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  • Use of the triglyceride-glucose index (TyG) in cardiovascular disease patients
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2020-01-15
    Javad Alizargar; Chyi-Huey Bai; Nan-Chen Hsieh; Shu-Fang Vivienne Wu

    Da Silva et al. showed that the triglyceride-glucose (TyG) index was positively associated with a higher prevalence of symptomatic coronary artery disease (CAD). TyG has been used in healthy individuals as a marker of insulin resistance. The use of this index as a marker of atherosclerosis in cardiovascular disease (CVD) patients might be influenced by diabetes and the hyperlipidemic state that led to CVD. Certain considerations might be necessary before we conclude that the TyG index can be used as a marker of atherosclerosis in CVD patients. These factors can highlight the role of fasting blood glucose and triglyceride levels that are used in the TyG formula. Comparing the fasting blood glucose and/or triglyceride levels with the TyG index in these patients to show how much value the TyG index can add to clinical practice seems to be necessary. Conclusions of such studies might be biased by these facts. Stratification by CAD disease category cannot help achieve an understanding of the role of TyG in CVD. Correlations do not imply causation, so the use of the TyG index as an index in CAD patients is questionable.

    更新日期:2020-01-15
  • Sodium–glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2020-01-10
    M. Arow; M. Waldman; D. Yadin; V. Nudelman; A. Shainberg; N. G. Abraham; D. Freimark; R. Kornowski; D. Aravot; E. Hochhauser; M. Arad

    Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin—SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12–14 weeks old WT or db/db mice (n = 4–8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5–33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium–calcium exchanger (NCX) and the sodium–hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.

    更新日期:2020-01-11
  • Efficacy of dapagliflozin versus sitagliptin on cardiometabolic risk factors in Japanese patients with type 2 diabetes: a prospective, randomized study (DIVERSITY-CVR)
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2020-01-07
    Ayako Fuchigami; Fumika Shigiyama; Toru Kitazawa; Yosuke Okada; Takamasa Ichijo; Mariko Higa; Toru Hiyoshi; Ikuo Inoue; Kaoru Iso; Hidenori Yoshii; Takahisa Hirose; Naoki Kumashiro

    Few prospective studies have compared the cardiovascular benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors. We aimed to clarify the efficacy of dapagliflozin versus sitagliptin for modulating cardiometabolic risk factors including high glycated hemoglobin (HbA1c) levels, hypoglycemia, and body weight. This prospective, randomized, open-label, blinded-endpoint, parallel-group trial enrolled 340 Japanese patients with early-stage type 2 diabetes receiving metformin alone or no glucose-lowering agents, who were randomized to receive dapagliflozin or sitagliptin for 24 weeks. The primary endpoint was the proportion of patients who achieved the composite endpoint of HbA1c level maintenance < 7.0% (53 mmol/mol), avoidance of hypoglycemia (maintenance of sensor glucose ≥ 3.0 mmol/L or ≥ 54 mg/dL), and ≥ 3.0% body weight loss from baseline. Secondary endpoints included components of the primary endpoint, other metabolic indices, and glucose variability indices measured using flash glucose monitoring. Clinical characteristics of patients were age, 58.1 ± 12.2 years; known duration of diabetes, 5.8 ± 6.1 years; body weight, 74.7 ± 14.2 kg; body mass index, 27.9 ± 4.1 kg/m2; and HbA1c level, 7.8 ± 0.8% at baseline. The achievement ratio of primary endpoint was significantly higher in the dapagliflozin group than in the sitagliptin group (24.4% vs. 13.8%, P < 0.05). While the rates of HbA1c level maintenance < 7.0% (53 mmol/mol) and avoidance of hypoglycemia were comparable between the groups (49.4 vs. 50.0% and 88.7 vs. 92.3% for dapagliflozin vs. sitagliptin, respectively), body weight loss of ≥ 3.0% was significantly achieved in the dapagliflozin group (54.4 vs. 19.6%, P < 0.001). Moreover, dapagliflozin was superior to sitagliptin regarding several secondary endpoints that modulate cardiometabolic risk, namely reducing fasting plasma glucose, insulin, uric acid, increasing high-density lipoprotein cholesterol, and suppressing the increase in serum creatinine and the decrease in estimated glomerular filtration rate. On the other hand, sitagliptin was superior to dapagliflozin in suppressing glucose variability. Compared to sitagliptin, dapagliflozin was significantly more effective at improving cardiometabolic risk factors, suggesting that SGLT2 inhibitors might be more suitable than DPP-4 inhibitors for preventing cardiovascular events in patients with early-stage but inadequately controlled type 2 diabetes. Trial registration Trial number, UMIN000028014; registered on June 30, 2017

    更新日期:2020-01-07
  • Pioglitazone and PPAR-γ modulating treatment in hypertensive and type 2 diabetic patients after ischemic stroke: a national cohort study
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2020-01-07
    Chi-Hung Liu; Tsong-Hai Lee; Yu-Sheng Lin; Pi-Shan Sung; Yi-Chia Wei; Yan-Rong Li

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) modulating treatment may have cardiovascular benefits in type 2 diabetes mellitus (T2DM) patients after ischemic stroke (IS). However, whether there are additional benefits from intensive PPAR-γ modulating treatments in Asian patients with T2DM and hypertension (HTN) after IS remains unknown. Between 2001 and 2013, patients admitted due to IS were identified from the National Health Insurance Research Database of Taiwan. Patients with T2DM and HTN using angiotensin receptor blockers were further included. Eligible patients were divided into two groups: (1) pioglitazone and (2) non-pioglitazone oral anti-diabetic agent groups. Propensity score matching (1:2) was used to balance the distribution of baseline characteristics, stroke severity and medications. The primary outcome was recurrent IS. Subgroup analysis for recurrent IS in pioglitazone and/or telmisartan users, the trend of IS risks across different PPAR-γ intensity treatments, and dose-dependent outcomes across different pioglitazone possession ratios were further studied. Statistical significance was set at p < 0.05 and p < 0.1 for clinical outcomes and interaction of subgroup analyses, respectively. There were 3190 and 32,645 patients in the pioglitazone and non-pioglitazone groups. Patients of the pioglitazone group had a lower risk of recurrent IS (subdistribution hazard ratio, 0.91; 95% confidence interval 0.84–0.99). Pioglitazone was also associated with reduced recurrent IS in patients who also used telmisartan (p for interaction = 0.071). A graded correlation was found a borderline significant trend between the intensity of PPAR-γ therapy and following IS (p = 0.076). The dose-dependent outcome also showed that a borderline significant trend that higher pioglitazone possession ratio was associated with a lower risk of recurrent IS (p = 0.068). The current study suggests that the use of pioglitazone in type 2 diabetic and hypertensive IS patients is associated with fewer recurrent IS events in an Asian population. Concurrent telmisartan use or a higher pioglitazone possession ratio may have a trend of increased pleiotropic effects, which could possibly be related to higher PPAR-γ effects. Future studies are warranted to confirm or refute the clinical effects and the possible mechanism of more intensive PPAR-γ-modulating treatments.

    更新日期:2020-01-07
  • Aspirin, clopidogrel and prasugrel monotherapy in patients with type 2 diabetes mellitus: a double-blind randomised controlled trial of the effects on thrombotic markers and microRNA levels
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2020-01-07
    William A. E. Parker; Christian Schulte; Temo Barwari; Fladia Phoenix; Sam M. Pearson; Manuel Mayr; Peter J. Grant; Robert F. Storey; Ramzi A. Ajjan

    Despite increased atherothrombotic risk in type 2 diabetes mellitus, (T2DM) the best preventative antithrombotic strategy remains undetermined. We defined the effects of three antiplatelet agents on functional readout and biomarker kinetics in platelet activation and coagulation in patients with T2DM. 56 patients with T2DM were randomised to antiplatelet monotherapy with aspirin 75 mg once daily (OD), clopidogrel 75 mg OD or prasugrel 10 mg OD during three periods of a crossover study. Platelet aggregation (PA) was determined by light-transmittance aggregometry and P-selectin expression by flow cytometry. Markers of fibrin clot dynamics, inflammation and coagulation were measured. Plasma levels of 14 miRNA were assessed by quantitative polymerase chain reactions. Of the 56 patients, 24 (43%) were receiving aspirin for primary prevention of ischaemic events and 32 (57%) for secondary prevention. Prasugrel was the strongest inhibitor of ADP-induced PA (mean ± SD maximum response to 20μmol/L ADP 77.6 ± 8.4% [aspirin] vs. 57.7 ± 17.6% [clopidogrel] vs. 34.1 ± 14.1% [prasugrel], p < 0.001), P-selectin expression (30 μmol/L ADP; 45.1 ± 21.4% vs. 27.1 ± 19.0% vs. 14.1 ± 14.9%, p < 0.001) and collagen-induced PA (2 μg/mL; 62.1 ± 19.4% vs. 72.3 ± 18.2% vs. 60.2 ± 18.5%, p < 0.001). Fibrin clot dynamics and levels of coagulation and inflammatory proteins were similar. Lower levels of miR-24 (p = 0.004), miR-191 (p = 0.019), miR-197 (p = 0.009) and miR-223 (p = 0.014) were demonstrated during prasugrel-therapy vs. aspirin. Circulating miR-197 was lower in those cardiovascular disease during therapy with aspirin (p = 0.039) or prasugrel (p = 0.0083). Prasugrel monotherapy in T2DM provided potent platelet inhibition and reduced levels of a number of platelet-associated miRNAs. miR-197 is a potential marker of cardiovascular disease in this population. Clinical outcome studies investigating prasugrel monotherapy are warranted in individuals with T2DM. Trial registration EudraCT, 2009-011907-22. Registered 15 March 2010, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011907-22/GB.

    更新日期:2020-01-07
  • Fasting plasma glucose variability and HbA1c are associated with peripheral artery disease risk in type 2 diabetes
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2020-01-07
    Chun-Pai Yang; Cheng-Chieh Lin; Chia-Ing Li; Chiu-Shong Liu; Chih-Hsueh Lin; Kai-Lin Hwang; Shing-Yu Yang; Tsai-Chung Li

    This study investigated whether visit-to-visit fasting plasma glucose (FPG) variability, as measured by the coefficient of variation (CV), increased peripheral artery disease (PAD) risk. Individuals with type 2 diabetes from the National Diabetes Care Management Program during the period 2002–2004, ≥ 30 years of age, and free of PAD (n = 30,932) were included and monitored until 2011. Cox proportional hazards regression models were implemented to analyze related determinants of PAD. A total of 894 incident cases of PAD were identified during an average 8.2 years of follow-up, resulting in a crude incidence rate of 3.53 per 1000 person-years. Both FPG-CV and HbA1c were significantly associated with PAD after multivariate adjustment, with corresponding hazard ratios of 1.24 [95% confidence interval (CI) 1.04–1.47] for FPG-CV in the third tertile and 1.50 (95% CI 1.10–2.04) for HbA1c ≥ 10%. The findings of the sensitivity analysis remained consistent after excluding potential confounders, demonstrating the consistency of the results. The associations between HbA1c, variability in FPG-CV, and PAD suggest a linked pathophysiological mechanism, suggesting the crucial role of glycemic variability in clinical management and therapeutic goals in preventing PAD in type 2 diabetes.

    更新日期:2020-01-07
  • Sodium-glucose co-transporter 2 inhibition as a mitochondrial therapy for atrial fibrillation in patients with diabetes?
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2020-01-07
    Salva R. Yurista; Herman H. W. Silljé; Michiel Rienstra; Rudolf A. de Boer; B. Daan Westenbrink

    While patients with type 2 diabetes mellitus (T2DM) are at increased risk to develop atrial fibrillation (AF), the mechanistic link between T2DM and AF-susceptibility remains unclear. Common co-morbidities of T2DM, particularly hypertension, may drive AF in the setting of T2DM. But direct mechanisms may also explain this relation, at least in part. In this regard, recent evidence suggests that mitochondrial dysfunction drives structural, electrical and contractile remodelling of atrial tissue in patients T2DM. Mitochondrial dysfunction may therefore be the mechanistic link between T2DM and AF and could also serve as a therapeutic target. An elegant series of experiments published in Cardiovascular Diabetology provide compelling new evidence to support this hypothesis. Using a model of high fat diet (HFD) and low-dose streptozotocin (STZ) injection, Shao et al. provide data that demonstrate a direct association between mitochondrial dysfunction and the susceptibility to develop AF. But the authors also demonstrated that the sodium-glucose co-transporter 2 inhibitors (SGLT2i) empagliflozin has the capacity to restore mitochondrial function, ameliorate electrical and structural remodelling and prevent AF. These findings provide a new horizon in which mitochondrial targeted therapies could serve as a new class of antiarrhythmic drugs.

    更新日期:2020-01-07
  • Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2020-01-07
    Hidekazu Tanaka; Fumitaka Soga; Kazuhiro Tatsumi; Yasuhide Mochizuki; Hiroyuki Sano; Hiromi Toki; Kensuke Matsumoto; Junya Shite; Hideyuki Takaoka; Tomofumi Doi; Ken-ichi Hirata

    The effect of sodium glucose cotransporter type 2 (SGLT2) inhibitor on left ventricular (LV) longitudinal myocardial function in type 2 diabetes mellitus (T2DM) patients with heart failure (HF) has remained unclear. We analyzed data from our previous prospective multicenter study, in which we investigated the effect of the SGLT2 inhibitor dapagliflozin on LV diastolic functional parameters of T2DM patients with stable HF at five institutions in Japan. Echocardiography was performed at baseline and 6 months after administration of dapagliflozin. LV diastolic function was defined as the ratio of mitral inflow E to mitral e′ annular velocities (E/e′). LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), which in turn was determined as the averaged peak longitudinal strain from standard LV apical views. E/e′ significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p = 0.020) as previously described, while GLS showed significant improvement from 15.5 ± 3.5% to 16.9 ± 4.1% (p < 0.01) 6 months after administration of dapagliflozin. Furthermore, improvement of GLS in HF with preserved ejection fraction patients was more significant from 17.0 ± 1.9% to 18.7 ± 2.0% (p < 0.001), compared to that in HF with mid-range ejection fraction and HF with reduced ejection fraction patients from 14.4 ± 2.4% to 15.5 ± 1.8% (p = 0.06) and from 8.1 ± 1.5% to 7.8 ± 2.1% (p = 0.44), respectively. It was noteworthy that multiple regression analysis showed that the change in GLS after administration of dapagliflozin was the only independent determinant parameters for the change in E/e′ after administration of dapagliflozin. Dapagliflozin was found to be associated with improvement of LV longitudinal myocardial function, which led to further improvement of LV diastolic function of T2DM patients with stable HF. GLS-guided management may thus lead to improved management of T2DM patients with stable HF.

    更新日期:2020-01-07
  • Impaired myocardial deformation and ventricular vascular coupling in obese adolescents with dysglycemia
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-12-19
    Preneet Cheema Brar; Anne Chun; Xiazhou Fan; Vivek Jani; Mary Craft; Puneet Bhatla; Shelby Kutty

    It is unknown that dysglycemia in obese adolescents has effects on myocardial deformation that are more pronounced when compared to obesity alone. We hypothesized that obesity associated abnormal glucose tolerance (dysglycemia) would have adverse effects on two-dimensional speckle tracking echocardiography derived longitudinal, radial and circumferential strain (LS, RS, CS) compared to age and gender lean controls. We also examined if changes in deformation would be reflected in abnormal ventricular vascular coupling indices (VVI). In a prospective cross-sectional design 39 obese adolescents (15.9 ± 1.7 years; 101.5 ± 39 kg; female − 58%) were compared to age and gender matched lean controls (15.7 ± 1.8 yrs, 60 ± 12.8 kg). Based on results from an oral glucose tolerance test (OGTT), obese adolescents were categorized as obese normoglycemic (ONG, n = 25) or obese dysglycemic (ODG, n = 14). Left ventricular (LV) global and average LS, CS, RS and strain rate were measured. LV ejection fraction and mass index were measured and VVI approximated as ratio of arterial elasticity (Ea) and end-systolic elastance (Ees). Adolescents with ODG had significantly (P = 0.005) impaired global LS (− 20.98% ± 2.8%) compared to controls (− 23.01% ± 2.3%). A similar (P = 0.0027) reduction was observed in average LS for adolescents with ODG (18.87% ± 2.5%) compared to controls (20.49% ± 2%). Global CS was also decreased (P = 0.03) in ODG (− 23.95%) compared to ONG (− 25.80). A similar trend was observed in average CS after multivariate regression for BMI and blood pressure. CS correlated with HbA1c in both groups (P = 0.05). VVI had a negative correlation with both LS (r = − 0.4, P = 0.025) and CS rate (r = − 0.36, P = 0.04). Myocardial strain and strain rate were significantly altered in obese adolescents. Unfavorable subclinical reductions in global and average CS were more pronounced in adolescents with dysglycemia compared to obese adolescents with normoglycemia and controls. These data indicate progressive worsening of subendocardial function across the spectrum of glucose tolerance. Strain rate was predictive of VVI in obese adolescents, suggesting strain rate may be a sensitive marker for cardiac remodeling in abnormal glucose homeostasis states.

    更新日期:2019-12-19
  • High-sensitivity troponin I and B-type natriuretic peptide biomarkers for prediction of cardiovascular events in patients with coronary artery disease with and without diabetes mellitus
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-12-17
    Yuen-Kwun Wong; Chloe Y. Y. Cheung; Clara S. Tang; JoJo S. H. Hai; Chi-Ho Lee; Kui-Kai Lau; Ka-Wing Au; Bernard M. Y. Cheung; Pak-Chung Sham; Aimin Xu; Karen S. L. Lam; Hung-Fat Tse

    High-sensitivity troponin I (hs-Tnl) and B-type natriuretic peptide (BNP) are promising prognostic markers for coronary artery disease (CAD). This prospective cohort study investigated whether a combination of these cardiac biomarkers with conventional risk factors would add incremental value for the prediction of secondary major adverse cardiovascular events (MACEs) in patients with CAD, with and without type 2 diabetes mellitus (T2DM). Baseline plasma level of hs-Tnl and BNP was measured in 2275 Chinese patients with stable CAD. Patients were monitored for new-onset of MACE over a median of 51 months. Cox proportional hazard model and area under the receiver operating characteristic curve (AUC) were used to assess the association of cardiac biomarkers with MACE and their predictive values in relationship with or without T2DM. During the follow up period 402 (18%) patients experienced a new-onset MACE with hs-Tnl and BNP level significantly higher than in those without MACE. In multivariable analyses, patients with elevated hs-Tnl (hazard ratio, 1.75 [95% CI 1.41–2.17]; P < 0.001) and BNP (hazard ratio, 1.42 [95% CI 1.15–1.75]; P = 0.001) were significantly associated with an increased risk of MACE after adjustment for variables of a risk factor model of age, sex, T2DM and hypertension. The risk factor model had an AUC of 0.64 for MACE prediction. The AUC significantly increased to 0.68 by the addition of hs-Tnl to the risk factor model. Subgroup analyses showed that hs-Tnl and BNP remained significant predictors of MACE in both patients with and without T2DM in multivariable models with higher risk of MACE evident in those without T2DM. Among patients without T2DM, addition of each biomarker yielded greater predictive accuracy than in T2DM patients, with AUC further increased to 0.75 when a combination of hs-Tnl and BNP was added to the risk factor model (age, sex and hypertension). Elevated hs-Tnl and BNP level are independent predictors of new-onset MACE in CAD patients, irrespective of diabetes status. Among CAD patients without T2DM, a combination of cardiac biomarkers hs-Tnl and BNP yield the greatest predictive value beyond conventional risk factors.

    更新日期:2019-12-18
  • Visit-to-visit variability of glycemia and vascular complications: the Hoorn Diabetes Care System cohort
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-12-12
    Roderick C. Slieker; Amber A. W. H. van der Heijden; Giel Nijpels; Petra J. M. Elders; Leen M. ’t Hart; Joline W. J. Beulens

    Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration. Individuals with type 2 diabetes (n = 6770) from the Hoorn Diabetes Care System cohort were included in this study. The coefficient of variation (CV) was calculated over 5-year sliding intervals. People divided in quintiles based on their CV. Cox proportional hazard models were used to investigate the role of glycemic CV as risk factor in diabetes-related complications and mortality. The coefficient of variation of glucose (FG-CV) increased with time, in contrast to HbA1c (HbA1c-CV). People with a high FG-CV were those with an early age of diabetes onset (ΔQ5–Q1 = − 2.39 years), a higher BMI (ΔQ5–Q1 = + 0.92 kg/m2), an unfavorable lipid profile, i.e. lower levels of HDL-C (ΔQ5–Q1 = − 0.06 mmol/mol) and higher triglycerides (ΔQ5–Q1 =+ 1.20 mmol/mol). People with the highest FG-CV in the first 5-year interval showed an increased risk of insulin initiation, retinopathy, macrovascular complications and mortality independent of mean glycemia, classical risk factors and medication use. For HbA1c, the associations were weaker and less consistent. Individuals with a higher FG-CV have an unfavorable metabolic profile and have an increased risk of developing micro- and macrovascular complications and mortality. The association of HbA1c-CV with metabolic outcomes and complications was less consistent in comparison to FG-CV.

    更新日期:2019-12-13
  • Prognostic value of HbA1c for in-hospital and short-term mortality in patients with acute coronary syndrome: a systematic review and meta-analysis
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-12-11
    Wenjun Pan; Haining Lu; Baotao Lian; Pengda Liao; Liheng Guo; Minzhou Zhang

    HbA1c, the most commonly used indicator of chronic glucose metabolism, is closely associated with cardiovascular disease. However, the relationship between HbA1c and the mortality of acute coronary syndrome (ACS) patients has not been elucidated yet. Here, we aim to conduct a systematic review assessing the effect of HbA1c on in-hospital and short-term mortality in ACS patients. Relevant studies reported before July 2019 were retrieved from databases including PubMed, Embase, and Central. Pooled relative risks (RRs) and the corresponding 95% confidence interval (CI) were calculated to evaluate the predictive value of HbA1c for the in-hospital mortality and short-term mortality. Data from 25 studies involving 304,253 ACS patients was included in systematic review. The pooled RR of in-hospital mortality was 1.246 (95% CI 1.113–1.396, p: 0.000, I2 = 48.6%, n = 14) after sensitivity analysis in studies reporting HbA1c as categorial valuable. The pooled RR was 1.042 (95% CI 0.904–1.202, p: 0.57, I2 = 82.7%, n = 4) in random-effects model for studies reporting it as continuous valuable. Subgroup analysis by diabetic status showed that elevated HbA1c is associated increased short-term mortality in ACS patients without diabetes mellitus (DM) history and without DM (RR: 2.31, 95% CI (1.81–2.94), p = 0.000, I2 = 0.0%, n = 5; RR: 2.56, 95% CI 1.38–4.74, p = 0.003, I2 = 0.0%, n = 2, respectively), which was not the case for patients with DM and patients from studies incorporating DM and non-DM individuals (RR: 1.16, 95% CI 0.79–1.69, p = 0.451, I2 = 31.9%, n = 3; RR: 1.10, 95% CI 0.51–2.38), p = 0.809, I2 = 47.4%, n = 4, respectively). Higher HbA1c is a potential indicator for in-hospital death in ACS patients as well as a predictor for short-term mortality in ACS patients without known DM and without DM.

    更新日期:2019-12-11
  • Metformin use and cardiovascular outcomes after acute myocardial infarction in patients with type 2 diabetes: a cohort study
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-12-09
    Daniel I. Bromage; Tom R. Godec; Mar Pujades-Rodriguez; Arturo Gonzalez-Izquierdo; S. Denaxas; Harry Hemingway; Derek M. Yellon

    The use of metformin after acute myocardial infarction (AMI) has been associated with reduced mortality in people with type 2 diabetes mellitus (T2DM). However, it is not known if it is acutely cardioprotective in patients taking metformin at the time of AMI. We compared patient outcomes according to metformin status at the time of admission for fatal and non-fatal AMI in a large cohort of patients in England. This study used linked data from primary care, hospital admissions and death registry from 4.7 million inhabitants in England, as part of the CALIBER resource. The primary endpoint was a composite of acute myocardial infarction requiring hospitalisation, stroke and cardiovascular death. The secondary endpoints were heart failure (HF) hospitalisation and all-cause mortality. 4,030 patients with T2DM and incident AMI recorded between January 1998 and October 2010 were included. At AMI admission, 63.9% of patients were receiving metformin and 36.1% another oral hypoglycaemic drug. Median follow-up was 343 (IQR: 1–1436) days. Adjusted analyses showed an increased hazard of the composite endpoint in metformin users compared to non-users (HR 1.09 [1.01–1.19]), but not of the secondary endpoints. The higher risk of the composite endpoint in metformin users was only observed in people taking metformin at AMI admission, whereas metformin use post-AMI was associated with a reduction in risk of all-cause mortality (0.76 [0.62–0.93], P = 0.009). Our study suggests that metformin use at the time of first AMI is associated with increased risk of cardiovascular disease and death in patients with T2DM, while its use post-AMI might be beneficial. Further investigation in well-designed randomised controlled trials is indicated, especially in view of emerging evidence of cardioprotection from sodium-glucose co-transporter-2 (SGLT2) inhibitors.

    更新日期:2019-12-09
  • Association of glycemic variability with left ventricular diastolic function in type 2 diabetes mellitus
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-12-05
    Shun Yokota; Hidekazu Tanaka; Yasuhide Mochizuki; Fumitaka Soga; Kentaro Yamashita; Yusuke Tanaka; Ayu Shono; Makiko Suzuki; Keiko Sumimoto; Jun Mukai; Makiko Suto; Hiroki Takada; Kensuke Matsumoto; Yushi Hirota; Wataru Ogawa; Ken-ichi Hirata

    Type 2 diabetes mellitus (T2DM) is a major cause of heart failure (HF) with preserved ejection fraction (HFpEF), usually presenting as left ventricular (LV) diastolic dysfunction. Thus, LV diastolic function should be considered a crucial marker of a preclinical form of DM-related cardiac dysfunction. However, the impact of glycemic variability (GV) on LV diastolic function in such patients remains unclear. We studied 100 asymptomatic T2DM patients with preserved LV ejection fraction (LVEF) without coronary artery disease (age: 60 ± 14 years, female: 45%). GV was evaluated as standard deviation of blood glucose level using continuous glucose monitoring system for at least 72 consecutive hours. LV diastolic function was defined as mitral inflow E and mitral e’ annular velocities (E/e’), and > 14 was determined as abnormal. E/e’ in patients with high GV (≥ 35.9 mg/dL) was significantly higher than that in patients with low GV (11.3 ± 3.9 vs. 9.8 ± 2.8, p = 0.03) despite similar age, gender-distribution, and hemoglobin A1c (HbA1c). Multivariate logistic regression analysis showed that GV ≥ 35.9 mg/dL (odds ratio: 3.67; 95% confidence interval: 1.02–13.22; p < 0.05) was an independently associated factor, as was age, of E/e’ > 14. In sequential logistic models for the associations of LV diastolic dysfunction, one model based on clinical variables including age, gender and hypertension was not improved by addition of HbA1c (p = 0.67) but was improved by addition of high GV (p = 0.04). Since HFpEF is a syndrome caused by diverse agents, reducing GV may represent a potential new therapeutic strategy for the prevention of the development of HFpEF in T2DM patients.

    更新日期:2019-12-05
  • Plasma omentin levels are inversely associated with atherosclerosis in type 2 diabetes patients with increased plasma adiponectin levels: a cross-sectional study
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-12-05
    Masami Nishimura; Tomoaki Morioka; Mariko Hayashi; Yoshinori Kakutani; Yuko Yamazaki; Masafumi Kurajoh; Katsuhito Mori; Shinya Fukumoto; Atsushi Shioi; Tetsuo Shoji; Masaaki Inaba; Masanori Emoto

    Omentin and adiponectin are among the anti-inflammatory and anti-atherogenic adipokines that have potentially beneficial effects on cardiovascular disorders. Recent studies indicate a paradoxical relationship between adiponectin and cardiovascular mortality across many clinical settings including type 2 diabetes. In this study, we characterized the clinical features of type 2 diabetes patients with increased adiponectin levels and examined the association between omentin and atherosclerosis in those patients. The subjects were 413 patients with type 2 diabetes. Fasting plasma omentin and total adiponectin levels were measured by enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasonography. The subjects were stratified according to the median value of plasma adiponectin. In high-adiponectin group, omentin levels were higher, while IMT tended to be greater than those in low-adiponectin group. The high-adiponectin group also exhibited older age, higher systolic blood pressure, lower kidney function, body mass index, and insulin resistance index compared to the low-adiponectin group. Multivariate analysis revealed that omentin levels were independently and negatively associated with IMT in high-adiponectin group, but not in low-adiponectin group, after adjusting for adiponectin levels and traditional cardiovascular risk factors. On the other hand, adiponectin levels were not significantly associated with IMT in either group. Plasma omentin levels are inversely associated with IMT in type 2 diabetes patients with increased adiponectin levels and multiple cardiovascular risk factors. This study suggests a protective role of omentin against atherosclerosis in type 2 diabetes patients, which is potentially influenced by adiponectin level and cardiovascular risk status.

    更新日期:2019-12-05
  • GLP-1 analog liraglutide-induced cardiac dysfunction due to energetic starvation in heart failure with non-diabetic dilated cardiomyopathy
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-28
    Aya Shiraki; Jun-ichi Oyama; Toshiyuki Nishikido; Koichi Node

    Glucagon-like peptide-1 (GLP-1) reduces cardiovascular events in diabetic patients; however, its counter-protective effects have also been suggested in patients with heart failure and the clear explanation for its mechanisms have not yet been offered. The effects of GLP-1 analog on cardiac function and energy metabolism, especially glycemic and lipid metabolisms were elucidated using non-diabetic J2N-k hamsters which showed spontaneous dilated cardiomyopathy. J2N-k hamsters were treated with PBS (HF group), low-dose (HF-L group) or high-dose liraglutide (HF-H group). In failing heart, GLP-1 analog exerted further deteriorated cardiac function (e.g. positive and negative dP/dt; p = 0.01 and p = 0.002, respectively) with overt fibrosis and cardiac enlargement (heart/body weight, 5.7 ± 0.2 in HF group versus 7.6 ± 0.2 in HF-H group; p = 0.02). The protein expression of cardiac muscles indicated the energy starvation status. Indirect calorimetry showed that failing hearts consumed higher energy and carbohydrate than normal hearts; moreover, this tendency was augmented by GLP-1 analog administration. Upon 10% glucose solution loading with GLP-1 analog administration (HF-H-G group) as complementary experiments, the cardiac function and fibrosis significantly ameliorated, whereas carbohydrate utilization augmented further and lipid utilization reduced more. The prognosis of HF-H-G group also significantly improved (p = 0.025). Glucagon-like peptide-1 analog caused the relative but desperate shortage of glycemic energy source for the failing cardiac muscles and it may restrict ATP synthesis, resulting in cardiac function deterioration. Therefore, appropriate energy supply and amount of carbohydrate intake should be carefully considered when administrating incretin-related drugs to patients with heart failure.

    更新日期:2019-11-29
  • Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-28
    Qingmiao Shao; Lei Meng; Sharen Lee; Gary Tse; Mengqi Gong; Zhiwei Zhang; Jichao Zhao; Yungang Zhao; Guangping Li; Tong Liu

    Diabetes mellitus is an important risk factor for atrial fibrillation (AF) development. Sodium–glucose co-transporter-2 (SGLT-2) inhibitors are used for the treatment of type 2 diabetes mellitus (T2DM). Their cardioprotective effects have been reported but whether they prevent AF in T2DM patients are less well-explored. We tested the hypothesis that the SGLT-2 inhibitor, empagliflozin, can prevent atrial remodeling in a diabetic rat model. High-fat diet and low-dose streptozotocin (STZ) treatment were used to induce T2DM. A total of 96 rats were randomized into the following four groups: (i) control (ii) T2DM, (iii) low-dose empagliflozin (10 mg/kg/day)/T2DM; and (iv) high-dose empagliflozin (30 mg/kg/day)/T2DM by the intragastric route for 8 weeks. Compared with the control group, left atrial diameter, interstitial fibrosis and the incidence of AF inducibility were significantly increased in the DM group. Moreover, atrial mitochondrial respiratory function, mitochondrial membrane potential, and mitochondrial biogenesis were impaired. Empagliflozin treatment significantly prevented the development of these abnormalities in DM rats, likely via the peroxisome proliferator-activated receptor-c coactivator 1α (PGC-1α)/nuclear respiratory factor-1 (NRF-1)/mitochondrial transcription factor A (Tfam) signaling pathway. Empagliflozin can ameliorate atrial structural and electrical remodeling as well as improve mitochondrial function and mitochondrial biogenesis in T2DM, hence may be potentially used in the prevention of T2DM-related atrial fibrillation.

    更新日期:2019-11-29
  • Epicardial adipose tissue predicts incident cardiovascular disease and mortality in patients with type 2 diabetes
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-08-30
    Regitse H. Christensen; Bernt Johan von Scholten; Christian S. Hansen; Magnus T. Jensen; Tina Vilsbøll; Peter Rossing; Peter G. Jørgensen

    Cardiac fat is a cardiovascular biomarker but its importance in patients with type 2 diabetes is not clear. The aim was to evaluate the predictive potential of epicardial (EAT), pericardial (PAT) and total cardiac (CAT) fat in type 2 diabetes and elucidate sex differences. EAT and PAT were measured by echocardiography in 1030 patients with type 2 diabetes. Follow-up was performed through national registries. The end-point was the composite of incident cardiovascular disease (CVD) and all-cause mortality. Analyses were unadjusted (model 1), adjusted for age and sex (model 2), plus systolic blood pressure, body mass index (BMI), low-density lipoprotein (LDL), smoking, diabetes duration and glycated hemoglobin (HbA1c) (model 3). Median follow-up was 4.7 years and 248 patients (191 men vs. 57 women) experienced the composite end-point. Patients with high EAT (> median level) had increased risk of the composite end-point in model 1 [Hazard ratio (HR): 1.46 (1.13; 1.88), p = 0.004], model 2 [HR: 1.31 (1.01; 1.69), p = 0.038], and borderline in model 3 [HR: 1.32 (0.99; 1.77), p = 0.058]. For men, but not women, high EAT was associated with a 41% increased risk of CVD and mortality in model 3 (p = 0.041). Net reclassification index improved when high EAT was added to model 3 (19.6%, p = 0.035). PAT or CAT were not associated with the end-point. High levels of EAT were associated with the composite of incident CVD and mortality in patients with type 2 diabetes, particularly in men, after adjusting for CVD risk factors. EAT modestly improved risk prediction over CVD risk factors.

    更新日期:2019-11-28
  • Evidence from routine clinical practice: EMPRISE provides a new perspective on CVOTs
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-08-31
    Guntram Schernthaner; Avraham Karasik; Agnė Abraitienė; Alexander S. Ametov; Zsolt Gaàl; Janusz Gumprecht; Andrej Janež; Susanne Kaser; Katarina Lalić; Boris N. Mankovsky; Evgeny Moshkovich; Marju Past; Martin Prázný; Gabriela Radulian; Lea Smirčić Duvnjak; Ivan Tkáč; Kārlis Trušinskis

    EMPA-REG OUTCOME is recognised by international guidelines as a landmark study that showed a significant cardioprotective benefit with empagliflozin in patients with type 2 diabetes (T2D) and cardiovascular disease. To assess the impact of empagliflozin in routine clinical practice, the ongoing EMPRISE study is collecting real-world evidence to compare effectiveness, safety and health economic outcomes between empagliflozin and DPP-4 inhibitors. A planned interim analysis of EMPRISE was recently published, confirming a substantial reduction in hospitalisation for heart failure with empagliflozin across a diverse patient population. In this commentary article, we discuss the new data in the context of current evidence and clinical guidelines, as clinicians experienced in managing cardiovascular risk in patients with T2D. We also look forward to what future insights EMPRISE may offer, as evidence is accumulated over the next years to complement the important findings of EMPA-REG OUTCOME.

    更新日期:2019-11-28
  • Sitagliptin does not reduce the risk of cardiovascular death or hospitalization for heart failure following myocardial infarction in patients with diabetes: observations from TECOS
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-03
    Michael A. Nauck; Darren K. McGuire; Karen S. Pieper; Yuliya Lokhnygina; Timo E. Strandberg; Axel Riefflin; Tuncay Delibasi; Eric D. Peterson; Harvey D. White; Russell Scott; Rury R. Holman

    To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses. During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81–1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83–1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83–1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes. In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration clinicaltrials.gov no. NCT00790205

    更新日期:2019-11-28
  • Improved long-term cardiovascular outcomes after intensive versus standard screening of diabetic complications: an observational study
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-16
    Mario Luca Morieri; Enrico Longato; Marta Mazzucato; Barbara Di Camillo; Arianna Cocchiglia; Lorenzo Gubian; Giovanni Sparacino; Angelo Avogaro; Gian Paolo Fadini; Saula Vigili de Kreutzenberg

    Complication screening is recommended for patients with type 2 diabetes (T2D), but the optimal screening intensity and schedules are unknown. In this study, we evaluated whether intensive versus standard complication screening affects long-term cardiovascular outcomes. In this observational study, we included 368 T2D patients referred for intensive screening provided as a 1-day session of clinical–instrumental evaluation of diabetic complications, followed by dedicated counseling. From a total of 4906 patients, we selected control T2D patients who underwent standard complication screening at different visits, by 2:1 propensity score matching. The primary endpoint was the 4p-MACE, defined as cardiovascular mortality, or non-fatal myocardial infarction, stroke, or heart failure. The Cox proportional regression analyses was used to compare outcome occurrence in the two groups, adjusted for residual confounders. 357 patients from the intensive screening group (out of 368) were matched with 683 patients in the standard screening group. Clinical characteristics were well balanced between the two groups, except for a slightly higher prevalence of microangiopathy in the intensive group (56% vs 50%; standardized mean difference 0.11, p = 0.1). Median follow-up was 5.6 years. The adjusted incidence of 4p-MACE was significantly lower in the intensive versus standard screening group (HR 0.70; 95% CI 0.52–0.95; p = 0.02). All components of the primary endpoint had nominally lower rates in the intensive versus standard screening group, which was particularly significant for heart failure (HR 0.43; 95% CI 0.22–0.83; p = 0.01). Among T2D patients attending a specialist outpatient clinic, intensive complication screening is followed by better long-term cardiovascular outcomes. No significant effect was noted for cardiovascular and all-cause mortality and the benefit was mainly driven by a reduced rate of hospitalization for heart failure.

    更新日期:2019-11-28
  • Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-16
    Eilon Ram; Jacob Lavee; Alexander Tenenbaum; Robert Klempfner; Enrique Z. Fisman; Elad Maor; Tal Ovdat; Sergei Amunts; Leonid Sternik; Yael Peled

    Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality following heart transplantation (HT). Reduced cardiovascular mortality and morbidity have been reported in non-HT patients treated with metformin. Given the high prevalence of type 2 diabetes mellitus (T2DM) in HT patients, we investigated the association between metformin therapy and cardiovascular outcomes after HT. The study population comprised 103 DM patients who had undergone HT between 1994 and 2018 and were prospectively followed-up. We excluded from the study patients with type 1 diabetes mellitus. Fifty-five HT patients (53%) in the cohort were treated with metformin. Clinical data were recorded on prospectively designed forms. The primary outcomes included CAV, survival, and the combined end-point of CAV or cardiovascular mortality. Kaplan–Meier survival analysis showed that the CAV rate at 20 years of follow-up was lower in DM patients treated with metformin than in those who were not (30 vs. 65%; log-rank p = 0.044). Similarly, the combined risk of CAV or cardiovascular mortality was lower in the metformin-treated patients than in those not receiving metformin (32 vs. 68%; log rank p = 0.01). Consistently, multivariate analysis adjusted for age and comorbidities showed that metformin therapy was independently associated with a significant 90% reduction (95% confidence interval 0.02–0.46, p = 0.003) in the risk for the development of CAV, and a 91% reduction (95% confidence interval 0.02–0.42; p = 0.003) in the risk for CAV or cardiovascular mortality. In diabetic HT patients, metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or cardiovascular mortality after HT.

    更新日期:2019-11-28
  • Staged complete revascularization or culprit-only percutaneous coronary intervention for multivessel coronary artery disease in patients with ST-segment elevation myocardial infarction and diabetes
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-17
    Kongyong Cui; Shuzheng Lyu; Hong Liu; Xiantao Song; Fei Yuan; Feng Xu; Min Zhang; Wei Wang; Mingduo Zhang; Dongfeng Zhang; Jinfan Tian

    Recently, several randomized trials have noted improved outcomes with staged percutaneous coronary intervention (PCI) of nonculprit vessels in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. However, it remains unclear whether diabetes status affects the outcomes after different revascularization strategies. This study thus compared the impact of diabetes status on long-term outcomes after staged complete revascularization with that after culprit-only PCI. From January 2006 to December 2015, 371 diabetic patients (staged PCI: 164, culprit-only PCI: 207) and 834 nondiabetic patients (staged PCI: 412, culprit-only PCI: 422) with STEMI and multivessel disease were enrolled. The primary endpoint was 5-year major adverse cardiac and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction (MI), stroke or unplanned revascularization. The rate of the 5-year composite primary endpoint for diabetic patients was close to that for nondiabetic patients (34.5% vs. 33.7%; adjusted hazard ratio [HR] 1.012, 95% confidence interval [CI] 0.815–1.255). In nondiabetic patients, the 5-year risks of MACCE (31.8% vs. 35.5%; adjusted HR 0.638, 95% CI 0.500–0.816), MI (4.6% vs. 9.2%; adjusted HR 0.358, 95% CI 0.200–0.641), unplanned revascularization (19.9% vs. 24.9%; adjusted HR 0.532, 95% CI 0.393–0.720), and the composite of cardiac death, MI or stroke (11.4% vs. 15.2%; adjusted HR 0.621, 95% CI 0.419–0.921) were significantly lower after staged PCI than after culprit-only PCI. In contrast, no significant difference was found between the two groups with respect to MACCE, MI, unplanned revascularization, and the composite of cardiac death, MI or stroke in diabetic patients. Significant interactions were found between diabetes status and revascularization assignment for the composite of cardiac death, MI or stroke (Pinteraction = 0.013), MI (Pinteraction = 0.005), and unplanned revascularization (Pinteraction = 0.013) at 5 years. In addition, the interaction tended to be significant for the primary endpoint of MACCE (Pinteraction = 0.053). Moreover, the results of propensity score-matching analysis were concordant with the overall analysis in both diabetic and nondiabetic population. In patients with STEMI and multivessel disease, diabetes is not an independent predictor of adverse cardiovascular events at 5 years. In nondiabetic patients, an approach of staged complete revascularization is superior to culprit-only PCI, whereas the advantage of staged PCI is attenuated in diabetic patients. Trial registration This study was not registered in an open access database

    更新日期:2019-11-28
  • Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-24
    Shih-Chieh Shao; Kai-Cheng Chang; Ming-Jui Hung; Ning-I Yang; Yuk-Ying Chan; Hui-Yu Chen; Yea-Huei Kao Yang; Edward Chia-Cheng Lai

    To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin. We conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium–glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients’ age, sex, laboratory data, co-morbidities, and concomitant medications. We identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73–1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14–2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49–1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80–1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49–0.95). The risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.

    更新日期:2019-11-28
  • Disease–treatment interactions in the management of patients with obesity and diabetes who have atrial fibrillation: the potential mediating influence of epicardial adipose tissue
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-24
    Milton Packer

    Both obesity and type 2 diabetes are important risk factors for atrial fibrillation (AF), possibly because they both cause an expansion of epicardial adipose tissue, which is the source of proinflammatory adipocytokines that can lead to microvascular dysfunction and fibrosis of the underlying myocardium. If the derangement of epicardial fat adjoins the left atrium, the result is an atrial myopathy, which is clinically manifest as AF. In patients with AF, there is a close relationship between epicardial fat volume and the severity of electrophysiological abnormalities in the adjacent myocardial tissues, and epicardial fat mass predicts AF in the general population. The expansion of epicardial adipose tissue in obesity and type 2 diabetes may also affect the left ventricle, impairing its distensibility and leading to heart failure with a preserved ejection fraction (HFpEF). Patients with obesity or type 2 diabetes with AF often have HFpEF, but the diagnosis may be missed, if dyspnea is attributed to increased body mass or to the arrhythmia. The expected response to the treatment for obesity, diabetes or AF may be influenced by their effects on epicardial inflammation and the underlying atrial and ventricular myopathy. Bariatric surgery and metformin reduce epicardial fat mass and ameliorate AF, whereas insulin promotes adipogenesis and cardiac fibrosis, and its use is accompanied by an increased risk of AF. Rate control strategies for AF may impair exercise tolerance, because they allow for greater time for ventricular filling in patients who cannot tolerate volume loading because of cardiac fibrosis and HFpEF. At the same time, both obesity and diabetes decrease the expected success rate of rhythm control strategies for AF (e.g., electrical cardioversion or catheter ablation), because increased epicardial adipose tissue volumes and cardiac fibrosis are important determinants of AF recurrence following these procedures.

    更新日期:2019-11-28
  • Intrinsic calcification angle: a novel feature of the vulnerable coronary plaque in patients with type 2 diabetes: an optical coherence tomography study
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-24
    Sebastian Reith; Andrea Milzi; Enrico Domenico Lemma; Rosalia Dettori; Kathrin Burgmaier; Nikolaus Marx; Mathias Burgmaier

    Coronary calcification is associated with high risk for cardiovascular events. However, its impact on plaque vulnerability is incompletely understood. In the present study we defined the intrinsic calcification angle (ICA) as the angle externally projected by a vascular calcification and analyzed its role as novel feature of coronary plaque vulnerability in patients with type 2 diabetes. Optical coherence tomography was used to determine ICA in 219 calcifications from 56 patients with stable coronary artery disease (CAD) and 143 calcifications from 36 patients with acute coronary syndrome (ACS). We then used finite elements analysis to gain mechanistic insight into the effects of ICA. Minimal (139.8 ± 32.8° vs. 165.6 ± 21.6°, p < 0.001) and mean ICA (164.1 ± 14.3° vs. 176.0 ± 8.4°, p < 0.001) were lower in ACS vs. stable CAD patients. Mean ICA predicted ACS with very good diagnostic efficiency (AUC = 0.840, 95% CI 0.797–0.882, p < 0.001, optimal cut-off 175.9°); younger age (OR 0.95 per year, 95% CI 0.92–0.98, p = 0.002), male sex (OR 2.18, 95% CI 1.41–3.38, p < 0.001), lower HDL-cholesterol (OR 0.82 per 10 mg/dl, 95% CI 0.68–0.98, p = 0.029) and ACS (OR 14.71, 95% CI 8.47–25.64, p < 0.001) were determinants of ICA < 175.9°. A lower ICA predicted ACS (OR for 10°-variation 0.25, 95% CI 0.13–0.52, p < 0.001) independently from fibrous cap thickness, presence of macrophages or extension of lipid core. In finite elements analysis we confirmed that lower ICA causes increased stress on a lesion’s fibrous cap; this effect was potentiated in more superficial calcifications and adds to the destabilizing role of smaller calcifications. Our clinical and mechanistic data for the first time identify ICA as a novel feature of coronary plaque vulnerability.

    更新日期:2019-11-28
  • Serial coronary computed tomography angiography-verified coronary plaque progression: comparison of stented patients with or without diabetes
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-24
    Rui Shi; Ke Shi; Zhi-gang Yang; Ying-kun Guo; Kai-yue Diao; Yue Gao; Yi Zhang; Shan Huang

    Patients with Diabetes mellitus (DM) are susceptible to coronary artery disease (CAD). However, the impact of DM on plaque progression in the non-stented segments of stent-implanted patients has been rarely reported. This study aimed to evaluate the impact of DM on the prevalence, characteristics and severity of coronary computed tomography angiography (CCTA) verified plaque progression in stented patients. A comparison between diabetic and non-diabetic patients was performed. A total of 98 patients who underwent clinically indicated serial CCTAs arranged within 1 month before and at least 6 months after percutaneous coronary intervention (PCI) were consecutively included. All the subjects were categorized into diabetic group (n = 36) and non-diabetic groups (n = 62). Coronary stenosis extent scores, segment involvement scores (SIS), segment stenosis scores (SSS) at baseline and follow-up CCTA were quantitatively assessed. The prevalence, characteristics and severity of plaque progression was evaluated blindly to the clinical data and compared between the groups. During the median 1.5 year follow up, a larger number of patients (72.2% vs 40.3%, P = 0.002), more non-stented vessels (55.7% vs 23.2%, P < 0.001) and non-stented segments (10.3% vs 4.4%, P < 0.001) showed plaque progression in DM group, compared to non-DM controls. More progressive lesions in DM patients were found to be non-calcified plaques (31.1% vs 12.8%, P = 0.014) or non-stenotic segments (6.6% vs 3.0%, p = 0.005) and were more widely distributed on left main artery (24.2% vs 5.2%, p = 0.007), the right coronary artery (50% vs 21.1%, P = 0.028) and the proximal left anterior artery (33.3% vs 5.1%, P = 0.009) compared to non-DM patients. In addition, DM patients possessed higher numbers of progressive segments per patient, ΔSIS and ΔSSS compared with non-DM individuals (P < 0.001, P = 0.029 and P < 0.001 respectively). A larger number of patients with at least two progressive lesions were found in the DM group (P = 0.006). Multivariate logistic regression analysis demonstrated that DM (OR: 4.81; 95% CI 1.64–14.07, P = 0.004) was independently associated with plaque progression. DM is closely associated with the prevalence and severity of CCTA verified CAD progression. These findings suggest that physicians should pay attention to non-stent segments and the management of non-stent segment plaque progression, particularly to DM patients.

    更新日期:2019-11-28
  • Renal glucosuria is associated with lower body weight and lower rates of elevated systolic blood pressure: results of a nationwide cross-sectional study of 2.5 million adolescents
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-25
    Boris Fishman; Gadi Shlomai; Gilad Twig; Estela Derazne; Alexander Tenenbaum; Enrique Z. Fisman; Adi Leiba; Ehud Grossman

    Gene coding mutations found in sodium glucose co-transporters (SGLTs) are known to cause renal glucosuria. SGLT2 inhibitors have recently been shown to be effective hypoglycemic agents as well as possessing cardiovascular and renal protective properties. These beneficial effects have to some extent, been attributed to weight loss and reduced blood pressure. The aim of the current study was to evaluate the prevalence of renal glucosuria amongst a large cohort of Israeli adolescents and to investigate whether renal glucosuria is associated with lower body weight and lower blood pressure values. Medical and socio-demographic data were collected from the Israeli Defense Force’s conscription center’s database. A cross-sectional study to evaluate the association between conscripts diagnosed as overweight [BMI percentiles of ≥ 85 and < 95 and obesity (≥ 95 BMI percentile)] and afflicted with renal glucosuria was conducted. In addition, we assessed the association of renal glucosuria with elevated diastolic and systolic blood pressure. Multinomial regression models were used. The final study cohort comprised 2,506,830 conscripts of whom 1108 (0.044%) were diagnosed with renal glucosuria, unrelated to diabetes mellitus, with males twice as affected compared to females. The adjusted odds ratio for overweight and obesity was 0.66 (95% CI 0.50–0.87) and 0.62 (95% CI 0.43–0.88), respectively. Adolescents afflicted with renal glucosuria were also less likely to have an elevated systolic blood pressure of 130–139 mmHg with an adjusted odds ratio of 0.74 (95% CI 0.60–0.90). Renal glucosuria is associated with lower body weight and obesity as well as with lower rates of elevated systolic blood pressure.

    更新日期:2019-11-28
  • Atrial fibrillation and its arrhythmogenesis associated with insulin resistance
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-26
    Yi-Hsin Chan; Gwo-Jyh Chang; Ying-Ju Lai; Wei-Jan Chen; Shang-Hung Chang; Li-Man Hung; Chi-Tai Kuo; Yung-Hsin Yeh

    Insulin resistance (IR) is considered as a risk factor for atrial fibrillation (AF) even before diabetes develops. The pathophysiology and underlying mechanism are largely unclear. We investigated the corresponding mechanism in two IR models of rats fed 15-week high-fat (HFa) and high-fructose/cholesterol (HFr) diets. AF was evaluated and induced by burst atrial pacing. Isolated atrial myocytes were used for whole-cell patch clamp and calcium assessment. Ex vivo whole heart was used for optical mapping. Western blot and immunofluorescence were used for quantitative protein evaluation. Both HFa and HFr rat atria were vulnerable to AF evaluated by burst atrial pacing. Isolated atrial myocytes from HFa and HFr rats revealed significantly increased sarcoplasmic reticulum calcium content and diastolic calcium sparks. Whole-heart mapping showed prolonged calcium transient duration, conduction velocity reduction, and repetitive ectopic focal discharge in HFa and HFr atria. Protein analysis revealed increased TGF-β1 and collagen expression; increased superoxide production; abnormal upregulation of calcium-homeostasis-related proteins, including oxidized CaMKIIδ, phosphorylated-phospholamban, phosphorylated-RyR-2, and sodium-calcium exchanger; and increased Rac1 activity in both HFa and HFr atria. We observed that inhibition of CaMKII suppressed AF in both HF and HFr diet-fed rats. In vitro palmitate-induced IR neonatal cardiomyocytes and atrial fibroblasts expressed significantly more TGF-β1 than did controls, suggesting paracrine and autocrine effects on both myocytes and fibroblasts. IR engenders both atrial structural remodeling and abnormal intracellular calcium homeostasis, contributing to increased AF susceptibility. The inhibition of CaMKII may be a potential therapeutic target for AF in insulin resistance.

    更新日期:2019-11-28
  • Pericoronary fat inflammation and Major Adverse Cardiac Events (MACE) in prediabetic patients with acute myocardial infarction: effects of metformin
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-09-30
    Celestino Sardu; Nunzia D’Onofrio; Michele Torella; Michele Portoghese; Francesco Loreni; Simone Mureddu; Giuseppe Signoriello; Lucia Scisciola; Michelangela Barbieri; Maria Rosaria Rizzo; Marilena Galdiero; Marisa De Feo; Maria Luisa Balestrieri; Giuseppe Paolisso; Raffaele Marfella

    Pericoronary adipose tissue inflammation might lead to the development and destabilization of coronary plaques in prediabetic patients. Here, we evaluated inflammation and leptin to adiponectin ratio in pericoronary fat from patients subjected to coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). Furthermore, we compared the 12-month prognosis of prediabetic patients compared to normoglycemic patients (NG). Finally, the effect of metformin therapy on pericoronary fat inflammation and 12-months prognosis in AMI-prediabetic patients was also evaluated. An observational prospective study was conducted on patients with first AMI referred for CABG. Participants were divided in prediabetic and NG-patients. Prediabetic patients were divided in two groups; never-metformin-users and current-metformin-users receiving metformin therapy for almost 6 months before CABG. During the by-pass procedure on epicardial coronary portion, the pericoronary fat was removed from the surrounding stenosis area. The primary endpoints were the assessments of Major-Adverse-Cardiac-Events (MACE) at 12-month follow-up. Moreover, inflammatory tone was evaluated by measuring pericoronary fat levels of tumor necrosis factor-α (TNF-α), sirtuin 6 (SIRT6), and leptin to adiponectin ratio. Finally, inflammatory tone was correlated to the MACE during the 12-months follow-up. The MACE was 9.1% in all prediabetic patients and 3% in NG-patients. In prediabetic patients, current-metformin-users presented a significantly lower rate of MACE compared to prediabetic patients never-metformin-users. In addition, prediabetic patients showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to NG-patients (P < 0.001). Prediabetic never-metformin-users showed higher inflammatory tone and leptin to adiponectin ratio in pericoronary fat compared to current-metformin-users (P < 0.001). Remarkably, inflammatory tone and leptin to adiponectin ratio was significantly related to the MACE during the 12-months follow-up. Prediabetes increase inflammatory burden in pericoronary adipose tissue. Metformin by reducing inflammatory tone and leptin to adiponectin ratio in pericoronary fat may improve prognosis in prediabetic patients with AMI. Trial registration Clinical Trial NCT03360981, Retrospectively Registered 7 January 2018

    更新日期:2019-11-28
  • Effects of 1 year of exercise training versus combined exercise training and weight loss on body composition, low-grade inflammation and lipids in overweight patients with coronary artery disease: a randomized trial
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-01
    Lene Rørholm Pedersen; Rasmus Huan Olsen; Christian Anholm; Arne Astrup; Jesper Eugen-Olsen; Mogens Fenger; Lene Simonsen; Rosemary L. Walzem; Steen Bendix Haugaard; Eva Prescott

    Dyslipidaemia and low-grade inflammation are central in atherogenesis and linked to overweight and physical inactivity. Lifestyle changes are important in secondary prevention of coronary artery disease (CAD). We compared the effects of combined weight loss and interval training with interval training alone on physical fitness, body composition, dyslipidaemia and low-grade inflammation in overweight, sedentary participants with CAD. Seventy CAD patients, BMI 28–40 kg/m2 and age 45–75 years were randomised to (1) 12 weeks’ aerobic interval training (AIT) at 90% of peak heart rate three times/week followed by 40 weeks’ AIT twice weekly or (2) a low energy diet (LED) (800–1000 kcal/day) for 8–10 weeks followed by 40 weeks’ weight maintenance including AIT twice weekly and a high-protein/low-glycaemic load diet. Effects of the intervention were evaluated by physical fitness, body weight and composition. Dyslipidaemia was described using both biochemical analysis of lipid concentrations and lipoprotein particle subclass distribution determined by density profiling. Low-grade inflammation was determined by C-reactive protein, soluble urokinase-type plasminogen activator receptor and tumour necrosis factor α. Effects on continuous outcomes were tested by mixed-models analysis. Twenty-six (74%) AIT and 29 (83%) LED + AIT participants completed the study. At baseline subject included 43 (78%) men; subjects averages were: age 63 years (6.2), body weight 95.9 kg (12.2) and VO2peak 20.7 mL O2/kg/min (4.9). Forty-six (84%) had pre-diabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). LED + AIT reduced body weight by 7.2 kg (− 8.4; − 6.1) and waist circumference by 6.6 cm (− 7.7; − 5.5) compared to 1.7 kg (− 0.7; − 2.6) and 3.3 cm (− 5.1; − 1.5) after AIT (within-group p < 0.001, between-group p < 0.001 and p = 0.018, respectively). Treatments caused similar changes in VO2peak and lowering of total cholesterol, triglycerides, non-HDL cholesterol and low-grade inflammation. A shift toward larger HDL particles was seen following LED + AIT while AIT elicited no change. Both interventions were feasible. Both groups obtained improvements in VO2peak, serum-lipids and inflammation with superior weight loss and greater central fat loss following LED + AIT. Combined LED induced weight loss and exercise can be recommended to CAD patients. Trial registration NCT01724567, November 12, 2012, retrospectively registered (enrolment ended in April 2013).

    更新日期:2019-11-28
  • The impact of body weight and diabetes on new-onset atrial fibrillation: a nationwide population based study
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-01
    Yun Gi Kim; Kyung-Do Han; Jong-Il Choi; Ki Yung Boo; Do Young Kim; Suk-Kyu Oh; Kwang-No Lee; Jaemin Shim; Jin Seok Kim; Young-Hoon Kim

    Being obese or underweight, and having diabetes are important risk factors for new-onset atrial fibrillation (AF). However, it is unclear whether there is any interaction between body weight and diabetes in regard to development of new-onset AF. We aimed to evaluate the role of body weight status and various stage of diabetes on new-onset AF. This was a nationwide population based study using National Health Insurance Service (NHIS) data. A total of 9,797,418 patients who underwent national health check-ups were analyzed. Patients were classified as underweight [body mass index (BMI) < 18.5], normal reference group (18.5 ≤ BMI < 23.0), upper normal (23.0 ≤ BMI < 25.0), overweight (25.0 ≤ BMI < 30.0), or obese (BMI ≥ 30.0) based on BMI. Diabetes were categorized as non-diabetic, impaired fasting glucose (IFG), new-onset diabetes, diabetes < 5 years, and diabetes ≥ 5 years. Primary outcome end point was new-onset AF. New-onset AF was defined as one inpatient or two outpatient records of International Classification of Disease, Tenth Revision (ICD-10) codes in patients without prior AF diagnosis. During 80,130,161 patient*years follow-up, a total of 196,136 new-onset AF occurred. Obese [hazard ration (HR) = 1.327], overweight (HR = 1.123), upper normal (HR = 1.040), and underweight (HR = 1.055) patients showed significantly increased risk of new-onset AF compared to the normal reference group. Gradual escalation in the risk of new-onset AF was observed along with advancing diabetic stage. Body weight status and diabetes were independently associated with new-onset AF and at the same time, had synergistic effects on the risk of new-onset AF with obese diabetic patients having the highest risk (HR = 1.823). Patients with obesity, overweight, underweight, and diabetes had significantly increased risk of new-onset AF. Body weight status and diabetes had synergistic effects on the risk of new-onset AF. The risk of new-onset AF increased gradually with advancing diabetic stage. This study suggests that maintaining optimal body weight and glucose homeostasis might prevent new-onset AF.

    更新日期:2019-11-28
  • Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-04
    Milton Packer

    Four large-scale trials in type 2 diabetes have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the occurrence of serious heart failure events. Additionally, the DAPA-HF trial demonstrated a benefit of dapagliflozin to reduce major adverse outcomes in patients with established heart failure with a reduced ejection fraction. The trial sheds light on potential mechanisms. In DAPA-HF, the benefits of dapagliflozin on heart failure were seen to a similar extent in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related cardiotoxicity. The action of SGLT2 inhibitors to promote ketogenesis is also primarily a feature of the action of these drugs in patients with diabetes, raising doubts that enhanced ketogenesis contributes to the benefit on heart failure. Also, dapagliflozin does not have a meaningful effect to decrease circulating natriuretic peptides, and it did not potentiate the actions of diuretics in DAPA-HF; moreover, intensification of diuretics therapy does not reduce cardiovascular death, questioning a benefit of SGLT2 inhibitors that is mediated by an action on renal sodium excretion. Finally, although hematocrit increases with SGLT2 inhibitors might favorably affect patients with coronary artery disease, in DAPA-HF, the benefit of dapagliflozin was similar in patients with or without an ischemic cardiomyopathy; furthermore, increases in hematocrit do not favorably affect the clinical course of patients with heart failure. Therefore, the results of DAPA-HF do not support many currently-held hypotheses about the mechanism of action of SGLT2 inhibitors in heart failure. Ongoing trials are likely to provide further insights.

    更新日期:2019-11-28
  • Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-05
    Julie R. Lundgren; Kristine Færch; Daniel R. Witte; Anna E. Jonsson; Oluf Pedersen; Torben Hansen; Torsten Lauritzen; Jens J. Holst; Dorte Vistisen; Marit E. Jørgensen; Signe S. Torekov; Nanna B. Johansen

    Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD. This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m2, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex. A greater GLP-1 response was associated with lower central systolic and diastolic BP of − 1.17 mmHg (95% confidence interval (CI) − 2.07 to − 0.27 mmHg, P = 0.011) and − 0.74 mmHg (95% CI − 1.29 to − 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of − 1.27 mmHg (95% CI − 2.20 to − 0.33 mmHg, P = 0.008) and − 1.00 (95% CI − 1.56 to − 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: − 4.94 (95% CI − 8.56 to − 1.31) mmHg, central diastolic BP: − 3.05 (95% CI − 5.29 to − 0.80) mmHg, brachial systolic BP: − 5.18 (95% CI − 8.94 to − 1.42) mmHg, and brachial diastolic BP: − 2.96 (95% CI − 5.26 to − 0.67) mmHg). Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality. Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005

    更新日期:2019-11-28
  • Genetic predisposition to type 2 diabetes is associated with severity of coronary artery disease in patients with acute coronary syndromes
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-08
    Qiwen Zheng; Jie Jiang; Yong Huo; Dafang Chen

    Accumulating evidence has shown that type 2 diabetes (T2D) and coronary artery disease (CAD) may stem from a ‘common soil’. The aim of our study was to examine the association between genetic predisposition to T2D and the risk of severe CAD among patients with acute coronary syndromes (ACS) undergoing angiography. The current case–control study included 1414 ACS patients with at least one major epicardial vessel stenosis > 50% enrolled in the ACS Genetic Study. The severity of CAD was quantified by the number of coronary arteries involved. Genetic risk score (GRS) was calculated using 41 common variants that robustly associated with increased risk of T2D in East Asians. Logistic regression models were used to estimate the association between GRS and the severity of CAD. In the age-, sex- and BMI-adjusted model, each additional risk allele was associated with a 6% increased risk of multi-vessel disease (OR = 1.06, 95% CI 1.02–1.09). The OR was 1.43 (95% CI 1.08–1.89) for the risk of severe CAD when comparing the extreme tertiles of T2D-GRS. The association was not reduced after further adjustment for conventional cardiovascular risk factors. Additional adjustment for T2D status in our regression model attenuated the association by approximately one quarter. In subgroup analysis, the strengths of the associations between GRS and the severity of CAD were broadly similar in terms of baseline demographic information and disease characteristics. Our data indicated that genetic predisposition to T2D is associated with elevated risk of severe CAD. This association revealed a possible causal relationship and is partially mediated through diabetic status.

    更新日期:2019-11-28
  • Hypomagnesemia is associated with new-onset diabetes mellitus following heart transplantation
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-11
    Yael Peled; Eilon Ram; Jacob Lavee; Alexander Tenenbaum; Enrique Z. Fisman; Dov Freimark; Robert Klempfner; Leonid Sternik; Michael Shechter

    Diabetes mellitus (DM) is a major cause of morbidity and mortality following heart transplantation (HT), with 21% and 35% of survivors being affected within 1 and 5 years following HT, respectively. Magnesium deficiency is common among HT patients treated with calcineurin inhibitors and is a known risk factor for DM in non-HT patients. We therefore investigated the association between serum Mg (s-Mg) levels and new-onset diabetes after transplantation (NODAT). Between 2002 and 2017, 102 non-DM HT patients were assessed. In accordance with the mean value of all s-Mg levels recorded during the first year post-HT, patients were divided into high s-Mg (≥ 1.8 mg/dL) and low s-Mg (< 1.8 mg/dL) groups. The endpoint was NODAT, defined according to the diagnostic criteria of the American Diabetes Association. Baseline clinical and demographic characteristics for the high (n = 45) and low s-Mg (n = 57) groups were similar. Kaplan–Meier survival analysis showed that 15-year freedom from NODAT was significantly higher among patients with high vs low s-Mg (85% vs 46% log-rank test, p < 0.001). Consistently, multivariate analysis adjusted for age, gender, immunosuppression therapies, BMI and mean creatinine values in the first year post-HT, showed that low s-Mg was independently associated with a significant > 8-fold increased risk for NODAT (95% CI 2.15–32.63, p = 0.003). Stroke rate was significantly higher in patients with low s-Mg levels vs high s-Mg (14% vs 0, p = 0.025), as well as long term mortality (HR 2.6, 95% CI 1.02–6.77, p = 0.05). Low s-Mg level post-HT is an independent risk factor for NODAT in HT patients. The implications of interventions, focusing on preventing or correcting low s-Mg, for the risk of NODAT and for clinical outcomes should be evaluated.

    更新日期:2019-11-28
  • Phenotyping diabetic cardiomyopathy in Europeans and South Asians
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-11
    Elisabeth H. M. Paiman; Huub J. van Eyk; Maurice B. Bizino; Ilona A. Dekkers; Paul de Heer; Johannes W. A. Smit; Ingrid M. Jazet; Hildo J. Lamb

    The pathogenesis and cardiovascular impact of type 2 diabetes (T2D) may be different in South Asians compared with other ethnic groups. The phenotypic characterization of diabetic cardiomyopathy remains debated and little is known regarding differences in T2D-related cardiovascular remodeling across ethnicities. We aimed to characterize the differences in left ventricular (LV) diastolic and systolic function, LV structure, myocardial tissue characteristics and aortic stiffness between T2D patients and controls and to assess the differences in T2D-related cardiovascular remodeling between South Asians and Europeans. T2D patients and controls of South Asian and European descent underwent 3 Tesla cardiovascular magnetic resonance imaging (CMR) and cardiac proton-magnetic resonance spectroscopy (1H-MRS). Differences in cardiovascular parameters between T2D patients and controls were examined using ANCOVA and were reported as mean (95% CI). Ethnic group comparisons in the association of T2D with cardiovascular remodeling were made by adding the interaction term between ethnicity and diabetes status to the model. A total of 131 individuals were included (54 South Asians [50.1 ± 8.7 years, 33% men, 33 patients vs. 21 controls) and 77 Europeans (58.8 ± 7.0 years, 56% men, 48 patients vs. 29 controls)]. The ratio of the transmitral early and late peak filling rate (E/A) was lower in T2D patients compared with controls, in South Asians [− 0.20 (− 0.36; − 0.03), P = 0.021] and Europeans [− 0.20 (− 0.36; − 0.04), P = 0.017], whereas global longitudinal strain and aortic pulse wave velocity were similar. South Asian T2D patients had a higher LV mass [+ 22 g (15; 30), P < 0.001] (P for interaction by ethnicity = 0.005) with a lower extracellular volume fraction [− 1.9% (− 3.4; − 0.4), P = 0.013] (P for interaction = 0.114), whilst European T2D patients had a higher myocardial triglyceride content [+ 0.59% (0.35; 0.84), P = 0.001] (P for interaction = 0.002) than their control group. Diabetic cardiomyopathy was characterized by impaired LV diastolic function in South Asians and Europeans. Increased LV mass was solely observed among South Asian T2D patients, whereas differences in myocardial triglyceride content between T2D patients and controls were only present in the European cohort. The diabetic cardiomyopathy phenotype may differ between subsets of T2D patients, for example across ethnicities, and tailored strategies for T2D management may be required.

    更新日期:2019-11-28
  • Impact of free fatty acids on prognosis in coronary artery disease patients under different glucose metabolism status
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-14
    Jing-Lu Jin; Ye-Xuan Cao; Hui-Hui Liu; Hui-Wen Zhang; Yuan-Lin Guo; Na-Qiong Wu; Cheng-Gang Zhu; Rui-Xia Xu; Ying Gao; Jing Sun; Qian Dong; Jian-Jun Li

    The aim of the present study is to examine the effects of free fatty acids (FFAs) on major cardiovascular events (MACEs) in patients with stable coronary artery disease (CAD) and different glucose metabolism status. In this study, we consecutively enrolled 5443 patients from March 2011 to May 2015. Patients were categorized according to both status of glucose metabolism status [diabetes mellitus (DM), pre-diabetes (Pre-DM), normal glycaemia regulation (NGR)] and FFAs levels. All subjects were followed up for the occurrence of the MACEs. During a median of 6.7 years’ follow-up, 608 MACEs occurred. A twofold higher FFAs level was independently associated with MACEs after adjusting for confounding factors [Hazard Ratio (HR): 1.242, 95% confidence interval (CI) 1.084–1.424, p value = 0.002]. Adding FFAs to the Cox model increased the C-statistic by 0.015 (0.005–0.027). No significant difference in MACEs was observed between NGR and Pre-DM groups (p > 0.05). When patients were categorized by both status of glucose metabolism and FFAs levels, medium and high FFAs were associated with significantly higher risk of MACEs in Pre-DM [1.736 (1.018–2.959) and 1.779 (1.012–3.126), all p-value < 0.05] and DM [2.017 (1.164–3.494) and 2.795 (1.619–4.824), all p-value < 0.05]. The present data indicated that baseline FFAs levels were associated with the prognosis in DM and Pre-DM patients with CAD, suggesting that FFAs may be a valuable predictor in patients with impaired glucose metabolism.

    更新日期:2019-11-28
  • Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-17
    Ruth L. Coleman; Charles A. B. Scott; Zhihui Lang; M. Angelyn Bethel; Jaakko Tuomilehto; Rury R. Holman

    Alpha-glucosidase inhibitors (AGIs) have been shown to reduce incident type 2 diabetes but their impact on cardiovascular (CV) disease remains controversial. We sought to identify the overall impact of AGIs with respect to incident type 2 diabetes in individuals with impaired glucose tolerance (IGT), and CV outcomes in those with IGT or type 2 diabetes. We used PubMed and SCOPUS to identify randomized controlled trials reporting the incidence of type 2 diabetes and/or CV outcomes that had compared AGIs with placebo in populations with IGT or type 2 diabetes, with or without established CV disease. Eligible studies were required to have ≥ 500 participants and/or ≥ 100 endpoints of interest. Meta-analyses of available trial data were performed using random effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes and CV outcomes. Of ten trials identified, three met our inclusion criteria for incident type 2 diabetes and four were eligible for CV outcomes. The overall HR (95% CI) comparing AGI with placebo for incident type 2 diabetes was 0.77 (0.67–0.88), p < 0.0001, and for CV outcomes was 0.98 (0.89–1.10), p = 0.85. There was little to no heterogeneity between studies, with I2 values of 0.03% (p = 0.43) and 0% (p = 0.79) for the two outcomes respectively. Allocation of people with IGT to an AGI significantly reduced their risk of incident type 2 diabetes by 23%, whereas in those with IGT or type 2 diabetes the impact on CV outcomes was neutral.

    更新日期:2019-11-28
  • Relationships of coronary culprit-plaque characteristics with duration of diabetes mellitus in acute myocardial infarction: an intravascular optical coherence tomography study
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-19
    Zhaoxue Sheng; Peng Zhou; Chen Liu; Jiannan Li; Runzhen Chen; Jinying Zhou; Li Song; Hanjun Zhao; Hongbing Yan

    Diabetes mellitus (DM) or pre-diabetes status is closely associated with features of vulnerable coronary lesions in patients with stable coronary heart disease or acute coronary syndrome. However, the association between duration of diabetes and the morphologies and features of vulnerable plaques has not been fully investigated in patients with acute myocardial infarction (AMI). We enrolled a total of 279 patients who presented with AMI between March 2017 and March 2019 and underwent pre-intervention optical coherence tomography imaging of culprit lesions. Patients with DM were divided into two subgroups: a Short-DM group with DM duration of < 10 years and a Long-DM group with DM duration of ≥ 10 years. Baseline clinical data and culprit-plaque characteristics were compared between patients without DM (the non-DM group), those in the Short-DM group, and those in the Long-DM group. Patients with DM represented 34.1% of the study population (95 patients). The Short- and Long-DM groups included 64 (67.4%) and 31 patients (32.6%), respectively. Glycated hemoglobin A1c (HbA1c) levels were significantly higher in the Long-DM group than the Non- or Short-DM groups (8.4% [Long-DM] versus 5.7% [Non-DM] and 7.6% [Short-DM], P < 0.001). In addition, the highest prevalence of lipid-rich plaques, thin-cap fibroatheroma (TCFA), and plaque ruptures of culprit lesions were observed in the Long-DM group (lipid-rich plaques: 80.6% [Long-DM] versus 52.2% [Non-DM] and 62.5% [Short-DM], P = 0.007; TCFA: 41.9% [Long-DM] versus 19.6% [Non-DM] and 31.3% [Short-DM], P = 0.012; plaque rupture: 74.2% [Long-DM] versus 46.7% [Non-DM] and 48.4% [Short-DM], P = 0.017). The frequency of calcification was significantly higher among patients with DM than among those without (62.1% versus 46.2%, P = 0.016); however, no significant differences were found between the DM subgroups (61.3% [Long-DM] versus 62.5% [Short-DM], P = 0.999). Increased duration of DM combined with higher HbA1c levels influences culprit-plaque characteristics in patients with DM who suffer AMI. These findings might account for the higher risks of cardiac death in DM patients with long disease duration. Trial registration This study is registered at clinicaltrials.gov as NCT03593928

    更新日期:2019-11-28
  • Efficacy of visceral fat estimation by dual bioelectrical impedance analysis in detecting cardiovascular risk factors in patients with type 2 diabetes
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-22
    Yoko Omura-Ohata; Cheol Son; Hisashi Makino; Ryo Koezuka; Mayu Tochiya; Tamiko Tamanaha; Ichiro Kishimoto; Kiminori Hosoda

    Visceral fat area (VFA) is a good surrogate marker of obesity-related disorders, such as hypertension, dyslipidemia and glucose intolerance. Although estimating the VFA by X-ray computed tomography (CT) is the primary index for visceral obesity, it is expensive and requires invasive radiation exposure. Dual bioelectrical impedance analysis (BIA) is a simple and reliable method to estimate VFA; however, the clinical usefulness of dual BIA remains unclear in patients with type 2 diabetes (T2D). We estimated the VFAs by dual BIA and CT in 98 patients with T2D and assessed anthropometric parameters, blood test results, and the presence of comorbid hypertension and dyslipidemia. We compared the correlation between the VFAs examined by dual BIA and CT. Furthermore, we performed the receiver operating characteristic (ROC) analyses for the VFAs to detect the presence of comorbid hypertension and/or dyslipidemia with T2D, which are major comorbidities of visceral obesity, and estimated the area under the curve (AUC). The measurement error between the VFAs by dual BIA and CT was significantly higher among patients with brain natriuretic peptide (BNP) ≥ 100 pg/mL than those with BNP < 100 pg/mL (39.2% ± 31.1% vs. 24.1% ± 18.6%, P < 0.05). After excluding patients with BNP ≥ 100 pg/mL, the VFA by dual BIA significantly correlated with the VFA by CT (r = 0.917; P < 0.0001). The AUC in the ROC analysis for the VFA by dual BIA to detect the presence of comorbid hypertension and/or dyslipidemia with T2D was almost equivalent to that for the VFA by CT. In patients with T2D without elevated BNP > 100 pg/mL as indicator for fluid accumulation interfering with BIA, estimation of the VFA by dual BIA significantly correlated with that by CT and also detected comorbid hypertension and/or dyslipidemia with T2D equivalent to those detected by CT. Hence, dual BIA could be an alternative to CT as a standard method for estimating the VFA in patients with diabetes.

    更新日期:2019-11-28
  • Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-22
    Lindsay E. Clegg; Robert C. Penland; Srinivas Bachina; David W. Boulton; Marcus Thuresson; Hiddo J. L. Heerspink; Stephanie Gustavson; C. David Sjöström; James A. Ruggles; Adrian F. Hernandez; John B. Buse; Robert J. Mentz; Rury R. Holman

    Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39–1.17) and EQW alone (0.85, 0.48–1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16–0.90) and compared with EQW (0.41, 0.17–0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94–2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40–3.35 mL/min/1.73 m2/year). This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.

    更新日期:2019-11-28
  • Cholesterol levels and development of cardiovascular disease in Koreans with type 2 diabetes mellitus and without pre-existing cardiovascular disease
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-22
    Mee Kyoung Kim; Kyungdo Han; Han Na Joung; Ki-Hyun Baek; Ki-Ho Song; Hyuk-Sang Kwon

    The aim of the present study was to identify a threshold for the cholesterol level at which the risk of cardiovascular disease (CVD) begins to increase in people with type 2 diabetes mellitus (DM). Using the Korean National Health Insurance Service database, 2,077,135 people aged ≥ 40 years with type 2 DM who underwent regular health checks between 2009 and 2012 were included. Subjects with previous CVD were excluded. Cox regression analyses were performed to estimate the risk of CVD for each low-density lipoprotein cholesterol (LDL-C) group using the < 70 mg/dL as the reference group. There were 78,560 cases of stroke (3.91%), and 50,791 myocardial infarction (MI, 2.53%) during a median follow-up of 7.1 years. Among participants not taking statins, LDL-C levels of 130–159 mg/dL and ≥ 160 mg/dL were significantly associated with the risk of MI: the hazard ratios (HRs) (95% confidence interval) were 1.19 (1.14–1.25) and 1.53 (1.46–1.62), respectively. Among participants taking statins, all categories of LDL-C level ≥ 70 mg/dL were significantly associated with increased risk of stroke and MI. We identified an increased risk of CVD in people with an LDL-C level ≥ 130 mg/dL among individuals with type 2 DM not taking statins. The risk of CVD was significantly higher in those taking statins with an LDL-C level ≥ 70 mg/dL.

    更新日期:2019-11-28
  • Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-30
    A. Lorenzo-Almorós; T. Hang; C. Peiró; L. Soriano-Guillén; J. Egido; J. Tuñón; Ó. Lorenzo

    Gestational diabetes mellitus (GDM) is defined as the presence of high blood glucose levels with the onset, or detected for the first time during pregnancy, as a result of increased insulin resistance. GDM may be induced by dysregulation of pancreatic β-cell function and/or by alteration of secreted gestational hormones and peptides related with glucose homeostasis. It may affect one out of five pregnancies, leading to perinatal morbidity and adverse neonatal outcomes, and high risk of chronic metabolic and cardiovascular injuries in both mother and offspring. Currently, GDM diagnosis is based on evaluation of glucose homeostasis at late stages of pregnancy, but increased age and body-weight, and familiar or previous occurrence of GDM, may conditionate this criteria. In addition, an earlier and more specific detection of GDM with associated metabolic and cardiovascular risk could improve GDM development and outcomes. In this sense, 1st–2nd trimester-released biomarkers found in maternal plasma including adipose tissue-derived factors such as adiponectin, visfatin, omentin-1, fatty acid-binding protein-4 and retinol binding-protein-4 have shown correlations with GDM development. Moreover, placenta-related factors such as sex hormone-binding globulin, afamin, fetuin-A, fibroblast growth factors-21/23, ficolin-3 and follistatin, or specific micro-RNAs may participate in GDM progression and be useful for its recognition. Finally, urine-excreted metabolites such as those related with serotonin system, non-polar amino-acids and ketone bodies, may complete a predictive or early-diagnostic panel of biomarkers for GDM.

    更新日期:2019-11-28
  • Short-term treatment with high dose liraglutide improves lipid and lipoprotein profile and changes hormonal mediators of lipid metabolism in obese patients with no overt type 2 diabetes mellitus: a randomized, placebo-controlled, cross-over, double-blind clinical trial
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-31
    Natia Peradze; Olivia M. Farr; Nikolaos Perakakis; Iolanda Lázaro; Aleix Sala-Vila; Christos S. Mantzoros

    Long-term treatment with up to 1.8 mg liraglutide improves cardiovascular and all-cause mortality in patients with type 2 diabetes at high risk for cardiovascular disease (CVD) and is currently under investigation in subjects without diabetes. Aim of our study was to investigate whether high dose (3 mg) short-term (5 weeks) treatment with liraglutide in obese patients with no overt type 2 diabetes affects metabolites, lipid and lipoprotein profile and components of activin–follistatin axis in cardiovascular beneficial or detrimental way. Twenty obese patients participated in a randomized, placebo-controlled, cross-over, double-blind study and were administrated liraglutide 3 mg or placebo for 5 weeks. Metabolites, fatty acids, lipid–lipoprotein profile and concentrations of activins and follistatins (250 parameters) were assessed in serum at start and completion of each treatment. Concentrations of important cardiovascular markers such as total, free and remnant cholesterol were reduced with liraglutide before and after adjusting for weight loss. Similarly, reductions in number of small and medium size LDL particles and in their total lipid concentration were observed with liraglutide and partially weight-loss related. Tyrosine levels were reduced and behenic acid levels were increased whereas only minor changes were observed in HDL, VLDL and IDL. Concentrations of activin AB and follistatin were significantly reduced in liraglutide-treated group. Treatment of obese patients without overt type 2 diabetes with high dose of liraglutide for a short period of time induces changes in lipid–lipoprotein and hormonal profile that are suggestive of lower risk of atherosclerosis and CVD. Trial registration ClinicalTrials.gov Identifier: NCT02944500. Study ID Number 2015P000327. Registered November 2016

    更新日期:2019-11-28
  • Diabetes and baseline glucose are associated with inflammation, left ventricular function and short- and long-term outcome in acute coronary syndromes: role of the novel biomarker Cyr 61
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-31
    Patric Winzap; Allan Davies; Roland Klingenberg; Slayman Obeid; Marco Roffi; François Mach; Lorenz Räber; Stephan Windecker; Christian Templin; Fabian Nietlispach; David Nanchen; Baris Gencer; Olivier Muller; Christian M. Matter; Arnold von Eckardstein; Thomas F. Lüscher

    Hyperglycemia in the setting of an acute coronary syndrome (ACS) impacts short term outcomes, but little is known about longer term effects. We therefore designed this study to firstly determine the association between hyperglycemia and short term and longer term outcomes in patients presenting with ACS and secondly evaluate the prognostic role of diabetes, body mass index (BMI) and the novel biomarker Cyr61 on outcomes. The prospective Special Program University Medicine-Acute Coronary Syndrome (SPUM-ACS) cohort enrolled 2168 patients with ACS between December 2009 and October 2012, of which 2034 underwent PCI (93.8%). Patients were followed up for 12 months. Events were independently adjudicated by three experienced cardiologists. Participants were recruited from four tertiary hospitals in Switzerland: Zurich, Geneva, Lausanne and Bern. Participants presenting with acute coronary syndromes and who underwent coronary angiography were included in the analysis. Patients were grouped according to history of diabetes (or HbA1c greater than 6%), baseline blood sugar level (BSL; < 6, 6–11.1 and > 11.1 mmol/L) and body mass index (BMI). The primary outcome was major adverse cardiac events (MACE) which was a composite of myocardial infarction, stroke and all-cause death. Secondary outcomes included the individual components of the primary endpoint, revascularisations, bleeding events (BARC classification) and cerebrovascular events (ischaemic or haemorrhagic stroke or TIA). Patients with hyperglycemia, i.e. BSL ≥ 11.1 mmol/L, had higher levels of C-reactive protein (CRP), white blood cell count (WBC), creatinine kinase (CK), higher heart rates and lower left ventricular ejection fraction (LVEF) and increased N-terminal pro-brain natriuretic peptide. At 30 days and 12 months, those with BSL ≥ 11.1 mmol/L had more MACE and death compared to those with BSL < 6.0 mmol/L or 6.0–11.1 mmol/L (HR-ratio 4.78 and 6.6; p < 0.001). The novel biomarker Cyr61 strongly associated with high BSL and STEMI and was independently associated with 1 year outcomes (HR 2.22; 95% CI 1.33–3.72; Tertile 3 vs. Tertile 1). In this large, prospective, independently adjudicated cohort of in all comers ACS patients undergoing PCI, both a history of diabetes and elevated entry glucose was associated with inflammation and increased risk of MACE both at short and long-term. The mediators might involve increased sympathetic activation, inflammation and ischemia as reflected by elevated Cyr61 levels leading to larger levels of troponin and lower LVEF. Trial registration Clinical Trial Registration Number: NCT01000701. Registered October 23, 2009

    更新日期:2019-11-28
  • Luseogliflozin attenuates neointimal hyperplasia after wire injury in high-fat diet-fed mice via inhibition of perivascular adipose tissue remodeling
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-31
    Yusaku Mori; Michishige Terasaki; Munenori Hiromura; Tomomi Saito; Hideki Kushima; Masakazu Koshibu; Naoya Osaka; Makoto Ohara; Tomoyasu Fukui; Hirokazu Ohtaki; Hirano Tsutomu; Sho-ichi Yamagishi

    Excess fat deposition could induce phenotypic changes of perivascular adipose tissue (PVAT remodeling), which may promote the progression of atherosclerosis via modulation of adipocytokine secretion. However, it remains unclear whether and how suppression of PVAT remodeling could attenuate vascular injury. In this study, we examined the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor, luseogliflozin on PVAT remodeling and neointima formation after wire injury in mice. Wilt-type mice fed with low-fat diet (LFD) or high-fat diet (HFD) received oral administration of luseogliflozin (18 mg/kg/day) or vehicle. Mice underwent bilateral femoral artery wire injury followed by unilateral removal of surrounding PVAT. After 25 days, injured femoral arteries and surrounding PVAT were analyzed. In LFD-fed lean mice, neither luseogliflozin treatment or PVAT removal attenuated the intima-to-media (I/M) ratio of injured arteries. However, in HFD-fed mice, luseogliflozin or PVAT removal reduced the I/M ratio, whereas their combination showed no additive reduction. In PVAT surrounding injured femoral arteries of HFD-fed mice, luseogliflozin treatment decreased the adipocyte sizes. Furthermore, luseogliflozin reduced accumulation of macrophages expressing platelet-derived growth factor-B (PDGF-B) and increased adiponectin gene expression. Gene expression levels of Pdgf-b in PVAT were correlated with the I/M ratio. Our present study suggests that luseogliflozin could attenuate neointimal hyperplasia after wire injury in HFD-fed mice partly via suppression of macrophage PDGF-B expression in PVAT. Inhibition of PVAT remodeling by luseogliflozin may be a novel therapeutic target for vascular remodeling after angioplasty.

    更新日期:2019-11-28
  • Association of PCSK9 plasma levels with metabolic patterns and coronary atherosclerosis in patients with stable angina
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-10-31
    Chiara Caselli; Serena Del Turco; Rosetta Ragusa; Valentina Lorenzoni; Michiel De Graaf; Giuseppina Basta; Arthur Scholte; Raffaele De Caterina; Danilo Neglia

    Aim of this study was to evaluate the relationship of plasma PCSK9 with metabolic and inflammatory profile and coronary atherosclerotic burden in patients with suspected CAD enrolled in the EVINCI study. PCSK9 was measured in 539 patients (60.3 ± 8.6 years, 256 males) with symptoms of CAD characterized by risk factors, bio-humoral profiles, and treatment. N = 412 patients underwent coronary computed tomography angiography (CTA) to assess the presence and characteristics of coronary atherosclerosis. A CTA score, combining extent, severity, composition, and location of plaques was computed. Patients were divided according to PCSK9 quartiles: I (< 136 ng/mL), II–III (136–266 ng/mL), and IV quartile (> 266 ng/mL). Compared with patients in quartile IV, patients in quartile I had a higher prevalence of the metabolic syndrome and higher values of body mass index. LDL- and HDL-cholesterol were significantly lower in patients in the quartile I than in those in quartile IV. Coronary CTA documented normal vessels in 30% and obstructive CAD in 35% of cases without differences among PCSK9 quartiles. Compared with patients with the highest levels, patients with the lowest PCSK9 levels had a higher CTA score mainly due to higher number of mixed non-obstructive coronary plaques. At multivariable analysis including clinical, medications, and lipid variables, PCSK9 was an independent predictor of the CTA score (coefficient − 0.129, SE 0.03, P < 0.0001), together with age, male gender, statins, interleukin-6, and leptin. In patients with stable CAD, low PCSK9 plasma levels are associated with a particular metabolic phenotype (low HDL cholesterol, the metabolic syndrome, obesity, insulin resistance and diabetes) and diffuse non-obstructive coronary atherosclerosis. Trial registration ClinicalTrials.gov NCT00979199. Registered September 17, 2009

    更新日期:2019-11-28
  • Glucose and insulin levels are associated with arterial stiffness and concentric remodeling of the heart
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-04
    Marcello Ricardo Paulista Markus; Susanne Rospleszcz; Till Ittermann; Sebastian Edgar Baumeister; Sabine Schipf; Ulrike Siewert-Markus; Roberto Lorbeer; Corinna Storz; Violetta Ptushkina; Annette Peters; Christa Meisinger; Fabian Bamberg; Matthias Nauck; Martin Bahls; Henry Völzke; Stephan Burkhard Felix; Robin Bülow; Wolfgang Rathmann; Marcus Dörr

    Mortality attributable to heart failure remains high. The prevalence of heart failure in patients with diabetes mellitus ranges from 19 to 26%. It is estimated that up to 21.1 million adults in the United States have diagnosed diabetes mellitus and around 80.8 million have impaired fasting glucose. We investigated the associations of fasting glucose (FG) and fasting insulin (FI), the homeostasis model assessment-insulin resistance index (HOMA-IR) and 2-h postload glucose (2HG) and insulin (2HI) with parameters of left ventricular geometry and function and arterial stiffness determined by magnetic resonance imaging in individuals without diagnosed type 2 diabetes. Cross-sectional analyses of 1001 individuals (453 women, 45.3%), aged 21 to 80 years, from two independent population-based studies, the Study of Health in Pomerania (SHIP-TREND-0) and KORA FF4 Study. FG, FI, HOMA-IR, 2HG and 2HI, as well as glucose tolerance categories, were analyzed for associations with heart and arterial parameters using multivariable-adjusted linear regression models. In total, 390 individuals (39%) had prediabetes (isolated impaired fasting glucose, isolated glucose tolerance or both), and 49 (4.9%) were found to have unknown type 2 diabetes. In the multivariable-adjusted analysis, positive linear associations of FG, FI, HOMA-IR, 2HG and 2HI with arterial stiffness index and left ventricular wall-thickness and concentricity and inverse linear associations with left ventricular end-diastolic volume were observed. A 1 mmol/l higher FG was associated with a 1.18 ml/m2.7 (1.80 to 0.57; p < 0.001) lower left ventricular end-diastolic volume index, a 0.042 mm/m2.7 (0.014 to 0.070) higher left ventricular wall-thickness index, a 0.12 mmHg m2.7/ml (0.06 to 0.17; p < 0.001) greater arterial stiffness index and a 0.037 g/ml (0.018 to 0.056; p < 0.001) higher left ventricular concentricity. Our findings suggest that higher glucose levels in the prediabetic range and insulin resistance might lead to higher arterial stiffness and concentric remodeling of the heart.

    更新日期:2019-11-28
  • Liraglutide improves lipid metabolism by enhancing cholesterol efflux associated with ABCA1 and ERK1/2 pathway
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-09
    Ya-Ru Wu; Xiao-Yun Shi; Chun-Yan Ma; Yue Zhang; Rui-Xia Xu; Jian-Jun Li

    Reverse cholesterol transport (RCT) is an important cardioprotective mechanism and the decrease in cholesterol efflux can result in the dyslipidemia. Although liraglutide, a glucagon like peptide-1 analogue, has mainly impacted blood glucose, recent data has also suggested a beneficial effect on blood lipid. However, the exact mechanism by which liraglutide modulates lipid metabolism, especially its effect on RCT, remain undetermined. Hence, the aim of the present study was to investigate the potential impacts and potential underlying mechanisms of liraglutide on the cholesterol efflux in both db/db mice and HepG2 cells. Six-week old db/db mice with high fat diet (HFD) and wild type mice were administered either liraglutide (200 μg/kg) or equivoluminal saline subcutaneously, twice daily for 8 weeks and body weight was measured every week. After the 8-week treatment, the blood was collected for lipid evaluation and liver was obtained from the mice for hematoxylin–eosin (HE) staining, red O staining and Western blotting. Cholesterol efflux was assessed by measuring the radioactivity in the plasma and feces after intraperitoneal injection of 3H-labeled cholesterol. HepG2 Cells were treated with different concentrations of glucose (0, 5, 25, and 50 mmol/L) with or without liraglutide (1000 nmol/L) for 24 h. The intracellular cholesterol efflux was detected by BODIPY-cholesterol fluorescence labeling. Real-time PCR or Western blotting was used to examine the expression levels of ABCA1, ABCG1 and SR-B1. Liraglutide significantly decreased blood glucose, serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). It also reduced liver lipid deposition in db/db mice fed with HFD. Moreover, the movement of 3H-cholesterol from macrophages to plasma and feces was significantly enhanced in db/db mice fed with HFD after liraglutide adminstration. In vitro study, liraglutide could promote the cholesterol efflux of HepG2 cells under high glucose, and also increase the expression of ABCA1 by activating the ERK1/2 pathway. Liraglutide could improve lipid metabolism and hepatic lipid accumulation in db/db mice fed with HFD by promoting reversal of cholesterol transport, which was associated with the up-regulation of ABCA1 mediated by the ERK1/2 phosphorylation.

    更新日期:2019-11-28
  • Incremental role of glycaemic variability over HbA1c in identifying type 2 diabetic patients with high platelet reactivity undergoing percutaneous coronary intervention
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-09
    Annunziata Nusca; Dario Tuccinardi; Claudio Proscia; Rosetta Melfi; Silvia Manfrini; Antonio Nicolucci; Antonio Ceriello; Paolo Pozzilli; Gian Paolo Ussia; Francesco Grigioni; Germano Di Sciascio

    Diabetic patients with on-treatment high platelet reactivity (HPR) show an increased risk of thrombotic events. Whether measuring glycated haemoglobin (HbA1c) levels and/or glycaemic variability (GV) may help identifying diabetic patients at higher risk deserving tailored antiplatelet and/or glucose lowering strategies is unknown. We aimed to investigate the relationship between GV, HbA1c levels and platelet reactivity in patients with type 2 diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI). Platelet reactivity was measured in type 2 DM patients using VerifyNow P2Y12 assay. HPR was defined as P2Y12 Reaction Unit (PRU) > 240. GV was expressed through mean amplitude of glycaemic excursions (MAGE) and coefficient of variance (CV) by using the iPro™ continuous glucose recorder. Thirty-five patients (age 70 ± 9 years, 86% male, mean HbA1c 7.2 ± 1.0%) on clopidogrel therapy were enrolled. HbA1c was independently associated with HPR (OR 7.25, 95% CI 1.55–33.86, p = 0.012). Furthermore, when factored into the model, GV indexes provided independent (OR 1.094, 95% CI 1.007–1.188, p < 0.034) and additional (p < 0.001) diagnostic significance in identifying diabetic patients with HPR. Glyco-metabolic state significantly correlates with HPR in well-controlled type 2 DM patients on clopidogrel therapy. HbA1c identifies patients at higher thrombotic risk but the highest diagnostic accuracy is achieved by combining GV and HbA1c. Whether individualized antithrombotic and glucose-lowering therapies based on the assessment of these parameters may reduce the incidence of thrombotic events in patients undergoing PCI should be further investigated.

    更新日期:2019-11-28
  • Circulating levels of mitochondrial uncoupling protein 2, but not prohibitin, are lower in humans with type 2 diabetes and correlate with brachial artery flow-mediated dilation
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-09
    Mamatha Kakarla; Venkata K. Puppala; Sudhi Tyagi; Amberly Anger; Kathryn Repp; Jingli Wang; Rong Ying; Michael E. Widlansky

    Excessive reactive oxygen species from endothelial mitochondria in type 2 diabetes individuals (T2DM) may occur through multiple related mechanisms, including production of mitochondrial reactive oxygen species (mtROS), inner mitochondrial membrane (Δψm) hyperpolarization, changes in mitochondrial mass and membrane composition, and fission of the mitochondrial networks. Inner mitochondrial membrane proteins uncoupling protein-2 (UCP2) and prohibitin (PHB) can favorably impact mtROS and mitochondrial membrane potential (Δψm). Circulating levels of UCP2 and PHB could potentially serve as biomarker surrogates for vascular health in patients with and without T2DM. Plasma samples and data from a total of 107 individuals with (N = 52) and without T2DM (N = 55) were included in this study. Brachial artery flow mediated dilation (FMD) was measured by ultrasound. ELISA was performed to measure serum concentrations of PHB1 and UCP2. Mitochondrial membrane potential was measured from isolated leukocytes using JC-1 dye. Serum UCP2 levels were significantly lower in T2DM subjects compared to control subjects (3.01 ± 0.34 vs. 4.11 ± 0.41 ng/mL, P = 0.04). There were no significant differences in levels of serum PHB. UCP2 levels significantly and positively correlated with FMDmm (r = 0.30, P = 0.03) in T2DM subjects only and remained significant after multivariable adjustment. Within T2DM subjects, serum PHB levels were significantly and negatively correlated with UCP2 levels (ρ = − 0.35, P = 0.03). Circulating UCP2 levels are lower in T2DM patients and correlate with endothelium-dependent vasodilation in conduit vessels. UCP2 could be biomarker surrogate for overall vascular health in patients with T2DM and merits additional investigation.

    更新日期:2019-11-28
  • Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-09
    Kausik K. Ray; Stefano Del Prato; Dirk Müller-Wieland; Bertrand Cariou; Helen M. Colhoun; Francisco J. Tinahones; Catherine Domenger; Alexia Letierce; Jonas Mandel; Rita Samuel; Maja Bujas-Bobanovic; Lawrence A. Leiter

    Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015

    更新日期:2019-11-28
  • High triglyceride–glucose index is associated with poor prognosis in patients with acute ST-elevation myocardial infarction after percutaneous coronary intervention
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-13
    Erfei Luo; Dong Wang; Gaoliang Yan; Yong Qiao; Bo Liu; Jiantong Hou; Chengchun Tang

    Insulin resistance (IR) is considered a pivotal risk factor for cardiometabolic diseases, and the triglyceride–glucose index (TyG index) has emerged as a reliable surrogate marker of IR. Although several recent studies have shown the association of the TyG index with vascular disease, no studies have further investigated the role of the TyG index in acute ST-elevation myocardial infarction (STEMI). The objective of the present study was to evaluate the potential role of the TyG index as a predictor of prognosis in STEMI patients after percutaneous coronary intervention (PCI). The study included 1092 STEMI patients who underwent PCI. The patients were divided into 4 quartiles according to TyG index levels. Clinical characteristics, fasting plasma glucose (FPG), triglycerides (TGs), other biochemical parameters, and the incidence of major adverse cardiovascular and cerebral events (MACCEs) during the follow-up period were recorded. The TyG index was calculated using the following formula: ln[fasting TGs (mg/dL) × FPG (mg/dL)/2]. The incidence of MACCEs and all-cause mortality within 30 days, 6 months and 1 year after PCI were higher among STEMI patients with TyG index levels in the highest quartile. The TyG index was significantly associated with an increased risk of MACCEs in STEMI patients within 1 year after PCI, independent of confounding factors, with a value of 1.529 (95% CI 1.001–2.061; P = 0.003) for those in the highest quartile. The area under the curve (AUC) of the TyG index predicting the occurrence of MACCEs in STEMI patients after PCI was 0.685 (95% CI 0.610–0.761; P = 0.001). The results also revealed that Killip class > 1, anaemia, albumin, uric acid, number of stents and left ventricular ejection fraction (LVEF) were independent predictors of MACCEs in STEMI patients after PCI (all P < 0.05). This study indicated an association between higher TyG index levels and increased risk of MACCEs in STEMI patients for the first time, and the TyG index might be a valid predictor of clinical outcomes in STEMI patients undergoing PCI. Trial Registration ChiCTR1900024577.

    更新日期:2019-11-28
  • Lysine pathway metabolites and the risk of type 2 diabetes and cardiovascular disease in the PREDIMED study: results from two case-cohort studies
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-13
    Cristina Razquin; Miguel Ruiz-Canela; Clary B. Clish; Jun Li; Estefania Toledo; Courtney Dennis; Liming Liang; Albert Salas-Huetos; Kerry A. Pierce; Marta Guasch-Ferré; Dolores Corella; Emilio Ros; Ramon Estruch; Enrique Gómez-Gracia; Montse Fitó; Jose Lapetra; Dora Romaguera; Angel Alonso-Gómez; Lluis Serra-Majem; Jordi Salas-Salvadó; Frank B. Hu; Miguel A. Martínez-González

    The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Biomarkers potentially modifiable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the effect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the effects of these metabolites on CVD or T2D risk. Two unstratified case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantified using liquid chromatography–tandem mass spectrometry, at baseline and after 1-year of intervention. In weighted Cox regression models, we found that baseline lysine (HR+1 SD increase = 1.26; 95% CI 1.06–1.51) and 2-AAA (HR+1 SD increase = 1.28; 95% CI 1.05–1.55) were both associated with a higher risk of T2D, but not with CVD. A significant interaction (p = 0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a significant effect on 1-year changes of the metabolites. Our results provide an independent prospective replication of the association of 2-AAA with future risk of T2D. We show an association of lysine with subsequent CVD risk, which is apparently diabetes-dependent. No evidence of effects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003

    更新日期:2019-11-28
  • The oral glucose tolerance test-derived incremental glucose peak is associated with greater arterial stiffness and maladaptive arterial remodeling: The Maastricht Study
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-14
    Yuri D. Foreman; Martijn C. G. J. Brouwers; Tos T. J. M. Berendschot; Martien C. J. M. van Dongen; Simone J. P. M. Eussen; Marleen M. J. van Greevenbroek; Ronald M. A. Henry; Alfons J. H. M. Houben; Carla J. H. van der Kallen; Abraham A. Kroon; Koen D. Reesink; Miranda T. Schram; Nicolaas C. Schaper; Coen D. A. Stehouwer

    Daily glucose variability may contribute to vascular complication development irrespective of mean glucose values. The incremental glucose peak (IGP) during an oral glucose tolerance test (OGTT) can be used as a proxy of glucose variability. We investigated the association of IGP with arterial stiffness, arterial remodeling, and microvascular function, independent of HbA1c and other confounders. IGP was calculated as the peak minus baseline plasma glucose value during a seven-point OGTT in 2758 participants (age: 60 ± 8 years; 48% women) of The Maastricht Study, an observational population-based cohort. We assessed the cross-sectional associations between IGP and arterial stiffness (carotid-femoral pulse wave velocity [cf-PWV], carotid distensibility coefficient [carDC]), arterial remodeling (carotid intima-media thickness [cIMT]; mean [CWSmean] and pulsatile [CWSpuls] circumferential wall stress), and microvascular function (retinal arteriolar average dilatation; heat-induced skin hyperemia) via multiple linear regression with adjustment for age, sex, HbA1c, cardiovascular risk factors, lifestyle factors, and medication use. Higher IGP was independently associated with higher cf-PWV (regression coefficient [B]: 0.054 m/s [0.020; 0.089]) and with higher CWSmean (B: 0.227 kPa [0.008; 0.446]). IGP was not independently associated with carDC (B: − 0.026 10−3/kPa [− 0.112; 0.060]), cIMT (B: − 2.745 µm [− 5.736; 0.245]), CWSpuls (B: 0.108 kPa [− 0.054; 0.270]), retinal arteriolar average dilatation (B: − 0.022% [− 0.087; 0.043]), or heat-induced skin hyperemia (B: − 1.380% [− 22.273; 19.513]). IGP was independently associated with aortic stiffness and maladaptive carotid remodeling, but not with carotid stiffness, cIMT, and microvascular function measures. Future studies should investigate whether glucose variability is associated with cardiovascular disease.

    更新日期:2019-11-28
  • Prospective study of hemoglobin A1c and incident carotid artery plaque in Chinese adults without diabetes
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-14
    Renying Xu; Ting Zhang; Yanping Wan; Zhuping Fan; Xiang Gao

    Diabetes has been reported to be associated with carotid artery plaque (CAP). However, it remains unclear whether hemoglobin A1c (HbA1c) level, a marker for long-term glycemic status, is associated with altered CAP risk in individuals with fasting blood glucose (FBG) concentrations below the current cutoff for diabetes. Included were 16,863 Chinese adults (aged 18 years or more; 9855 men and 7008 women) with fasting blood glucose < 7.0 mmol/L at baseline (2013). Both HbA1c level and CAP (assessed via ultrasound B-mode imaging) were annually assessed during 2014–2018. All the participants were further classified into three groups based on baseline HbA1c level: ≤ 5.6%, 5.7–6.4%, and ≥ 6.5%. We used Cox proportional-hazards model to evaluate the association between HbA1c level and incident CAP, adjusting for a series of potential confounders. During 5 years of follow up, 3942 incident CAP cases were identified. Individuals with higher baseline HbA1c had higher future risk of CAP (p-trend < 0.001). In the full-adjusted model, each percent increase of HbA1c was associated with a 56% (HR = 1.56, 95% CI 1.37, 1.78) higher risk of CAP. Excluding participants with chronic inflammation, as assessed by high-sensitivity C-reactive protein and white blood cell, and those with FBG ≥ 5.6 mmol/L at baseline generated similar results. Elevated HbA1c level was associated with high risk of developing CAP in Chinese adults without FBG defined diabetes.

    更新日期:2019-11-28
  • Characteristics of atheromatosis in the prediabetes stage: a cross-sectional investigation of the ILERVAS project
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-15
    Enric Sánchez; Àngels Betriu; Carolina López-Cano; Marta Hernández; Elvira Fernández; Francisco Purroy; Marcelino Bermúdez-López; Cristina Farràs-Sallés; Silvia Barril; Reinald Pamplona; Ferran Rius; Cristina Hernández; Rafael Simó; Albert Lecube

    Prediabetes has recently been associated with subclinical atheromatous disease in the middle-aged population. Our aim was to characterize atheromatous plaque burden by the number of affected territories and the total plaque area in the prediabetes stage. Atheromatous plaque burden (quantity of plaques and total plaque area) was assessed in 12 territories from the carotid and femoral regions using ultrasonography in 6688 non-diabetic middle-aged subjects without cardiovascular disease. Prediabetes was defined by glycosylated hemoglobin (HbA1c) between 5.7 and 6.4% according to the American Diabetes Association guidelines. Prediabetes was diagnosed in 33.9% (n = 2269) of the ILERVAS participants. Subjects with prediabetes presented a higher prevalence of subclinical atheromatous disease than participants with HbA1c < 5.7% (70.4 vs. 67.5%, p = 0.017). In the population with prediabetes this was observed at the level of the carotid territory (p < 0.001), but not in the femoral arteries. Participants in the prediabetes stage also presented a significantly higher number of affected territories (2 [1;3] vs. 1 [0;3], p = 0.002), with a positive correlation between HbA1c levels and the number of affected territories (r = 0.068, p < 0.001). However, atheromatosis was only significantly (p = 0.016) magnified by prediabetes in those subjects with 3 or more cardiovascular risk factors. The multivariable logistic regression model showed that the well-established cardiovascular risk factors together with HbA1c were independently associated with the presence of atheromatous disease in participants with prediabetes. When males and females were analyzed separately, we found that only men with prediabetes presented both carotid and femoral atherosclerosis, as well as an increase of total plaque area in comparison with non-prediabetic subjects. The prediabetes stage is accompanied by an increased subclinical atheromatous disease only in the presence of other cardiovascular risk factors. Prediabetes modulates the atherogenic effect of cardiovascular risk factors in terms of distribution and total plaque area in a sex-dependent manner. Trial registration NCT03228459 (clinicaltrials.gov)

    更新日期:2019-11-28
  • Diabetes mellitus and other cardiovascular risk factors in lower-extremity peripheral artery disease versus coronary artery disease: an analysis of 1,121,359 cases from the nationwide databases
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-15
    Mitsuyoshi Takahara; Osamu Iida; Shun Kohsaka; Yoshimitsu Soga; Masahiko Fujihara; Toshiro Shinke; Tetsuya Amano; Yuji Ikari

    Lower-extremity peripheral artery disease (LE-PAD) and coronary artery disease (CAD) are both pathologically rooted in atherosclerosis, and their shared clinical features regarding the exposure to cardiovascular risk factors have been emphasized. However, comparative data of the two cardiovascular diseases (CVDs) were so far lacking. The purpose of this study was to directly compare the clinical profile between cases undergoing endovascular therapy (EVT) for LE-PAD and those undergoing percutaneous coronary intervention (PCI). Data were extracted from the nationwide procedural databases of EVT and PCI in Japan (J-EVT and J-PCI) between 2012 and 2017. A total of 1,121,359 cases (103,887 EVT cases for critical limb ischemia [CLI] or intermittent claudication and 1,017,472 PCI cases for acute coronary syndrome [ACS] or stable angina) were analyzed. Heterogeneity in clinical profile between CVDs was evaluated using the C statistic of the logistic regression model for which dependent variable was one CVD versus another, and explanatory variables were clinical profile. When two CVDs were completely discriminated from each other by the developed model, the C statistic (discrimination ability) of the model would be equal to 1, indicating that the two CVDs were completely different in clinical profile. On the other hand, when two CVDs were identical in clinical profile, the developed model would not discriminate them at all, with the C statistic equal to 0.5. Mean age was 73.5 ± 9.3 years in LE-PAD patients versus 70.0 ± 11.2 years in CAD patients (P < 0.001). The prevalence of diabetes mellitus and end-stage renal disease was 1.96- and 6.39-times higher in LE-PAD patients than in CAD patients (both P < 0.001). The higher prevalence was observed irrespective of age group. The exposure to other cardiovascular risk factors and the likelihood of cardiovascular risk clustering also varied between the diseases. The between-disease heterogeneity in patient profile was particularly evident between CLI and ACS, with the C statistic equal to 0.833 (95% CI 0.831–0.836). The current study, an analysis based on nationwide procedural databases, confirmed that patient profiles were not identical but rather considerably different between clinically significant LE-PAD and CAD warranting revascularization.

    更新日期:2019-11-28
  • Heart failure with insulin degludec versus glargine U100 in patients with type 2 diabetes at high risk of cardiovascular disease: DEVOTE 14
    Cardiovasc. Diabetol. (IF 5.948) Pub Date : 2019-11-15
    Richard E. Pratley; Mansoor Husain; Ildiko Lingvay; Thomas R. Pieber; Thomas Mark; Hans A. Saevereid; Daniel Vega Møller; Bernard Zinman

    Heart failure (HF) is a common cardiovascular complication of type 2 diabetes (T2D). This secondary analysis investigated baseline factors and treatment differences associated with risk of hospitalization for HF (hHF), and the possible association between severe hypoglycemia and hHF. DEVOTE was a treat-to-target, double-blind cardiovascular outcomes trial in patients (n = 7637) with T2D and high cardiovascular risk randomized to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). The main endpoint of this secondary analysis was time to first hHF (standardized MedDRA Query definition). Severe hypoglycemia was adjudicated (American Diabetes Association definition). The main endpoint and the temporal association between severe hypoglycemia and hHF were analyzed with a Cox proportional hazards regression model. Predictors of time to first hHF were identified using baseline variables. Overall, 372 (4.9%) patients experienced hHF (550 events). There was no significant difference in the risk of hHF between treatments (hazard ratio [HR] 0.88 [0.72;1.08]95% CI, p = 0.227). Prior HF (HR 4.89 [3.90;6.14]95% CI, p ≤ 0.0001) was the strongest predictor of future hHF events. The risk of hHF significantly increased after (HR 2.2), and within a week after (HR 11.1), experiencing a severe hypoglycemic episode compared with before an episode. In patients with T2D and high cardiovascular risk there were no treatment differences in terms of hHF. Prior HF was the strongest predictor of future hHF events, and there was an association between severe hypoglycemia and subsequent hHF. Further research should evaluate whether the risk of hHF can be modified by treatments aimed at reducing hypoglycemia. Trial Registration NCT01959529

    更新日期:2019-11-28
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