Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

Aims/hypothesis  

Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes.     

Myocardial dysfunction in mitochondrial diabetes treated with Coenzyme Q10

Maternally-inherited diabetes and deafness (MIDD) has been related to an A to G transition in the mitochondrial tRNA Leu (UUR) gene at the base pair 3243. Although some previous articles have reported that this mutation may be a cause of cardiomyopathy in diabetes, the degree of cardiac involvement and a specific treatment has not been established. Here, we reported a case of a patient with MIDD who developed congestive heart failure and the therapeutic usefulness of Coenzyme Q10 (CoQ10). In our patient, after the introduction of Coenzyme Q10 150 mg/day, there was a gradual improvement on left ventricular function evaluated by echocardiography. The fractional shortening (FS) and ejection fraction (EF) increased from 26 to 34% and from 49 to 64%, respectively. No side effects were noted. Three months after CoQ10 discontinuation, the parameters of systolic function evaluated by echocardiography decreased, suggesting that CoQ10 had a beneficial effect. Identification of diabetes and cardiomyopathy due to mitochondrial gene mutation may have therapeutic implications and Coenzyme Q10 is a possible adjunctive treatment in such patients.     

Allopurinol attenuates oxidative stress and cardiac fibrosis in angiotensin II-induced cardiac diastolic dysfunction

Aims: Oxidative stress and fibrosis is implicated in cardiac remodeling and failure. We tested whether allopurinol could decrease myocardial oxidative stress and attenuate cardiac fibrosis and left ventricular diastolic dysfunction in angiotensin II (AngII)‐induced hypertensive mice. Methodology: We used 8‐week‐old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or allopurinol in daily doses, which did not lower blood pressure. Results: Allopurinol improved diastolic dysfunction in angiotensin II‐induced hypertensive mice, which was associated with the amelioration of cardiac fibrosis. However, allopurinol showed no effect on the increased systolic blood pressure by angiotensin II infusion. The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) [GSH/GSSG] was decreased and malondialdehyde levels were increased in the hearts of AngII‐treated mice. Allopurinol also inhibited both the decrease in the GSH/GSSG ratio and the increase in malondialdehyde levels in the heart. Infusion of AngII‐induced upregulation of transfer growth factor (TGF)‐β1, Smad3 expression and downregulation of Smad7 expression. Treatment with allopurinol reduced cardiac levels of TGF‐β1, Smad3, and increased Smad7 expression. Conclusions: These results suggest that allopurinol prevents pathological remodeling of the heart in AngII‐induced hypertensive mice. The antioxidative effect of allopurinol contributes to the regression of AngII‐induced cardiac diastolic dysfunction. These effects of allopurinol to prevent cardiac fibrosis are mediated at least partly through modulation of the TGF‐β1/Smad signaling pathway.     

Coenzyme Q10 attenuates the progression of cardiomyopathy in hamsters

Coenzyme Q10 (10 mg/kg/day) or digoxin (2 micrograms/kg/day) was given orally to cardiomyopathic hamsters (BIO 14.6) for 8 weeks from 12 weeks of age. The left ventricular weight per gram of body weight (mg/g) was lower (p less than 0.01) in the coenzyme Q10 group (3.09 +/- 0.13) than in the digoxin (3.32 +/- 0.20) and control (3.44 +/- 0.14) groups. Left ventricular function was evaluated in isovolumically beating hearts. Left ventricular developed pressure (63 +/- 5 vs. 54 +/- 10 mmHg, p less than 0.05), -dP/dt (1385 +/- 100 vs. 1211 +/- 136 mmHg/sec, p less than 0.05), and -dP/dt (1068 +/- 126 vs. 896 +/- 141 mmHg/sec, p less than 0.05) were greater in the coenzyme Q10 than in the control group. The time constant of left ventricular relaxation was shorter in the coenzyme Q10 group than in the control group (25 +/- 3 vs. 28 +/- 3 msec, p less than 0.05). By contrast, in the digoxin group, the indices of left ventricular function did not differ from the control group. These results suggest that coenzyme Q10, but not digoxin, attenuated disease progression and preserved left ventricular function in cardiomyopathic hamsters.     

Coenzyme Q10 improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus

Aim/hypothesis: We assessed whether dietary supplementation with coenzyme Q₁₀ improves endothelial function of the brachial artery in patients with Type II (non-insulin-dependent) diabetes mellitus and dyslipidaemia. Methods: A total of 40 patients with Type II diabetes and dyslipidaemia were randomized to receive 200 mg of coenzyme Q₁₀ or placebo orally for 12 weeks. Endothelium-dependent and independent function of the brachial artery was measured as flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation, respectively. A computerized system was used to quantitate vessel diameter changes before and after intervention. Arterial function was compared with 18 non-diabetic subjects. Oxidative stress was assessed by measuring plasma F₂-isoprostane concentrations, and plasma antioxidant status by oxygen radical absorbance capacity. Results: The diabetic patients had impaired flow-mediated dilation [3.8 % (SEM 0.5) vs 6.4 % (SEM 1.0), p = 0.016], but preserved glyceryl-trinitrate-mediated dilation, of the brachial artery compared with non-diabetic subjects. Flow-mediated dilation of the brachial artery increased by 1.6 % (SEM 0.3) with coenzyme Q₁₀ and decreased by –0.4 % (SEM 0.5) with placebo (p = 0.005); there were no group differences in the changes in pre-stimulatory arterial diameter, post-ischaemic hyperaemia or glyceryl-trinitrate-mediated dilation response. Coenzyme Q₁₀ treatment resulted in a threefold increase in plasma coenzyme Q₁₀ (p < 0.001) but did not alter plasma F₂-isoprostanes, oxygen radical absorbance capacity, lipid concentrations, glycaemic control or blood pressure. Conclusion/interpretation: Coenzyme Q₁₀ supplementation improves endothelial function of conduit arteries of the peripheral circulation in dyslipidaemic patients with Type II diabetes. The mechanism could involve increased endothelial release and/or activity of nitric oxide due to improvement in vascular oxidative stress, an effect that might not be reflected by changes in plasma F₂-isoprostane concentrations. [Diabetologia (2002) 45: 420–426] Received: 14 August 2001 and in revised form: 15 November 2001     

CCN2/CTGF attenuates myocardial hypertrophy and cardiac dysfunction upon chronic pressure-overload

Background

Myocardial CCN2/CTGF (connective tissue growth factor) is strongly induced in heart failure (HF) and acts as a cardioprotective factor in ischemia/reperfusion injury. However, its functional role in myocardial hypertrophy remains unresolved.

Methods and results

Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate control (NLC) mice were subjected to chronic pressure-overload by abdominal aortic banding. After 4 weeks of persistent pressure-overload, a time point at which compensatory hypertrophy of the left ventricle (LV) prevails, Tg-CTGF mice displayed diminished increase of LV mass compared with NLC. At study end-point after 12 weeks of sustained aortic constriction, the mice displayed LV dilatation and reduced cardiac function. Repeated transthoracic echocardiography during the 12 weeks of chronic pressure-overload, revealed attenuation of LV dilatation and virtually sustained systolic function in Tg-CTGF mice compared with NLC mice. Also, increase of LV mass was blunted in Tg-CTGF versus NLC mice at study end-point. Consistently, increases of myocardial ANP, BNP and skeletal α-actin mRNA levels were blunted in Tg-CTGF mice subjected to chronic pressure-overload. Furthermore, cardiac myocytes from Tg-CTGF mice displayed increased phospho-NFATc2 levels and attenuated hypertrophic response upon stimulation with α₁-adrenoceptor agonist, indicating that CTGF attenuates hypertrophic signaling in cardiac myocytes. Increase of myocardial collagen contents in mice subjected to aortic banding was similar in Tg-CTGF and NLC mice, indicating that CTGF have minimal impact on myocardial collagen deposition.

Conclusion

This study provides novel evidence that CTGF attenuates cardiac hypertrophy upon chronic pressure-overload due to inhibition of signaling mechanisms that promote pathologic myocardial hypertrophy.     

Whole blood aggregation and coagulation in db/db and ob/ob mouse models of type 2 diabetes

Type 2 diabetes in humans is associated with a significant hypercoagulable state; however, the effects of this on stroke and cardiovascular disease are not completely understood. The genetic mutations in db/db and ob/ob mice produce metabolic abnormalities similar to type 2 diabetes, but little is known about their platelet or coagulation properties. The objective of this study was therefore to examine platelet function and coagulation in db/db and ob/ob mice to determine the degree of alteration induced by type 2 diabetes. Male db/db and ob/ob mice, 8-16 weeks old, and their respective genetic control mice were used for all experiments. To examine platelet function and coagulation, we measured ADP-induced whole blood aggregation at baseline and after inhibition with aspirin and fucoidan, whole blood coagulation by thromboelastography, and platelet CD61 expression by flow cytometry. Both db/db and ob/ob mice demonstrated significantly less ADP-induced whole blood aggregation compared with control mice (db/db mice, P < 0.001; ob/ob mice, P < 0.01). Aggregation was significantly inhibited with aspirin in all groups; however, fucoidan inhibited aggregation only in control mice. The db/db and ob/ob mice demonstrated significantly less maximal clot strength compared with control mice (P < 0.01), and ob/ob mice demonstrated premature clot fibrinolysis measured by thromboelastography. In conclusion, the db/db and ob/ob type 2 diabetes mouse models do not demonstrate a hypercoagulable state similar to humans with this disease. We caution their use for studying cardiovascular and cerebrovascular disease in the setting of type 2 diabetes.     

不同血糖控制水平对2型糖尿病患者左室结构和功能的影响

目的 探讨不同血糖控制水平对2型糖尿病患者左室结构和功能的影响。方法 选择2009年9月~2011年1月于巴中市中心医院就诊的2型糖尿病患者40例作为糖尿病组,另选择性别年龄匹配的健康志愿者40例为正常对照组。对糖尿病组患者进行规范化治疗,观察期24个月,比较治疗前后患者左室结构和功能的超声学参数。随访末,根据血糖控制水平将糖尿病组分为良好组(HbA1c<7.6%,n=17)、中等组(7.6%≤HbA1c≤9%,n=14)和不良组(HbA1c>9%,n=9) 3个亚组,比较随访前后3组的超声学参数的变化。结果 在基线水平糖尿病等容舒张期时间（IVRT）糖尿病组明显高于对照组(P<0.05),E/A低于对照组(P<0.05),两组在室间隔厚度（IVS）、左室后壁厚度（LVPW）、左室舒张末内径（LVEDD）及左室收缩功能等方面差异无统计学意义;随访前后,血糖控制良好组左室结构和功能超声参数差异无统计学意义;中等组和不良组不同程度地出现IVS、LVPW及左室质量指数(LVMI)增加, IVRT延长和E/A降低,差异均有统计学意义(P<0.05)。结论 2型糖尿病患者容易发生左室舒张功能减退,积极控制血糖可以延缓左室肥厚的发生,但不能改善左室舒张功能,血糖控制不良会加速左室重构和加重左室舒张功能不全。     

Coenzyme Q10: contractile dysfunction of the myocardial cell and metabolic therapy]

Coenzyme Q10, a mitoquinone involved in mitochondrial energy synthesis and the removal of free radicals, may be lacking in a number of cardiac pathologies leading to reduced contractile activity. The administration of exogenous coenzyme Q10 may help to improve contractile activity. In order to assess this hypothesis 63 patients suffering from altered myocardial contractile function (29 dilated cardiopathies, 15 valvular cardiopathies, 19 ischemic cardiopathies) which presented a NYHA class above 2 were selected. The study was open and patients were subdivided into two groups, one of which received conventional therapy alone whereas the other also received exogenous coenzyme Q10. After 4 months of follow-up clinical (NYHA class, effort tolerance) and echocardiographical (ventricular diameter and contraction fraction %) parameters were evaluated. In those patients treated with coenzyme Q10 and suffering from dilated cardiomyopathy a significant reduction in the NYHA class and a marked improvement in echocardiographic parameters were observed at the end of this period. The variations observed in other groups of patients treated were less conspicuous and not always statistically significant. The results of this study confirm that the association of coenzyme Q10 and conventional therapy may lad to a marked improvement in contractile function and correlated clinical conditions.     

Heart rate variability and diastolic dysfunction in patients with type 2 diabetes mellitus

Cardiovascular autonomic neuropathy is a common form of autonomic dysfunction in diabetes mellitus (DM) and associates abnormalities in heart rate control and in vascular dynamics. This study evaluates the impact of diabetes mellitus on left ventricular diastolic dysfunction (LVDD) and heart rate variability in a group of type 2 diabetes mellitus without signs of cardiovascular disease. The study group consisted of 58 patients, aged 61 ± 8 years, diagnosed with type 2 DM. The subjects were selected from a series of 104 consecutive diabetic patients. All the subjects were on oral therapy or on diet for DM, and ECG was normal for all the subjects. The control group consisted of 45 healthy subjects, matched for age and sex. Heart rate variability was measured using a 24-h ECG monitoring system, and standard 2D and Doppler echocardiography was performed in all the subjects. There are significant differences between groups regarding disease duration, longer in patients with impaired relaxation (11.22 ± 9.17 vs. 8.31 ± 8.95 years), and disease control, worse in impaired relaxation group. Heart rate in impaired relaxation group is significantly higher than in controls, and higher, but not significantly, when compared with normal group (91 ± 10, vs. 88 ± 11 and 71 ± 11, respectively). Cardiac autonomic neuropathy was associated with LVDD in patients with type 2 DM, but without clinically manifest heart disease. Twenty-four-hour ECG monitoring and echocardiography can detect diabetic cardiomyopathy in early stages and should be performed in all subjects.     

Prevalence of diastolic dysfunction in normotensive, asymptomatic patients with well-controlled type 2 diabetes mellitus

To evaluate the prevalence of left ventricular (LV) diastolic dysfunction in patients with type 2 diabetes mellitus free of cardiovascular disease, we studied 86 normotensive men and women (mean age 46 +/- 6 years) with Doppler echocardiography. All subjects were asymptomatic for ischemic heart disease or heart failure. The traditional transmitral filling patterns were used to characterize diastolic physiology. The Valsalva maneuver was used to differentiate normal from pseudonormal LV filling pattern. All patients had a normal electrocardiogram at rest and a negative result on exercise echocardiography for inducible wall motion abnormalities. Global LV systolic function was normal (mean LV ejection fraction 58%, range 53% to 76%). Diastolic dysfunction was found in 41 subjects (47%) of which 26 (30%) had impaired relaxation and 15 (17%) had a pseudonormal filling pattern. The mean LV mass index was 101 g/m2 (range 86 to 122). All patients with a normal-filling physiology had gender-adjusted normal LV mass index (mean 93 +/- 11 g/m2), whereas 62% of those with either abnormal relaxation (mean 103 +/- 12 g/m2, p <0.001) or a pseudonormal pattern (mean 110 +/- 12 g/m2, p <0.001) had increased LV mass index. No subject in this cohort had restrictive diastolic physiology. In conclusion, diastolic dysfunction in type 2 diabetes mellitus patients is often found despite adequate metabolic control and freedom from clinically detectable heart disease. The Valsalva maneuver can unmask an additional 17% of patients with subclinical abnormal LV filling pattern, who otherwise would be classified as having a normal diastolic physiology. Increased LV mass index is closely associated with abnormal LV filling characteristics.     

The relationship of cardiac diastolic dysfunction to concurrent hormonal and metabolic status in type I diabetes mellitus

The presence of diabetic cardiomyopathy and its relationship to concurrent hormonal and metabolic status have not been defined in patients with uncomplicated type I diabetes mellitus. Accordingly, radionuclide left ventricular angiograms and simultaneous metabolic profiles were obtained in 8 type I diabetic patients who had no major diabetic complications and in 11 normal subjects. Occult coronary artery disease was excluded by electrocardiogram exercise testing. Hemodynamics and systolic function did not differ between the groups. However, the peak filling rate (PFR; end-diastolic volumes per s) was less in the diabetic patients at rest [mean, 4.1 +/- 0.2 (+/- SE) vs. 4.8 +/- 0.2; P less than 0.05] and during aerobic (6.8 +/- 0.2 vs. 8.30 +/- 0.3; P less than 0.01) and anaerobic exercise (8.8 +/- 0.3 vs. 9.8 +/- 0.4; P less than 0.05). The time to PFR was prolonged in the diabetic patients at rest (174 +/- 10 vs. 133 +/- 7 ms; P less than 0.01) and during anaerobic exercise (126 +/- 5 vs. 103 +/- 6 ms; P less than 0.01). Plasma glucose and insulin levels were elevated in the diabetic patients at rest and during exercise. Otherwise, the metabolic and hormonal levels did not differ between the groups. In the diabetic patients, no single metabolic or hormonal parameter correlated with PFR or time to PFR. Impairment of diastolic filling also did not correlate with level of glycosylated hemoglobin or duration of diabetes. The alteration in diastolic filling present in type I diabetic patients who have no other diabetic complications may represent the earliest functional effect of diabetic cardiomyopathy.     

Quantitative investigation of cardiomyocyte hypertrophy and myocardial fibrosis over 6 years after cardiac transplantation

Objectives. This study was performed to determine the degree and time course over 6 years of cardiomyocyte hypertrophy and myocardial fibrosis of the cardiac allograft in transplanted patients.Background. Diastolic dysfunction and to a certain extent systolic dysfunction are common cardiac findings after heart transplantation. The development of posttransplant cardiomyocyte hypertrophy and myocardial fibrosis likely contributes to these derangements.Methods. Cardiomyocyte diameter and percent fibrosis were determined in serial endomyocardial biopsy specimens obtained from 1 month up to 6 years following heart transplantation in 50 patients. Endomyocardial biopsy specimens from 40 patients with primary dilated cardiomyopathy and 11 normal subjects were similarly analyzed for control data. Analyses were performed in a blinded format using a validated computerized image analysis system (Optimas 5.2).Results. Early (1 month) cardiomyocyte enlargement decreased to the smallest diameter 6 months posttransplant, but thereafter progressively increased by 10% to 20% over the subsequent 5- to 6-year period. Although not statistically established, principal stimuli may include a discrepancy in body size (recipient > donor), coronary allograft vasculopathy and posttransplant systemic hypertension. Percent myocardial fibrosis rose early (1 to 2 months) posttransplant and thereafter remained at the same modest level of severity.Conclusions. Cardiomyocyte diameter of the transplanted heart gradually increases over time, while percent myocardial fibrosis rises early and remains in a modestly elevated plateau after 2 months posttransplant. These histostructural changes likely contribute to the hemodynamic and cardiac functional alterations commonly observed posttransplant.     

Regression of cardiac hypertrophy in type 2 diabetes with hypertension by candesartan

This study was designed to compare the effect of candesartan on cardiac left ventricular mass in Japanese patients with that of amlodipine. A total of 40 type 2 diabetic patients with hypertension and left ventricular hypertrophy (LVH) were randomly assigned to receive candesartan (n=20) or amlodipine (n=20). The two treatments when administered for 6 months significantly reduced systolic and diastolic blood pressures (BPs) to a comparable extent. Notably, candesartan significantly reduced left ventricular mass index (LVMI: from 131.5+/-4.5 to 112.1+/-5.9g/m(2), P=0.0009, M+/-S.E.M.), LV posterior wall thickness (PWTd: from 10.3+/-0.3 to 9.1+/-0.3mm, P=0.0052) and interventricular septal thickness (IVSTd: from 10.7+/-0.4 to 9.3+/-0.4mm, P=0.0019) as determined by echocardiography in diastole, but amlodipine treatment did not. LVMI, PWTd and IVSTd were decreased more significantly by the treatment with candesartan than by that with amlodipine (P=0.020, 0.031 and 0.043). The present study thus revealed that candesartan effectively induced regression of LVH in type 2 diabetic patients with hypertension due to effects beyond reduction in BP.     

Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats

We tested the hypothesis that long-term growth hormone (GH) replacement in aged rats would preserve diastolic function and attenuate left ventricular remodeling associated with normal aging. Male Brown Norway x F344 rats were randomized to receive twice daily injections of porcine GH (200 microg/injection, subcutaneous) or saline from 24 to 30 months of age. Adult rats (6- to 9-months old) received saline injections throughout the study. Thirty-month-old, saline-treated rats exhibited low levels of insulin-like growth factor 1 (IGF-1), impaired diastolic left ventricular filling (Doppler), increased cardiac angiotensin II (Ang II), reduced plasma Ang II, and increased cardiac collagen. GH administration in old rats restored IGF-1 and diastolic indices to values comparable to those of adults. These effects were associated with reduced cardiac Ang II and attenuations in cardiac collagen. Age-related decreases in GH and IGF-1 may contribute to the decline in diastolic function of aging, in part through alterations in renin-angiotensin system-mediated ventricular remodeling.     

Association of arterial wave properties and diastolic dysfunction in patients with type 2 diabetes mellitus

Left ventricular (LV) diastolic dysfunction and increased arterial stiffness are prevalent in patients with type 2 diabetes mellitus (DM). Because the systemic vasculature plays a pivotal role in myocardial loading, this study aimed to determine the effect of arterial characteristics on LV diastolic function in patients with type 2 DM. Conventional echocardiography and tissue Doppler imaging were performed in 155 patients with type 2 DM (88 men; mean age 55 +/- 11 years) with preserved LV ejection fractions (>50%). Patients were stratified into groups on the basis of LV diastolic function (normal, n = 53; delayed relaxation, n = 79; pseudonormal, n = 23). Arterial wave reflection parameters and central blood pressure were determined by radial tonometry. Arterial (brachial and carotid) structure and function were determined by standard ultrasound methods. There were no significant differences among the groups on central pressure or arterial function. LV filling pressure, determined by the ratio of early transmitral inflow velocity to diastolic early tissue velocity (E/E'), was significantly correlated with central pulse pressure (r = 0.21, p <0.05). Late diastolic inflow velocity (A) was significantly associated with central pulse pressure (r = 0.32, p <0.001), total arterial compliance (r = -0.35, p <0.001), and carotid artery stiffness (r = 0.34, p <0.001). Multiple regression analysis found central but not brachial pulse pressure independently predicted E/E' and A. In conclusion, increased central pulse pressure, possibly due to amplified pressure wave reflections, is independently associated with abnormal LV diastolic function in patients with type 2 DM.