjects with T2DM are shown in Table 4. In terms of cardiac structure, interventricular septal diameter, LV posterior wall thickness, LV wall thickness, LV relative wall thickness, LV mass, LV mass index, and LA diameter increased gradually as BMD reduced. However, LV diameter in end diastole, LV diameter in end systole, and LV ejection fraction were not significantly different. In terms of LV diastolic function, E and E/A ratio decreased gradually and A velocity and E/E ratio increased gradually as BMD reduced. The prevalence of LV diastolic dysfunction was calculated in diabetic men with normal BMD, osteopenia, and osteoporosis (Fig. 1). Diastolic dysfunction was present in 45.5% of the
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Table 2 Echocardiographic features of the subjects with and without T2DM. Variables
T2DM (+)
Cardiac structure LVEDD (mm) LVESD (mm) IVSD (mm) LVPWT (mm) LVWT (mm) LVRWT LV mass (g) LV mass index (g/m2.7 ) LA diameter (mm) LV ejection fraction (%)
49.8 27.5 9.7 10.0 19.7 0.40 183.7 44.3 35.0 62.7
± ± ± ± ± ± ± ± ± ±
5.5 4.8 1.4 1.2 1.9 0.06 43.0 12.1 4.6 3.8
50.0 27.2 9.1 9.5 1 8.6 0.38 171.4 41.3 32.8 62.3
± ± ± ± ± ± ± ± ± ±
5.5 4.9 1.2 1.1 1.6 0.05 36.3 10.3 4.7 3.8
0.631 0.430 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.001 < 0.001 0.263
63.5 72.6 0.93 7.0 9.5
± ± ± ± ±
13.8 19.3 0.28 1.4 2.7
62.6 59.6 1.13 7.3 8.9
± ± ± ± ±
12.4 15.0 0.39 1.6 2.2
0.334 < 0.001 < 0.001 0.005 0.002
LV diastolic function E velocity (cm/s) A velocity (cm/s) E/A ratio E (cm/s) E/E ratio
T2DM (−)
P value
LV: left ventricular; LA: left atrial; LVEDD: LV diameter in end diastole; LVESD: LV diameter in end systole; IVSD: inter-ventricular septal diameter; LVPWT: LV posterior wall thickness; LVRWT: LV relative wall thickness; LVWT: LV wall thickness; E: the peak early diastolic transmitral flow velocity; A: the peak late diastolic transmitral flow velocity; E : the peak early diastolic mitral annular velocity. P value was calculated by the student’s t-test or Mann-Whitney U test or Chi2 test.
Fig. 1. The association between BMD and prevalence rate of left ventricular diastolic dysfunction (%). Male participants with T2DM were stratified into three groups: normal, osteopenia, and osteoporosis.
normal BMD group, in 64.2% of the osteopenia group and in 70.6% of the osteoporosis group (P < 0.001). The results indicated that the prevalence of LV diastolic dysfunction increased as BMD reduced in T2DM. The partial correlations between BMD and LV diastolic function parameters in T2DM are shown in Table 5. FN BMD was inversely correlated with E/E ratio, and positively correlated with E and E/A ratio even after age, BMI, drinking, smoking status, physical activity, SBP, DBP, FPG, TC, TG, HDL, LDL, eGFR, heart rate, haemoglobin A1c , and T2DM duration. In multivariable logistic regression analysis, there were significant associations between osteopenia or osteoporosis and LV
Table 3 Clinical characteristics of patients with T2DM. Variables
Normal BMD
Osteopenia
Osteoporosis
P value
Number Age (years) BMI (kg/m2 ) Smoker (n, %) Drinking (n, %) Physical activity (n, %) SBP (mmHg) DBP (mmHg) TC (mmol/L) TG (mmol/L) HDL (mmol/L) LDL (mmol/L) FPG (mmol/L) Hemoglobin A1c (%) Hemoglobin A1c (mmol/mol) Heart rate (bpm) L2-4 BMD (g/cm2 ) T-score L2-4 (SD) FN BMD (g/cm2 ) T-score FN (SD) eGFR (mL/min/1.73 m2 ) Hypertension (n, %) Statins (n, %) T2DM duration (years) Insulin (%) Sulfonylureas (%) Metformin (%) Acarbose (%) Glinides (%)
123 64.5 (9.3) 25.0 (3.3) 39 (31.7) 54 (43.9) 25 (20.3) 133.6 (12.0) 76.9 (9.5) 4.85 (0.87) 3.98 (3.25–4.51) 1.33 (1.07–1.51) 2.45 (0.83) 6.53 (6.10–6.96) 6.7 (0.9) 50 (9.8) 76.3 (12.7) 1.073 (0.199) −0.355 (0.333) 0.807 (0.124) −0.399 (0.360) 75.5 (15.4) 57 (46.3) 30 (24.4) 4.1 (2.2) 19 (15.4) 45 (36.6) 37 (30.1) 24 (19.5) 17 (13.8)
109 66.5 (9.2) 25.1 (3.4) 37 (33.9) 41 (37.6) 21 (19.3) 136.3 (9.9) 76.9 (7.7) 5.15 (1.09) 3.96 (3.52–4.74) 1.30 (1.09–1.54) 2.64 (0.84) 6.76 (6.26–7.45) 6.9 (0.8) 52 (8.7) 74.4 (13.1) 0.928 (0.268) −1.363 (0.678) 0.722 (0.132) −1.442 (0.638) 74.5 (16.0) 51 (46.8) 33 (30.3) 4.2 (2.1) 19 (17.4) 43 (39.4) 38 (34.9) 22 (20.2) 19 (17.4)
102 69.3 (8.8) 25.9 (3.2) 39 (38.2) 43 (42.2) 21 (20.6) 139.6 (10.9) 79.9 (8.6) 5.13 (0.95) 4.57 (3.60–5.06) 1.29 (1.13–1.43) 2.75 (0.88) 6.83 (6.32–7.35) 7.3 (1.2) 56 (13.1) 76.6 (12.4) 0.841 (0.162) −2.483 (0.851) 0.509 (0.188) −2.514 (0.663) 67.3 (15.1) 61 (59.8) 36 (35.3) 4.8 (1.5) 26 (25.5) 42 (41.2) 26 (25.5) 29 (28.4) 24 (23.5)
0.001 0.102 0.586 0.611 0.968 < 0.001 0.014 0.035 0.001 0.614 0.022 0.002 < 0.001 < 0.001 0.370 < 0.001 < 0.001 0.001 < 0.001 < 0.001 0.083 0.201 0.024 0.139 0.774 0.333 0.220 0.166
P value was calculated by one-way ANOVA test or Kruskal-Wallis H or Chi2 test. Abbreviations: see to Table 1.
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Table 4 Echocardiographic features of the subjects with T2DM. Variables
Normal BMD
Cardiac structure LVEDD (mm) LVESD (mm) IVSD (mm) LVPWT (mm) LVWT (mm) LVRWT LV mass (g) LV mass index (g/m2.7 ) LA diameter (mm) LV ejection fraction (%)
49.2 27.3 9.4 9.7 19.0 0.39 171.4 41.5 34.1 62.4
± ± ± ± ± ± ± ± ± ±
5.3 4.9 1.5 1.1 1.8 0.06 36.6 10.6 4.2 3.7
49.9 27.3 9.6 9.9 19.4 0.39 175.6 42.6 34.2 62.3
± ± ± ± ± ± ± ± ± ±
5.9 4.9 1.2 1.2 1.8 0.06 40.8 11.1 4.7 4.0
50.5 27.8 10.3 10.4 20.7 0.42 186.2 44.6 36.8 63.4
± ± ± ± ± ± ± ± ± ±
5.3 4.7 1.2 1.1 1.7 0.05 42.2 12.1 4.5 3.7
0.209 0.647 < 0.001 < 0.001 < 0.001 0.006 < 0.001 0.015 < 0.001 0.098
63.2 60.3 1.09 7.2 9.2
± ± ± ± ±
15.0 15.7 0.28 1.4 3.0
63.0 76.8 0.87 7.1 9.2
± ± ± ± ±
12.7 18.2 0.27 1.2 2.5
64.6 82.9 0.81 6.5 10.2
± ± ± ± ±
13.4 16.4 0.21 1.4 2.6
0.662 < 0.001 < 0.001 0.001 0.005
LV diastolic function E velocity (cm/s) A velocity (cm/s) E/A ratio E (cm/s) E/E ratio
Osteopenia
Osteoporosis
P value
P value was calculated by one-way ANOVA test or Kruskal-Wallis H or Chi2 test. Abbreviations: see to Table 2. Table 5 Partial correlation coefficient (r) for BMD in relation to LV diastolic function parameters in T2DM. Peak E
E/A ratio
L2-4 BMD FN BMD
E/E ratio
r
P value
r
P value
r
P value
0.217 0.215
< 0.001 < 0.001
0.069 0.132
0.219 0.018
−0.099 −0.166
0.078 0.003
Adjusted for age, BMI, drinking, smoking status, physical activity, SBP, DBP, FPG, TC, TG, HDL, LDL, eGFR, heart rate, hemoglobin A1c , and T2DM duration. Variables such as TG, HDL, and FPG were logarithmically transformed before statistical analysis. Abbreviations: see to Table 1.
diastolic dysfunction after adjustment for age, BMI, drinking, smoking status, and physical activity (Table 6, model 1). The associations between osteopenia or osteoporosis and LV diastolic dysfunction were little affected after further adjustment for SBP, DBP, FPG, TC, TG, HDL, and LDL (model 2). The Table 6 Multivariable logistic regression analysis for the risk of diastolic dysfunction. Variables

OR (95% CI)
P values
Model 1 Normal BMD Osteopenia Osteoporosis
Reference 0.773 1.016
– 2.168 (1.268–3.701) 2.762 (1.560–4.891)
– 0.005 < 0.001
Model 2 Normal BMD Osteopenia Osteoporosis
Reference 0.678 0.785
– 1.969 (1.121–3.458) 2.193 (1.206–3.987)
– 0.018 0.010
Model 3 Normal BMD Osteopenia Osteoporosis
Reference 0.675 0.693
– 1.964 (1.109–3.479) 2.000 (1.061–3.770)
– 0.021 0.032
OR: odds ratio; CI: confidence interval. Model 1: adjusted for age, BMI, drinking, smoking status, and physical activity. Model 2: adjusted for age, BMI, drinking, smoking status, physical activity, SBP, DBP, FPG, TC, TG, HDL, and LDL. Model 3: adjusted for age, BMI, drinking, smoking status, physical activity, SBP, DBP, FPG, TC, TG, HDL, LDL, eGFR, heart rate, hypertension, hemoglobin A1c , T2DM duration, and use of statins.
results did not substantially change after exclusion of eGFR, heart rate, hypertension, haemoglobin A1c , T2DM duration, and use of statins (model 3). However, no association between BMD and LV diastolic function was found in subjects without T2DM (data not shown). Multiple linear regression analysis was performed to assess the correlation between E/A or E/e ratio and BMD in Table 7. Table 7 Multivariate linear regression analysis with E/A ratio or E/E ratio as the dependent variables. Variables

P value
Model 1: E/A ratio as the dependent variable SBP (mmHg) −0.138 −0.124 Hemoglobin A1c (%) L2-4 BMD (g/cm2 ) 0.132 0.118 FN BMD (g/cm2 ) 0.075 eGFR (mL/min/1.73 m2 )
0.001 0.001 0.001 0.004 0.043
Model 2: E/E ratio as the dependent variable −0.152 FN BMD (g/cm2 ) 0.094 Hemoglobin A1c (%) 0.093 BMI (kg/m2 )
< 0.001 0.021 0.032
: standardized regression coefficient. The P-value for entry was set at 0.05, and the P-value for removal was set at 0.10. Adjusted R2 = 0.127, P < 0.001 for the model 1 and adjusted R2 = 0.029, P = 0.005 for model 2, respectively. TG, HDL, and FPG were log-transformed before statistical analysis. Abbreviations: see to Table 1.
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Seventeen variables, including age, BMI, drinking, smoking status, physical activity, SBP, DBP, TC, TG, HDL, LDL, FPG, eGFR, BMD, heart rate, and T2DM duration entered into the original multivariate model. The results revealed that BMD was a significant factor for E/A and E/e ratio in patients with T2DM. 4. Discussion In this study, we found that LV diastolic function parameters showed significant differences as BMD reduced in T2DM group. Furthermore, BMD at femoral neck was correlated with LV diastolic function parameters in T2DM after adjusting for confounding factors. Multivariable logistic regression analysis revealed that osteopenia and osteoporosis were independently associated with LV diastolic dysfunction in T2DM. Our study indicated that BMD is decreased in men with T2DM. However, the reports on BMD in T2DM revealed contradictory results with higher, lower or similar values in comparison with control subjects [13]. These conflicting data may be related to the differences in study design, BMD measurement technology, BMD examination sites, small sample sizes, and selection of patients. In addition, most of previous studies selected female patients and the number of male patients was small. Recent studies demonstrated that BMD was reduced in male patients with T2DM [14–16]. In accordance with previous results, we found that blood pressure and blood lipid increased gradually, and kidney function reduced gradually, as BMD decreased [17–19]. Some studies reported the prevalence of LV diastolic dysfunction in T2DM [20,21]. Moreover, HbA1c and insulin resistance are associated with abnormal LV structure and diastolic function [22,23]. Consistent to the results, we found that LV mass and relative wall thickness are increased, E/A and E are decreased in men with T2DM. The mechanisms between reduced BMD and LV diastolic dysfunction in male T2DM remain unclear. Firstly, oxidative stress plays a key role in osteoporosis and T2DM. Hyperglycaemia, insulin resistance, and inflammatory cytokines in T2DM may increase the generation of oxygen free radicals and reduce insulin sensitivity. In parallel, oxidative stress regulates the activity of osteoblasts and osteoclasts through FoxO transcription factors and Wnt/-catenin signalling pathway. Recent studies demonstrated oxidized lipids not only inhibit mineralization of bone cells, but also promote mineralization of vascular cells [24]. Currently, a report confirmed that both osteoporosis and preclinical LV diastolic dysfunction are related to insulin resistance and inflammation [25,26]. Secondly, the association is related to abnormal ventricular-vascular coupling due to arterial stiffness [27]. Recent reports documented that arterial stiffness is increased in osteoporosis and diabetes [28,29]. Although no independent association was found between arterial stiffness and BMD in men from the general population [30], some studies observed increased arterial stiffness is associated with reduced BMD in hypertensive patients [31,32]. Elevated arterial stiffness raises the LV afterload by elevating the systolic blood pressure [33]. Thirdly, declining sex steroid levels contributed to bone loss in men. Moreover, the reduced level of sex hormones was related to hyperglycaemia and the degree of hyperglycaemia was
directly associated with the duration of sex hormone suppression [34]. A recent study confirmed that low testosterone is correlated with cardiovascular risk factors and LV diastolic dysfunction in men with T2DM [35]. Our study has important clinical implications. Male osteoporosis remains under-diagnosed and under-treated. Patients with osteoporosis have a higher risk of cardiovascular diseases than the subjects with normal bone mass [5]. Moreover, chronic heart failure was associated with a 4-fold increased risk for osteoporotic fractures [36]. Recently, a study revealed that alendronate, one of bisphosphonates, may reduce the risk of heart failure compared to control subjects [37]. However, other bisphosphonate users were at increased risk of heart failure. Therefore, further research on bisphosphonate and heart failure are warranted. Our results found that BMD is independently associated with LV diastolic dysfunction in T2DM. Consistent with our results, Hisashi et al. showed that reduced BMD is associated with LV diastolic dysfunction in hypertension [6]. LV diastolic dysfunction represents the earliest preclinical manifestation of diabetic cardiomyopathy, preceding systolic dysfunction [38]. Therefore, early intervention may reduce the risk of cardiovascular diseases in diabetic patients with osteoporosis. The present study is not without limitations. First, the crosssectional design precludes any causal interpretation. Prospective studies are required to draw firm conclusions. Second, the study population is restricted to one region of the nation, which limits the generalizability of our findings. Third, the study is lacking information about parathyroid hormone, vitamin D, testosterone and sex hormone binding globulin. In conclusion, osteoporosis may be an independent factor for LV diastolic dysfunction in men with T2DM. Our data suggested that early detection of abnormal BMD should warrant for early search of undetected LV diastolic dysfunction in diabetic men. Disclosure of interest The authors declare that they have no competing interest. Acknowledgments This study was supported by Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Heilongjiang Province, China. References [1] Bella JN, Palmieri V, Roman MJ, Liu JE, Welty TK, Lee ET, et al. Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: the Strong Heart Study. Circulation 2002;105:1928–33. [2] Blomstrand P, Engvall M, Festin K, Lindstrom T, Lanne T, Maret E, et al. Left ventricular diastolic function, assessed by echocardiography and tissue Doppler imaging, is a strong predictor of cardiovascular events, superior to global left ventricular longitudinal strain, in patients with type 2 diabetes. Eur Heart J Cardiovasc Imaging 2015;16:1000–7 [LID - jev027 (pii)].
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[20] Boyer JK, Thanigaraj S, Schechtman KB, Perez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol 2004;93:870–5. [21] Fontes-Carvalho R, Ladeiras-Lopes R, Bettencourt P, Leite-Moreira A, Azevedo A. Diastolic dysfunction in the diabetic continuum: association with insulin resistance, metabolic syndrome and type 2 diabetes. Cardiovasc Diabetol 2015;14:4. [22] Chaudhary AK, Aneja GK, Shukla S, Razi SM. Study on diastolic dysfunction in newly diagnosed type 2 diabetes mellitus and its correlation with glycosylated haemoglobin (HbA1c ). J Clin Diagn Res 2015;9:OC20–2. [23] Bajraktari G, Koltai MS, Ademaj F, Rexhepaj N, Qirko S, Ndrepepa G, et al. Relationship between insulin resistance and left ventricular diastolic dysfunction in patients with impaired glucose tolerance and type 2 diabetes. Int J Cardiol 2006;110:206–11. [24] Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M, Dobnig H. Vascular calcification and osteoporosis–from clinical observation towards molecular understanding. Osteoporos Int 2007;18:251–9. [25] Dahiya R, Shultz SP, Dahiya A, Fu J, Flatley C, Duncan D, et al. Relation of reduced preclinical left ventricular diastolic function and cardiac remodeling in overweight youth to insulin resistance and inflammation. Am J Cardiol 2015;115:1222–8. [26] Xia J, Zhong Y, Huang G, Chen Y, Shi H, Zhang Z. The relationship between insulin resistance and osteoporosis in elderly male type 2 diabetes mellitus and diabetic nephropathy. Ann Endocrinol (Paris) 2012;73:546–51. [27] MacIsaac RJ, Thomas MC, Panagiotopoulos S, Smith TJ, Hao H, Matthews DG, et al. Association between intrarenal arterial resistance and diastolic dysfunction in type 2 diabetes. Cardiovasc Diabetol 2008;7:15. [28] Seo SK, Cho S, Kim HY, Choi YS, Park KH, Cho DJ, et al. Bone mineral density, arterial stiffness, and coronary atherosclerosis in healthy postmenopausal women. Menopause 2009;16:937–43. [29] Prenner SB, Chirinos JA. Arterial stiffness in diabetes mellitus. Atherosclerosis 2015;238:370–9. [30] Kim NL, Jang HM, Kim SK, Ko KD, Hwang IC, Suh HS. Association of arterial stiffness and osteoporosis in healthy men undergoing screening medical examination. J Bone Metab 2014;21:133–41. [31] Masugata H, Senda S, Inukai M, Murao K, Hosomi N, Iwado Y, et al. Association between bone mineral density and arterial stiffness in hypertensive patients. Tohoku J Exp Med 2011;223:85–90. [32] El-Bikai R, Tahir MR, Tremblay J, Joffres M, Seda O, Sedova L, et al. Association of age-dependent height and bone mineral density decline with increased arterial stiffness and rate of fractures in hypertensive individuals. J Hypertens 2015;33:727–35 [discussion 735]. [33] London GM, Guerin AP. Influence of arterial pulse and reflected waves on blood pressure and cardiac function. Am Heart J 1999;138:220–4. [34] Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000;23:490–4. [35] Culic V, Busic Z. Testosterone may influence left ventricular diastolic function depending on previous myocardial infarction and smoking. Int J Cardiol 2015;186:67–71. [36] van Diepen S, Majumdar SR, Bakal JA, McAlister FA, Ezekowitz JA. Heart failure is a risk factor for orthopedic fracture: a population-based analysis of 16,294 patients. Circulation 2008;118:1946–52. [37] Grove EL, Abrahamsen B, Vestergaard P. Heart failure in patients treated with bisphosphonates. J Intern Med 2013;274:342–50. [38] Cosson S, Kevorkian JP. Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy. Diabetes Metab 2003;29:455–66.
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Original article
Bone mineral density is associated with left ventricular diastolic function in men with type 2 diabetes R.-T. Wang a,1 , H.-T. Liu a,1 , Y.-L. Zhao b , N. Li c , T. Liu d , X. Kong e , K.-J. Yu a,∗ a
Department of Intensive Care Unit, Harbin Medical University, the Third Affiliated Hospital, Harbin, Heilongjiang, China b Harbin Medical University (Da Qing), Harbin, Heilongjiang, China c Department of Cardiology, Harbin Medical University, the Second Affiliated Hospital, Harbin, Heilongjiang, China d Division of Hypothalamic Research, UT Southwestern Medical Center, Department of Internal Medicine, 75390 Dallas, TX, USA e Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215 Boston, MA, USA Received 9 October 2015; received in revised form 4 February 2016; accepted 15 February 2016
Abstract Aims. – Type 2 diabetes (T2DM) is associated with chronic heart failure and cardiomyopathy. Furthermore, low bone mineral density (BMD) predicts incident heart failure. Abnormal diastolic function reflects early changes in cardiac function and plays a key role in the development of heart failure. The purpose of this study was to investigate the association between BMD with left ventricular (LV) diastolic function in men with T2DM. Methods. – In all, 344 men with T2DM and 331 age-matched control subjects were enrolled. BMD measurements were performed. LV diastolic function and structure were assessed by echocardiographic evaluation. Results. – BMD was lower in men with T2DM than in controls. There were significant differences in the level of parameters reflecting cardiac structure and LV diastolic function between two groups. Moreover, LV diastolic function and structure parameters also showed significant differences as BMD reduced in T2DM group. BMD at femoral neck was correlated with LV diastolic function parameters in T2DM after adjusting for confounding factors. Multivariable logistic analysis revealed that osteopenia and osteoporosis were associated with diastolic dysfunction compared to the control in men with T2DM. However, no association between BMD and LV diastolic function was found in subjects without T2DM. Conclusion. – Osteoporosis may be an independent factor for LV diastolic dysfunction in men with T2DM. Our data suggested that early detection of abnormal BMD should warrant for early search of undetected LV diastolic dysfunction in diabetic men. © 2016 Elsevier Masson SAS. All rights reserved. Keywords: Bone mineral density; Brachial-ankle pulse wave velocity; Left ventricular diastolic function; Type 2 diabetes
1. Introduction
Abbreviations: T2DM, type 2 diabetes; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; FPG, fasting plasma glucose; eGFR, estimated glomerular filtration rate; FN, femoral neck; BMD, bone mineral density. ∗ Corresponding author at: Department of Intensive Care Unit, Harbin Medical University, the Third Affiliated Hospital, NO.150 Haping ST, Nangang District, 150081 Harbin, China. Tel.: +86 451 86298036; fax: +86 451 86298036. E-mail address: kaijiang [email protected] (K.-J. Yu). 1 R.-T. Wang and H.-T. Liu contributed equally to this work.
Type 2 diabetes (T2DM) is associated with ischemic heart disease and chronic heart failure. Moreover, individuals with T2DM may develop cardiomyopathy independent of hypertension and coronary artery disease. Abnormal diastolic function reflects early changes in cardiac function and plays a key role in the development of heart failure. Recent studies have shown that left ventricular (LV) diastolic dysfunction is associated with cardiovascular outcomes and mortality [1,2]. In parallel, osteoporosis has been suggested as an independent risk factor for cardiovascular disease [3]. Low bone mineral density (BMD) increased cardiovascular mortality [4].
http://dx.doi.org/10.1016/j.diabet.2016.02.001 1262-3636/© 2016 Elsevier Masson SAS. All rights reserved.
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Furthermore, subjects with cardiovascular disease have a higher risk of bone loss and fracture [5]. Currently, literature has emerged that shows common underlying biological processes might contribute to vascular calcification and bone mineralization [5]. The conclusions on the relationship between BMD and LV diastolic dysfunction were inconsistent. A study reported that BMD is associated with LV diastolic dysfunction in men with hypertension [6]. Another study found that BMD is not an independent determinant of left ventricular mass index in men [7]. This inconsistency may be due to small sample sizes and selected populations. Recently, a study demonstrated that low BMD predicts incident heart failure in healthy individuals [8]. On the basis of these observations, we hypothesized that low BMD might be an index for diastolic dysfunction in T2DM. However, some of above studies used ultrasound of the calcaneum as a measure of osteoporosis, yet dual energy X-ray absorptiometry (DEXA) is the standard method recommended to diagnose osteoporosis [6–8]. In this study, we aim to evaluate the association between BMD measured by DEXA and LV diastolic function in men with T2DM. 2. Methods 2.1. Participants Between January 2013 to December 2013, 344 men with T2DM were enrolled in the cross-sectional study. A total of 331 age-matched control subjects were also studied. All participants were recruited from the International Physical Examination and Healthy Center in Harbin. Male subjects with type 2 diabetes aged 50–80 y were recruited. Control subjects were randomly selected from the International Physical Examination and Healthy Center and were age matched in 5-year age groups. We combined sequential recruitment strategy and opportunistic recruitment strategy in this study. The recruited subjects were free of complications linked to diabetes (retinopathy, neuropathy, and arterial disease) except incipient nephropathy. Exclusion criteria were cancer, autoimmune diseases, chronic obstructive pulmonary disease, chronic inflammatory disease, chronic renal failure, chronic heart failure, Cushing disease, thyroid disease, hypogonadism, fractures, coronary heart disease, stroke, atrial fibrillation, and medical treatment with glucocorticoid, any sex hormones, glitazone, bisphosphonates, vitamin D or calcium. Our institutional ethics committee approved the study protocol, and all study subjects gave written informed consent. 2.2. Clinical examination Clinical data include medical history, alcohol consumption, smoking status, current use of medication, physical examination, and laboratory test. Cigarette smoking was defined as having smoked at least 100 cigarettes in one’s lifetime. Alcohol drinking was defined as the consumption of at least 30 g of alcohol per week for 1 year or more. Regular leisure-time
physical activity was defined as participation in moderate or vigorous activity for 30 minutes or more per day at least 3 days a week. Blood pressure was measured using a mercury-gravity sphygmomanometer in the sitting position after a 15-min rest. Systolic and diastolic blood pressures were determined twice with a 10-min interval and mean values were used in the analysis. Body mass index was calculated as weight/height squared (kg/m2 ). 2.3. Biochemical analyses All blood samples were drawn after subjects had fasted over-night. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), fasting plasma glucose (FPG), calcium, phosphorus, albumin, and prealbumin were determined by standard laboratory methods (Modular Analytics, Roche, Mannheim, Germany). The glycated hemoglobin (HbA1c ) level was measured using high-performance liquid chromatography method (VariantTM II; Bio-Rad, Hercules, CA, USA). All measurements were conducted within 2 h of sampling. Diagnosis of type 2 diabetes (T2DM) was based on American Diabetes Association criteria such as fasting plasma glucose ≥ 7.0 mmol/L, current treatment with a hypoglycaemic agent, or casual glucose ≥ 11.1 mmol/L. The Modification of Diet in Renal Disease (MDRD) equation was used to estimate glomerular filtration rate (eGFR). MDRD equation was: eGFR = 186.3 × (SCr)−1.154 × (age)−0.203 . 2.4. BMD measurement BMD at lumbar spine (L2–L4) and femoral neck (FN) was measured using dual-energy X-ray absorptiometry (DPX-MD; LUNAR, GE, Madison, WI, USA). BMD was expressed as g/cm2 and as T-score. Osteopenia or osteoporosis was defined according to lowest measured T-score value in either spine or femoral neck. The method was validated in a previous report [9]. Diagnostic classification was based on the World Health Organization criteria: BMD T-score ≥ −1.0 is normal; > −2.5 and < −1.0 is low bone mass (osteopenia); and ≤ −2.5 is osteoporosis. 2.5. Echocardiographic examination Echocardiography was performed by standardized procedures with Philips iE33 (Philips Ultrasound, Bothell, WA). LV linear dimensions were measured according to the American Society of Echocardiography’s recommendations [10]. LV mass was calculated with a validated formula and indexed for height2.7 [11]. LV ejection fraction was calculated by biplane modified Simpson’s rule. The peak early diastolic transmitral flow velocity (E), peak late diastolic transmitral flow velocity (A), and E/A ratio were measured using pulsed-wave Doppler imaging of the mitral valve inflow from the apical 4-chamber view. Peak early diastolic mitral annular velocity (e ) was measured in the septal position using spectral Doppler imaging. The e wave velocities from the septal and lateral walls were averaged and the E/e ratio
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was calculated as an indicator of LV filling pressure. Diastolic dysfunction was defined as: • E/A ≤ 0.7 (impaired relaxation, grade I); • or 0.7 < E/A ≤ 1.5 and e < 7 cm/s (pseudo-normalized pattern, grade II); • or E/A > 1.5 and e < 7 cm/s (restrictive pattern, grade III) [12]. Echocardiograms were analysed by an experienced echocardiographer blinded to clinical data and functional status. 2.6. Statistical analysis All data were expressed as means ± SD or medians (interquartile range) for continuous variables and percentages of the number for categorical variables. When baseline characteristics between two groups were compared, normally distributed continuous variables were compared with the Student t test and skewed-distributed with the Mann-Whitney U test. When baseline characteristics among three groups were compared, normally distributed continuous variables were compared with the one-way ANOVA and skewed-distributed with Kruskal-Wallis H test. The Chi2 test was used for categorical variables. The categories of the participants comprised the following: normal, osteopenia, and osteoporosis. Partial correlation coefficients were used to determine the relationship between BMD and LV diastolic function parameters after adjustment for several confounders. The distributions of continuous variables were evaluated. TG, HDL, and FPG were logarithmically transformed prior to analysis. Multivariable logistic regression model was used to identify the independent association between osteopenia or osteoporosis and LV diastolic dysfunction. Multiple linear regression analysis was performed to assess the correlation between E/A or E/e ratio and BMD. P-values of 0.05 or less were considered to be statistically significant. All analyses were run using the SPSS software package version 22.0 (SPSS Inc., Chicago, IL, USA). 3. Results The characteristics of participants stratified by T2DM status are shown in Table 1. The groups were well matched with respect to age. Patients with T2DM were more centrally obese, and had a greater frequency of microalbuminuria and hypertension than those without T2DM. They also had lower HDL, L2-4 BMD, FN BMD and higher SBP, DBP, TC, TG, LDL, FPG, and HbA1c than their counterparts without T2DM. However, age, heart rate, eGFR, T-score L2-4, T-score FN, albumin, prealbumin, calcium, phosphorus, and the proportion of smokers, drinking, physical activity and use of statins had no difference. The cardiac structure and LV diastolic function of the subjects stratified by T2DM status are shown in Table 2. Significant differences in cardiac structure parameters (Interventricular septal diameter, LV posterior wall thickness, LV wall thickness, LV relative wall thickness, LV mass, LV mass index, and LA diameter) were observed between the groups. In terms of LV diastolic function, A velocity and E/E ratio were increased and E and E/A
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Table 1 Characteristics of the participants according to T2DM status. Variables
With T2DM
Without T2DM
P value
Number Age (years) BMI (kg/m2 ) Smoker (n, %) Drinking (n, %) Physical activity (n, %) SBP (mmHg) DBP (mmHg) TC (mmol/L) TG (mmol/L) HDL (mmol/L) LDL (mmol/L) Albumin (g/L) Prealbumin (mg/L) Calcium (mmol/L) Phosphorus (mmol/L) FPG (mmol/L) Hemoglobin A1c (%) Hemoglobin A1c (mmol/mol) Heart rate (bpm) eGFR (mL/min/1.73 m2 ) L2-4 BMD (g/cm2 ) T-score L2-4 (SD) FN BMD (g/cm2 ) T-score FN (SD) Hypertension (n, %) Statins (n, %) Microalbuminuria (n, %)
334 66.6 (9.3) 25.3 (3.3) 115.0 (34.4) 138.0 (41.3) 67.0 (20.1) 136.3 (11.3) 77.8 (8.8) 5.03 (0.98) 4.19 (3.40–4.78) 1.31 (1.11–1.49) 2.60 (0.86) 44.5 (3.2) 310.3 (26.2) 2.40 (0.10) 1.13 (0.32) 6.66 (6.25–7.15) 6.9 (1.0) 52 (10.9) 75.8 (12.7) 72.7 (15.9) 0.955 (0.235) −1.334 (1.081) 0.688 (0.194) −1.385 (1.031) 169 (50.6) 99 (29.6) 47 (14.1)
331 67.2 (9.4) 24.5 (3.3) 131.0 (39.6) 121.0 (36.6) 62.0 (18.7) 132.4 (10.2) 75.2 (8.6) 4.85 (1.01) 3.58 (3.09–4.30) 1.36 (1.18–1.50) 2.34 (0.90) 44.1 (3.2) 310.6 (34.1) 2.39 (0.11) 1.15 (0.34) 5.39 (5.01–5.68) 5.4 (0.7) 36 (7.7) 74.0 (12.8) 74.0 (15.0) 1.021 (0.214) −1.328 (1.231) 0.770 (0.169) −1.437 (1.115) 98 (29.6) 94 (28.4) 16 (4.8)
0.451 0.002 0.169 0.208 0.665 < 0.001 < 0.001 0 016 < 0.001 0.036 < 0.001 0.099 0.888 0.218 0.372 < 0.001 < 0.001 < 0.001 0.070 0.271 < 0.001 0.949 < 0.001 0.539 0.009 0.724 < 0.001
Data are shown as means (SD) or median (inter-quartile range) or percentage. T2DM: type 2 diabetes; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglyceride; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol; FPG: fasting plasma glucose; eGFR: estimated glomerular filtration rate; FN: femoral neck; BMD: bone mineral density. P value was calculated by the student’s t-test or Mann-Whitney U test or Chi2 test.
ratio were reduced in T2DM compared with control subjects. However, E velocity was not significantly different. The characteristics of subjects with normal BMD, osteopenia, and osteoporosis in T2DM are shown in Table 3. Mean age, SBP, DBP, TC, TG, LDL, FPG, L2-4 BMD, T-score L24, FN BMD, T-score FN, T2DM duration, the percentage of hypertension increased, and eGFR reduced, as BMD decreased. However, BMI, HDL, heart rate and the percentage of smokers, drinking, physical activity, and the proportion using statins and anti-diabetic drugs had no difference. The echocardiographic parameters of the subjects with T2DM are shown in Table 4. In terms of cardiac structure, interventricular septal diameter, LV posterior wall thickness, LV wall thickness, LV relative wall thickness, LV mass, LV mass index, and LA diameter increased gradually as BMD reduced. However, LV diameter in end diastole, LV diameter in end systole, and LV ejection fraction were not significantly different. In terms of LV diastolic function, E and E/A ratio decreased gradually and A velocity and E/E ratio increased gradually as BMD reduced. The prevalence of LV diastolic dysfunction was calculated in diabetic men with normal BMD, osteopenia, and osteoporosis (Fig. 1). Diastolic dysfunction was present in 45.5% of the
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Table 2 Echocardiographic features of the subjects with and without T2DM. Variables
T2DM (+)
Cardiac structure LVEDD (mm) LVESD (mm) IVSD (mm) LVPWT (mm) LVWT (mm) LVRWT LV mass (g) LV mass index (g/m2.7 ) LA diameter (mm) LV ejection fraction (%)
49.8 27.5 9.7 10.0 19.7 0.40 183.7 44.3 35.0 62.7
± ± ± ± ± ± ± ± ± ±
5.5 4.8 1.4 1.2 1.9 0.06 43.0 12.1 4.6 3.8
50.0 27.2 9.1 9.5 1 8.6 0.38 171.4 41.3 32.8 62.3
± ± ± ± ± ± ± ± ± ±
5.5 4.9 1.2 1.1 1.6 0.05 36.3 10.3 4.7 3.8
0.631 0.430 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.001 < 0.001 0.263
63.5 72.6 0.93 7.0 9.5
± ± ± ± ±
13.8 19.3 0.28 1.4 2.7
62.6 59.6 1.13 7.3 8.9
± ± ± ± ±
12.4 15.0 0.39 1.6 2.2
0.334 < 0.001 < 0.001 0.005 0.002
LV diastolic function E velocity (cm/s) A velocity (cm/s) E/A ratio E (cm/s) E/E ratio
T2DM (−)
P value
LV: left ventricular; LA: left atrial; LVEDD: LV diameter in end diastole; LVESD: LV diameter in end systole; IVSD: inter-ventricular septal diameter; LVPWT: LV posterior wall thickness; LVRWT: LV relative wall thickness; LVWT: LV wall thickness; E: the peak early diastolic transmitral flow velocity; A: the peak late diastolic transmitral flow velocity; E : the peak early diastolic mitral annular velocity. P value was calculated by the student’s t-test or Mann-Whitney U test or Chi2 test.
Fig. 1. The association between BMD and prevalence rate of left ventricular diastolic dysfunction (%). Male participants with T2DM were stratified into three groups: normal, osteopenia, and osteoporosis.
normal BMD group, in 64.2% of the osteopenia group and in 70.6% of the osteoporosis group (P < 0.001). The results indicated that the prevalence of LV diastolic dysfunction increased as BMD reduced in T2DM. The partial correlations between BMD and LV diastolic function parameters in T2DM are shown in Table 5. FN BMD was inversely correlated with E/E ratio, and positively correlated with E and E/A ratio even after age, BMI, drinking, smoking status, physical activity, SBP, DBP, FPG, TC, TG, HDL, LDL, eGFR, heart rate, haemoglobin A1c , and T2DM duration. In multivariable logistic regression analysis, there were significant associations between osteopenia or osteoporosis and LV
Table 3 Clinical characteristics of patients with T2DM. Variables
Normal BMD
Osteopenia
Osteoporosis
P value
Number Age (years) BMI (kg/m2 ) Smoker (n, %) Drinking (n, %) Physical activity (n, %) SBP (mmHg) DBP (mmHg) TC (mmol/L) TG (mmol/L) HDL (mmol/L) LDL (mmol/L) FPG (mmol/L) Hemoglobin A1c (%) Hemoglobin A1c (mmol/mol) Heart rate (bpm) L2-4 BMD (g/cm2 ) T-score L2-4 (SD) FN BMD (g/cm2 ) T-score FN (SD) eGFR (mL/min/1.73 m2 ) Hypertension (n, %) Statins (n, %) T2DM duration (years) Insulin (%) Sulfonylureas (%) Metformin (%) Acarbose (%) Glinides (%)
123 64.5 (9.3) 25.0 (3.3) 39 (31.7) 54 (43.9) 25 (20.3) 133.6 (12.0) 76.9 (9.5) 4.85 (0.87) 3.98 (3.25–4.51) 1.33 (1.07–1.51) 2.45 (0.83) 6.53 (6.10–6.96) 6.7 (0.9) 50 (9.8) 76.3 (12.7) 1.073 (0.199) −0.355 (0.333) 0.807 (0.124) −0.399 (0.360) 75.5 (15.4) 57 (46.3) 30 (24.4) 4.1 (2.2) 19 (15.4) 45 (36.6) 37 (30.1) 24 (19.5) 17 (13.8)
109 66.5 (9.2) 25.1 (3.4) 37 (33.9) 41 (37.6) 21 (19.3) 136.3 (9.9) 76.9 (7.7) 5.15 (1.09) 3.96 (3.52–4.74) 1.30 (1.09–1.54) 2.64 (0.84) 6.76 (6.26–7.45) 6.9 (0.8) 52 (8.7) 74.4 (13.1) 0.928 (0.268) −1.363 (0.678) 0.722 (0.132) −1.442 (0.638) 74.5 (16.0) 51 (46.8) 33 (30.3) 4.2 (2.1) 19 (17.4) 43 (39.4) 38 (34.9) 22 (20.2) 19 (17.4)
102 69.3 (8.8) 25.9 (3.2) 39 (38.2) 43 (42.2) 21 (20.6) 139.6 (10.9) 79.9 (8.6) 5.13 (0.95) 4.57 (3.60–5.06) 1.29 (1.13–1.43) 2.75 (0.88) 6.83 (6.32–7.35) 7.3 (1.2) 56 (13.1) 76.6 (12.4) 0.841 (0.162) −2.483 (0.851) 0.509 (0.188) −2.514 (0.663) 67.3 (15.1) 61 (59.8) 36 (35.3) 4.8 (1.5) 26 (25.5) 42 (41.2) 26 (25.5) 29 (28.4) 24 (23.5)
0.001 0.102 0.586 0.611 0.968 < 0.001 0.014 0.035 0.001 0.614 0.022 0.002 < 0.001 < 0.001 0.370 < 0.001 < 0.001 0.001 < 0.001 < 0.001 0.083 0.201 0.024 0.139 0.774 0.333 0.220 0.166
P value was calculated by one-way ANOVA test or Kruskal-Wallis H or Chi2 test. Abbreviations: see to Table 1.
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Table 4 Echocardiographic features of the subjects with T2DM. Variables
Normal BMD
Cardiac structure LVEDD (mm) LVESD (mm) IVSD (mm) LVPWT (mm) LVWT (mm) LVRWT LV mass (g) LV mass index (g/m2.7 ) LA diameter (mm) LV ejection fraction (%)
49.2 27.3 9.4 9.7 19.0 0.39 171.4 41.5 34.1 62.4
± ± ± ± ± ± ± ± ± ±
5.3 4.9 1.5 1.1 1.8 0.06 36.6 10.6 4.2 3.7
49.9 27.3 9.6 9.9 19.4 0.39 175.6 42.6 34.2 62.3
± ± ± ± ± ± ± ± ± ±
5.9 4.9 1.2 1.2 1.8 0.06 40.8 11.1 4.7 4.0
50.5 27.8 10.3 10.4 20.7 0.42 186.2 44.6 36.8 63.4
± ± ± ± ± ± ± ± ± ±
5.3 4.7 1.2 1.1 1.7 0.05 42.2 12.1 4.5 3.7
0.209 0.647 < 0.001 < 0.001 < 0.001 0.006 < 0.001 0.015 < 0.001 0.098
63.2 60.3 1.09 7.2 9.2
± ± ± ± ±
15.0 15.7 0.28 1.4 3.0
63.0 76.8 0.87 7.1 9.2
± ± ± ± ±
12.7 18.2 0.27 1.2 2.5
64.6 82.9 0.81 6.5 10.2
± ± ± ± ±
13.4 16.4 0.21 1.4 2.6
0.662 < 0.001 < 0.001 0.001 0.005
LV diastolic function E velocity (cm/s) A velocity (cm/s) E/A ratio E (cm/s) E/E ratio
Osteopenia
Osteoporosis
P value
P value was calculated by one-way ANOVA test or Kruskal-Wallis H or Chi2 test. Abbreviations: see to Table 2. Table 5 Partial correlation coefficient (r) for BMD in relation to LV diastolic function parameters in T2DM. Peak E
E/A ratio
L2-4 BMD FN BMD
E/E ratio
r
P value
r
P value
r
P value
0.217 0.215
< 0.001 < 0.001
0.069 0.132
0.219 0.018
−0.099 −0.166
0.078 0.003
Adjusted for age, BMI, drinking, smoking status, physical activity, SBP, DBP, FPG, TC, TG, HDL, LDL, eGFR, heart rate, hemoglobin A1c , and T2DM duration. Variables such as TG, HDL, and FPG were logarithmically transformed before statistical analysis. Abbreviations: see to Table 1.
diastolic dysfunction after adjustment for age, BMI, drinking, smoking status, and physical activity (Table 6, model 1). The associations between osteopenia or osteoporosis and LV diastolic dysfunction were little affected after further adjustment for SBP, DBP, FPG, TC, TG, HDL, and LDL (model 2). The Table 6 Multivariable logistic regression analysis for the risk of diastolic dysfunction. Variables

OR (95% CI)
P values
Model 1 Normal BMD Osteopenia Osteoporosis
Reference 0.773 1.016
– 2.168 (1.268–3.701) 2.762 (1.560–4.891)
– 0.005 < 0.001
Model 2 Normal BMD Osteopenia Osteoporosis
Reference 0.678 0.785
– 1.969 (1.121–3.458) 2.193 (1.206–3.987)
– 0.018 0.010
Model 3 Normal BMD Osteopenia Osteoporosis
Reference 0.675 0.693
– 1.964 (1.109–3.479) 2.000 (1.061–3.770)
– 0.021 0.032
OR: odds ratio; CI: confidence interval. Model 1: adjusted for age, BMI, drinking, smoking status, and physical activity. Model 2: adjusted for age, BMI, drinking, smoking status, physical activity, SBP, DBP, FPG, TC, TG, HDL, and LDL. Model 3: adjusted for age, BMI, drinking, smoking status, physical activity, SBP, DBP, FPG, TC, TG, HDL, LDL, eGFR, heart rate, hypertension, hemoglobin A1c , T2DM duration, and use of statins.
results did not substantially change after exclusion of eGFR, heart rate, hypertension, haemoglobin A1c , T2DM duration, and use of statins (model 3). However, no association between BMD and LV diastolic function was found in subjects without T2DM (data not shown). Multiple linear regression analysis was performed to assess the correlation between E/A or E/e ratio and BMD in Table 7. Table 7 Multivariate linear regression analysis with E/A ratio or E/E ratio as the dependent variables. Variables

P value
Model 1: E/A ratio as the dependent variable SBP (mmHg) −0.138 −0.124 Hemoglobin A1c (%) L2-4 BMD (g/cm2 ) 0.132 0.118 FN BMD (g/cm2 ) 0.075 eGFR (mL/min/1.73 m2 )
0.001 0.001 0.001 0.004 0.043
Model 2: E/E ratio as the dependent variable −0.152 FN BMD (g/cm2 ) 0.094 Hemoglobin A1c (%) 0.093 BMI (kg/m2 )
< 0.001 0.021 0.032
: standardized regression coefficient. The P-value for entry was set at 0.05, and the P-value for removal was set at 0.10. Adjusted R2 = 0.127, P < 0.001 for the model 1 and adjusted R2 = 0.029, P = 0.005 for model 2, respectively. TG, HDL, and FPG were log-transformed before statistical analysis. Abbreviations: see to Table 1.
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Seventeen variables, including age, BMI, drinking, smoking status, physical activity, SBP, DBP, TC, TG, HDL, LDL, FPG, eGFR, BMD, heart rate, and T2DM duration entered into the original multivariate model. The results revealed that BMD was a significant factor for E/A and E/e ratio in patients with T2DM. 4. Discussion In this study, we found that LV diastolic function parameters showed significant differences as BMD reduced in T2DM group. Furthermore, BMD at femoral neck was correlated with LV diastolic function parameters in T2DM after adjusting for confounding factors. Multivariable logistic regression analysis revealed that osteopenia and osteoporosis were independently associated with LV diastolic dysfunction in T2DM. Our study indicated that BMD is decreased in men with T2DM. However, the reports on BMD in T2DM revealed contradictory results with higher, lower or similar values in comparison with control subjects [13]. These conflicting data may be related to the differences in study design, BMD measurement technology, BMD examination sites, small sample sizes, and selection of patients. In addition, most of previous studies selected female patients and the number of male patients was small. Recent studies demonstrated that BMD was reduced in male patients with T2DM [14–16]. In accordance with previous results, we found that blood pressure and blood lipid increased gradually, and kidney function reduced gradually, as BMD decreased [17–19]. Some studies reported the prevalence of LV diastolic dysfunction in T2DM [20,21]. Moreover, HbA1c and insulin resistance are associated with abnormal LV structure and diastolic function [22,23]. Consistent to the results, we found that LV mass and relative wall thickness are increased, E/A and E are decreased in men with T2DM. The mechanisms between reduced BMD and LV diastolic dysfunction in male T2DM remain unclear. Firstly, oxidative stress plays a key role in osteoporosis and T2DM. Hyperglycaemia, insulin resistance, and inflammatory cytokines in T2DM may increase the generation of oxygen free radicals and reduce insulin sensitivity. In parallel, oxidative stress regulates the activity of osteoblasts and osteoclasts through FoxO transcription factors and Wnt/-catenin signalling pathway. Recent studies demonstrated oxidized lipids not only inhibit mineralization of bone cells, but also promote mineralization of vascular cells [24]. Currently, a report confirmed that both osteoporosis and preclinical LV diastolic dysfunction are related to insulin resistance and inflammation [25,26]. Secondly, the association is related to abnormal ventricular-vascular coupling due to arterial stiffness [27]. Recent reports documented that arterial stiffness is increased in osteoporosis and diabetes [28,29]. Although no independent association was found between arterial stiffness and BMD in men from the general population [30], some studies observed increased arterial stiffness is associated with reduced BMD in hypertensive patients [31,32]. Elevated arterial stiffness raises the LV afterload by elevating the systolic blood pressure [33]. Thirdly, declining sex steroid levels contributed to bone loss in men. Moreover, the reduced level of sex hormones was related to hyperglycaemia and the degree of hyperglycaemia was
directly associated with the duration of sex hormone suppression [34]. A recent study confirmed that low testosterone is correlated with cardiovascular risk factors and LV diastolic dysfunction in men with T2DM [35]. Our study has important clinical implications. Male osteoporosis remains under-diagnosed and under-treated. Patients with osteoporosis have a higher risk of cardiovascular diseases than the subjects with normal bone mass [5]. Moreover, chronic heart failure was associated with a 4-fold increased risk for osteoporotic fractures [36]. Recently, a study revealed that alendronate, one of bisphosphonates, may reduce the risk of heart failure compared to control subjects [37]. However, other bisphosphonate users were at increased risk of heart failure. Therefore, further research on bisphosphonate and heart failure are warranted. Our results found that BMD is independently associated with LV diastolic dysfunction in T2DM. Consistent with our results, Hisashi et al. showed that reduced BMD is associated with LV diastolic dysfunction in hypertension [6]. LV diastolic dysfunction represents the earliest preclinical manifestation of diabetic cardiomyopathy, preceding systolic dysfunction [38]. Therefore, early intervention may reduce the risk of cardiovascular diseases in diabetic patients with osteoporosis. The present study is not without limitations. First, the crosssectional design precludes any causal interpretation. Prospective studies are required to draw firm conclusions. Second, the study population is restricted to one region of the nation, which limits the generalizability of our findings. Third, the study is lacking information about parathyroid hormone, vitamin D, testosterone and sex hormone binding globulin. In conclusion, osteoporosis may be an independent factor for LV diastolic dysfunction in men with T2DM. Our data suggested that early detection of abnormal BMD should warrant for early search of undetected LV diastolic dysfunction in diabetic men. Disclosure of interest The authors declare that they have no competing interest. Acknowledgments This study was supported by Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Heilongjiang Province, China. References [1] Bella JN, Palmieri V, Roman MJ, Liu JE, Welty TK, Lee ET, et al. Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: the Strong Heart Study. Circulation 2002;105:1928–33. [2] Blomstrand P, Engvall M, Festin K, Lindstrom T, Lanne T, Maret E, et al. Left ventricular diastolic function, assessed by echocardiography and tissue Doppler imaging, is a strong predictor of cardiovascular events, superior to global left ventricular longitudinal strain, in patients with type 2 diabetes. Eur Heart J Cardiovasc Imaging 2015;16:1000–7 [LID - jev027 (pii)].
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Please cite this article in press as: Wang R-T, et al. Bone mineral density is associated with left ventricular diastolic function in men with type 2 diabetes. Diabetes Metab (2016), http://dx.doi.org/10.1016/j.diabet.2016.02.001