Association of statin and/or renin-angiotensin-aldosterone system modulating therapy with mortality in adults with diabetes admitted to hospital with COVID-19: A retrospective multicentre European study.

BACKGROUND & AIMS: To assess the impact of pre-admission renin-angiotensin-aldosterone system inhibitor (RAASi) and statin use on mortality following COVID-19 hospitalization in adults with pre-existing diabetes. METHODS: Retrospective cohort study of adults with diabetes admitted to ninety-nine participating hospitals in the United Kingdom, France and Spain during the first wave of the COVID-19 pandemic. Logistic regression models adjusted for demographic factors and comorbidity were used to describe associations with mortality in hospital or within 28 days of admission and individual or combined RAASi and statin therapy prescription followed by a country level meta-analysis. RESULTS: Complete data were available for 3474 (42.6%) individuals. Prescribing patterns varied by country: 25-50% neither RAASi nor statin therapy, 14-36% both RAASi and statin therapy, 9-24% RAASi therapy alone, 12-36% statin alone. Overall, 20-37% of patients died within 28 days. Meta-analysis found no evidence of an association between mortality and prescription of RAASi therapy (OR 1.09, CI 0.78-1.52 (I2 22.2%)), statin (OR 0.97, CI 0.59-1.61 (I2 72.9%)) or both (OR 1.14, CI 0.67-1.92 (I2 78.3%)) compared to those prescribed neither drug class. CONCLUSIONS: This large multicentre, multinational study found no evidence of an association between mortality from COVID-19 infection in people with diabetes and use of either RAASi, statin or combination therapy. This provides reassurance that clinicians should not change their RAASi and statin therapy prescribing practice in people with diabetes during the COVID-19 pandemic.

Susceptibility Vessel Sign and Cardioembolic Etiology in the THRACE Trial.

PURPOSE: The susceptibility vessel sign (SVS) has been described on gradient echo (GRE) magnetic resonance imaging (MRI) in acute ischemic stroke patients by large vessel occlusion. The presence of SVS (SVS+) was associated with treatment outcome and stroke etiology with conflicting results. Based on multicenter data from the THRombectomie des Artères CErebrales (THRACE) study, we aimed to determine if the association between SVS and cardioembolic etiology (CE) was independent of GRE sequence parameters. MATERIAL AND METHODS: Patients with a pretreatment brain GRE sequence were identified. Logistic regression tested the association between SVS+, CE, time from onset to imaging and GRE sequence parameters (e.g. echo time, voxel size, field strength). We calculated the sensitivity, specificity, positive and negative predictive values (PPV and NPV) for the SVS to predict a stroke from a CE. RESULTS: An SVS+ was observed in 237 out of 287 (83%) patients. In the univariate analysis, there was a significant association between SVS+ and a CE with an odds ratio (OR) and 95% confidence interval (95% CI) of 2.10 (1.02-4.29), respectively (p = 0.04) but not with GRE sequence parameters. In multivariate analysis, there was an independent relationship between SVS+ and CE (OR [95% CI]: 2.14 [1.02-4.45], p = 0.04). Sensitivity and specificity of SVS+ to predict CE were 0.89 and 0.21, respectively. The PPV and NPV of SVS+ were 0.44 and 0.78, respectively. CONCLUSION: The presence of SVS is associated to CE, independent of GRE sequence parameters. While the specificity and the PPV of the sign were low, CE seems less likely in the absence of an SVS.

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. Conclusion: In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.

Could anticoagulation avoid bioprosthesis subclinical thrombosis in patients undergoing transcatheter aortic valve replacement?

BACKGROUND: Despite a lack of clear evidence, current European guidelines recommend antiplatelet therapy after transcatheter aortic valve replacement (TAVR). Recent investigations suggest that bioprosthesis thrombosis after TAVR is not uncommon and may be prevented by anticoagulation, but not by antiplatelet therapy. AIMS: The study objective was to assess the impact of the antithrombotic regimen on post-TAVR early haemodynamics. METHODS: Patients eligible for TAVR with an Edwards SAPIEN 3 valve were included in this prospective observational study. Patients undergoing long-term anticoagulation before TAVR continued their treatment, whereas previously non-anticoagulated patients received antiplatelet therapy. The primary endpoint was the mean transaortic gradient assessed by transthoracic echocardiography at the first post-TAVR follow-up. Safety was assessed by two composite endpoints: bleeding/vascular complications and major adverse postoperative events. RESULTS: Among 135 included patients, 78 were discharged on antiplatelet therapy and 57 on anticoagulation. Both groups had similar baseline characteristics, except for supraventricular arrhythmia (7.7% on antiplatelets vs. 89.5% on anticoagulation; P<0.001). At 1-2months after TAVR, the mean transaortic gradient was significantly higher in the antiplatelet therapy group versus the anticoagulation group (13.0±4.0 vs. 9.0±2.8mmHg; P<0.001, independently of prosthesis size). Safety analyses showed no significant differences of the composite endpoints. CONCLUSION: Prolonged anticoagulation after TAVR was associated with lower early transaortic gradients than antiplatelet therapy. Anticoagulation treatment may limit clinical and subclinical thrombosis without increasing early postoperative complications.

Deconditioning, fatigue and impaired quality of life in long-term survivors after allogeneic hematopoietic stem cell transplantation.

Long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk for treatment-related adverse events, that may worsen physical capacity and may induce fatigue and disability. The aims of this prospective study were to evaluate exercise capacity in allotransplant survivors and its relationship with fatigue and disability. Patient-reported outcomes and exercise capacity were evaluated in 71 non-relapse patients 1 year after allo-HSCT, using validated questionnaires, cardiopulmonary exercise testing (CPET) with measure of peak oxygen uptake (peakVO2) and deconditioning, pulmonary function testing, echocardiography and 6-min walk test. A high proportion (75.4%) of allo-HSCT survivors showed abnormal cardiopulmonary exercise testing parameters as compared to predicted normal values, including 49.3% patients who exhibited moderate to severe impairment in exercise capacity and 37.7% patients with physical deconditioning. PeakVO2 values were not accurately predicted by 6-min walk distances (r = 0.53). Disability and fatigue were strongly associated with decreased peakVO2 values (p = 0.002 and p = 0.008, respectively). Exercise capacity was reduced in most allo-HSCT long-term survivors. Because reduced exercise capacity was associated with fatigue, disability and a decrease in quality of life, cardiopulmonary exercise testing should be performed in every patient who reports fatigue and disability.

MRI Interscanner Agreement of the Association between the Susceptibility Vessel Sign and Histologic Composition of Thrombi.

BACKGROUND AND PURPOSE: The susceptibility vessel sign (SVS) on magnetic resonance imaging (MRI) is related to thrombus location, composition, and size in acute stroke. No previous study has determined its inter-MRI scanner variability. We aimed to compare the diagnostic accuracy in-vitro of four different MRI scanners for the characterization of histologic thrombus composition. METHODS: Thirty-five manufactured thrombi analogs of different composition that were histologically categorized as fibrin-dominant, mixed, or red blood cell (RBC)-dominant were scanned on four different MRI units with T2* sequence. Nine radiologists, blinded to thrombus composition and MRI scanner model, classified twice, in a 2-week interval, the SVS of each thrombus as absent, questionable, or present. We calculated the weighted kappa with 95% confidence interval (CI), sensitivity, specificity and accuracy of the SVS on each MRI scanner to detect RBC-dominant thrombi. RESULTS: The SVS was present in 42%, absent in 33%, and questionable in 25% of thrombi. The interscanner agreement was moderate to good, ranging from .45 (CI: .37-.52) to .67 (CI: .61-.74). The correlation between the SVS and the thrombus composition was moderate (κ: .50 [CI: .44-.55]) to good κ: .76 ([CI: .72-.80]). Sensitivity, specificity, and accuracy to identify RBC-dominant clots were significantly different between MRI scanners (P < .001). CONCLUSION: The diagnostic accuracy of SVS to determine thrombus composition varies significantly among MRI scanners. Normalization of T2*sequences between scanners may be needed to better predict thrombus composition in multicenter studies.

The QUIDAM study: Hydroquinidine therapy for the management of Brugada syndrome patients at high arrhythmic risk.

BACKGROUND: Although the implantable cardioverter-defibrillator (ICD) remains the main therapy for Brugada syndrome (BrS), it does not reduce life-threatening ventricular arrhythmia. Based on pathophysiologic mechanisms, hydroquinidine (HQ) has been suggested for effective prevention of arrhythmia. OBJECTIVE: The purpose of this study was to provide evidence-based data supporting HQ use to prevent life-threatening ventricular arrhythmia in high-risk patients with BrS. METHODS: We performed a prospective multicenter randomized (HQ vs placebo) double-blind study with two 18-month crossover phases in patients with BrS and implanted with an ICD. RESULTS: Among the 50 patients enrolled (mean age 47.0 ± 11.4 years, 42 [84%] male), 26 (52%) fully completed both phases. Thirty-four (68%) presented HQ-related side effects, mainly gastrointestinal, which led to discontinuation of the therapy in 13 (26%). HQ lengthened the QTc interval (409 ± 32 ms vs 433 ± 37 ms; P = .027) and increased repolarization dispersion as evaluated by Tpe max in precordial leads (89 ± 15 ms vs 108 ± 27 ms; P <.0001) with no significant changes in J-point elevation. During the 36-month follow-up, 1 appropriate ICD shock (0.97% event per year), 1 self-terminating ventricular fibrillation, and 1 inappropriate ICD shock occurred under placebo therapy. No arrhythmic events were reported under HQ therapy. CONCLUSION: Although HQ seems to be effective in preventing life-threatening ventricular arrhythmia, it could not be an alternative for ICD implantation. Its frequent side effects greatly reduce its probable compliance and therefore do not reveal a significant effect. HQ increases repolarization dispersal with no changes in BrS pattern, which could indicate a more complex action of HQ than its Ito blocking effect alone.

Sustained quality of life improvement after intracoronary injection of autologous bone marrow cells in the setting of acute myocardial infarction: results from the BONAMI trial.

PURPOSE: Cardiac cell therapy is a promising treatment for acute myocardial infarction (AMI), leading to cardiac function improvement. However, whether it translates into quality of life (QoL) improvement is unclear. We hypothesized that administration of bone marrow cells (BMC) to patients with AMI improves QoL. METHODS: In the multicenter BONAMI trial (NCT00200707), patients with reperfused AMI and decreased myocardial viability were randomized to intracoronary autologous BMC infusion (n = 52) or state-of-the-art therapy (n = 49). QoL data, derived from the Minnesota Living with Heart Failure questionnaire (MLHFQ), were obtained 1, 3, and 12 months after AMI and analyzed using a Rasch-family model. RESULTS: Using this model, QoL improved over time in the BMC group (p = 0.025) but not in the control group. Furthermore, the BMC-group patients displayed a better QoL than the control-group patients at 3 and 12 months post-AMI (p = 0.034 and p = 0.003, respectively). These findings were not detected when analyzing MLHFQ data using a standard method. Cardiac function, myocardial viability, mortality, and number of major adverse cardiac events did not differ between treatment groups. CONCLUSION: Our results suggest that BMC therapy can improve QoL, stressing the need for confirmation trials and for systematic QoL assessment in cardiac cell therapy trials .

Is there an inherited anatomical conformation favoring aneurysmal formation of the anterior communicating artery?

OBJECTIVE The pathophysiological mechanisms responsible for the formation of intracranial aneurysms (IAs) remain only partially elucidated. However, current evidence suggests a genetic component. The purpose of this study was to investigate the specific anatomical variations in the arterial complex that are associated with the presence of anterior communicating artery (ACoA) aneurysms in the familial forms of IAs. METHODS This multicenter study investigated bifurcation IAs in patients who had a sporadic ACoA IA without a family history of IA (SACAA group), in patients who had an ACoA IA with a family history of IA (FACAA group), and in their healthy first-degree relatives (HFDRs). Through the use of MR angiography (MRA) reconstructions, the symmetry of the A1 segments and the angle between the A1 and A2 segments were analyzed on 3D models for each group. These measurements were then compared among the 3 groups. RESULTS Twenty-four patients with SACAA, 24 patients with FACAA, and 20 HFDRs were included in the study. Asymmetrical configuration of the A1 segments was more frequent in the FACAA group than in the HFDR group (p = 0.002). The aneurysm-side A1-A2 angle was lower in the FACAA group (p = 0.003) and SACAA group (p = 0.007) than in the HFDR group. On the contralateral side, there was no difference in A1-A2 angles between groups. CONCLUSIONS The anatomical shape of the ACoA complex seems to be similarly associated with the presence of ACoA IAs in both the FACAA and SACAA groups. This highlights the role played by hemodynamic constraints in aneurysm formation and questions the hypothesis of the hereditary character of these anatomical shapes.

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is an arrhythmogenic disease associated with sudden cardiac death (SCD) that seldom manifests or is recognized in childhood. OBJECTIVES: The objectives of this study were to describe the clinical presentation of pediatric BrS to identify prognostic factors for risk stratification and to propose a data-based approach management. METHODS: We studied 106 patients younger than 19 years at diagnosis of BrS enrolled from 16 European hospitals. RESULTS: At diagnosis, BrS was spontaneous (n = 36, 34%) or drug-induced (n = 70, 66%). The mean age was 11.1 ± 5.7 years, and most patients were asymptomatic (family screening, (n = 67, 63%; incidental, n = 13, 12%), while 15 (14%) experienced syncope, 6(6%) aborted SCD or symptomatic ventricular tachycardia, and 5 (5%) other symptoms. During follow-up (median 54 months), 10 (9%) patients had life-threatening arrhythmias (LTA), including 3 (3%) deaths. Six (6%) experienced syncope and 4 (4%) supraventricular tachycardia. Fever triggered 27% of LTA events. An implantable cardioverter-defibrillator was implanted in 22 (21%), with major adverse events in 41%. Of the 11 (10%) patients treated with hydroquinidine, 8 remained asymptomatic. Genetic testing was performed in 75 (71%) patients, and SCN5A rare variants were identified in 58 (55%); 15 of 32 tested probands (47%) were genotype positive. Nine of 10 patients with LTA underwent genetic testing, and all were genotype positive, whereas the 17 SCN5A-negative patients remained asymptomatic. Spontaneous Brugada type 1 electrocardiographic (ECG) pattern (P = .005) and symptoms at diagnosis (P = .001) were predictors of LTA. Time to the first LTA event was shorter in patients with both symptoms at diagnosis and spontaneous Brugada type 1 ECG pattern (P = .006). CONCLUSION: Spontaneous Brugada type 1 ECG pattern and symptoms at diagnosis are predictors of LTA events in the young affected by BrS. The management of BrS should become age-specific, and prevention of SCD may involve genetic testing and aggressive use of antipyretics and quinidine, with risk-specific consideration for the implantable cardioverter-defibrillator.

Predictors of ventricular remodelling in patients with reperfused acute myocardial infarction and left ventricular dysfunction candidates for bone marrow cell therapy: insights from the BONAMI trial.

PURPOSE: Few data are available regarding the relation of left ventricular (LV) mechanical dyssynchrony to remodelling after acute myocardial infarction (MI) and stem cell therapy. We evaluated the 1-year time course of both LV mechanical dyssynchrony and remodelling in patients enrolled in the BONAMI trial, a randomized, multicenter controlled trial assessing cell therapy in patients with reperfused MI. METHODS: Patients with acute MI and ejection fraction (EF) ≤ 45 % were randomized to cell therapy or to control and underwent thallium single-photon emission computed tomography (SPECT), radionuclide angiography, and echocardiography at baseline, 3 months, and 1 year. Eighty-three patients with a comprehensive 1-year follow-up were included. LV dyssynchrony was assessed by the standard deviation (SD) of the LV phase histogram using radionuclide angiography. Remodelling was defined as a 20 % increase in LV end-systolic volume index (LVESVI) at 1 year. RESULTS: At baseline, LVEF, wall motion score index, and perfusion defect size were significantly impaired in the 43 patients (52 %) with LV remodelling (all p < 0.001), without significant increase in LV mechanical dyssynchrony. During follow-up, there was a progressive increase in LV SD (p = 0.01). Baseline independent predictors of LV remodelling were perfusion SPECT defect size (p = 0.001), LVEF (p = 0.01) and a history of hypertension (p = 0.043). Bone marrow cell therapy did not affect the time-course of LV remodelling and dyssynchrony. CONCLUSIONS: LV remodelling 1 year after reperfused MI is associated with progressive LV dyssynchrony and is related to baseline infarct size and ejection fraction, without impact of cell therapy on this process.

Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets.

BACKGROUND: PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters. METHODS: We performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg-1.min-1). FINDINGS: HF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman's correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=-0.59, p=0.0065) insulin sensitivity. CONCLUSIONS: Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.

Difference in mobilization of progenitor cells after myocardial infarction in smoking versus non-smoking patients: insights from the BONAMI trial.

INTRODUCTION: Although autologous bone marrow cell (BMC) therapy has emerged as a promising treatment for acute myocardial infarction (AMI), trials reported mixed results. In the BONAMI trial, active smoking reduced cardiac function recovery after reperfused AMI. Therefore, we hypothesized that variability in the functionality of BMCs retrieved from patients with cardiovascular risk factors may partly explain these mixed results. We investigated the characteristics of progenitor cells in active smokers and non-smokers with AMI and their potential impact on BMC therapy efficacy. METHODS: Bone marrow and blood samples from 54 smoking and 47 non-smoking patients enrolled in the BONAMI cell therapy trial were analyzed. RESULTS: The white BMC and CD45dimCD34+ cell numbers were higher in active smokers (P = 0.001, P = 0.03, respectively). In marked contrast, either bone marrow or blood endothelial progenitor CD45dimCD34 + KDR + cells (EPCs) were decreased in active smokers (P = 0.005, P = 0.04, respectively). Importantly, a multivariate analysis including cardiovascular risk factors confirmed the association between active smoking and lower EPC number in bone marrow (P = 0.04) and blood (P = 0.04). Furthermore, baseline circulating EPC count predicted infarct size decrease at three months post-AMI in non-smokers (P = 0.01) but not in active smokers. Interestingly, baseline circulating EPCs were no longer predictive of cardiac function improvement in the BMC therapy group. CONCLUSIONS: These data suggest that circulating EPCs play an important role in cardiac repair post-AMI only in non-smokers and that active smoking-associated EPC alterations may participate in the impairment of cardiac function recovery observed in smokers after AMI, an effect that was overridden by BMC therapy.

Parental electrocardiographic screening identifies a high degree of inheritance for congenital and childhood nonimmune isolated atrioventricular block.

BACKGROUND: The origin of congenital or childhood nonimmune isolated atrioventricular (AV) block remains unknown. We hypothesized that this conduction abnormality in the young may be a heritable disease. METHODS AND RESULTS: A multicenter retrospective study (13 French referral centers, from 1980-2009) included 141 children with AV block diagnosed in utero, at birth, or before 15 years of age without structural heart abnormalities and without maternal antibodies. Parents and matched control subjects were investigated for family history and for ECG screening. In parents, a family history of sudden death or progressive cardiac conduction defect was found in 1.4% and 11.1%, respectively. Screening ECGs from 130 parents (mean age 42.0 ± 6.8 years, 57 couples) were compared with those of 130 matched healthy control subjects. All parents were asymptomatic and in sinus rhythm, except for 1 with undetected complete AV block. Conduction abnormalities were more frequent in parents than in control subjects, found in 50.8% versus 4.6%, respectively (P<0.001). A long PR interval was found in 18.5% of the parents but never in control subjects (P<0.0001). Complete or incomplete right bundle-branch block was observed in 39.2% of the parents and 1.5% of the control subjects (P<0.0001). Complete or incomplete left bundle-branch block was found in 15.4% of the parents and 3.1% of the control subjects (P<0.0006). Estimated heritability for isolated conduction disturbances was 91% (95% confidence interval, 80%-100%). SCN5A mutation screening identified 2 mutations in 2 patients among 97 children. CONCLUSIONS: ECG screening in parents of children affected by idiopathic AV block revealed a high prevalence of conduction abnormalities. These results support the hypothesis of an inheritable trait in congenital and childhood nonimmune isolated AV block.

Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults.

BACKGROUND: Accumulating data suggest a novel role for bile acids (BAs) in modulating metabolic homeostasis. BA treatment has been shown to improve glucose tolerance and to increase energy expenditure in mice. Here, we investigated the relationship between fasting plasma BAs concentrations and metabolic parameters in humans. FINDINGS: Fasting plasma glucose, insulin and lipid profile were measured in 14 healthy volunteers, 20 patients with type 2 diabetes (T2D), and 22 non-diabetic abdominally obese subjects. Insulin sensitivity was also assessed by the determination of the glucose infusion rate (GIR) during a hyperinsulinemic-euglycemic clamp in a subgroup of patients (9 healthy and 16 T2D subjects). Energy expenditure was measured by indirect calorimetry. Plasma cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) concentrations were analyzed by gas chromatograph-mass spectrometry. In univariable analysis, a positive association was found between HOMA-IR and plasma CDCA (ß = 0.09, p = 0.001), CA (ß = 0.03, p = 0.09) and DCA concentrations (ß = 0.07, p < 0.0001). Spearman analysis retrieved an inverse relationship between plasma CDCA (r = -0.44, p = 0.03), CA (r = -0.65, p = 0.001) and the GIR. HOMA-IR remained positively associated with CDCA (ß = 0.11, p = 0.01), CA (ß = 0.04, p = 0.01) and DCA (ß = 0.06, p = 0.007) in multivariable analysis, after adjustment for age, gender, BMI, HbA1C and plasma lipid parameters. In contrast, HbA1c, energy expenditure and plasma lipid concentrations were not correlated with plasma BAs levels in multivariable analysis. CONCLUSIONS: Both plasma CDCA, CA and DCA concentrations were negatively associated with insulin sensitivity in a wide range of subjects.

Intracoronary autologous mononucleated bone marrow cell infusion for acute myocardial infarction: results of the randomized multicenter BONAMI trial.

AIMS: Intracoronary administration of autologous bone marrow cells (BMCs) leads to a modest improvement in cardiac function, but the effect on myocardial viability is unknown. The aim of this randomized multicentre study was to evaluate the effect of BMC therapy on myocardial viability in patients with decreased left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) and to identify predictive factors for improvement of myocardial viability. METHODS AND RESULTS: One hundred and one patients with AMI and successful reperfusion, LVEF ≤45%, and decreased myocardial viability (resting Tl201-SPECT) were randomized to either a control group (n = 49) or a BMC group (n = 52). Primary endpoint was improvement of myocardial viability 3 months after AMI. Baseline mean LVEF measured by radionuclide angiography was 36.3 ± 6.9%. Bone marrow cell infusion was performed 9.3 ± 1.7 days after AMI. Myocardial viability improved in 16/47 (34%) patients in the BMC group compared with 7/43 (16%) in the control group (P = 0.06). The number of non-viable segments becoming viable was 0.8 ± 1.1 in the control group and 1.2 ± 1.5 in the BMC group (P = 0.13). Multivariate analysis including major post-AMI prognostic factors showed a significant improvement of myocardial viability in BMC vs. control group (P = 0.03). Moreover, a significant adverse role for active smoking (P = 0.04) and a positive trend for microvascular obstruction (P = 0.07) were observed. CONCLUSION: Intracoronary autologous BMC administration to patients with decreased LVEF after AMI was associated with improvement of myocardial viability in multivariate-but not in univariate-analysis. A large multicentre international trial is warranted to further document the efficacy of cardiac cell therapy and better define a group of patients that will benefit from this therapy. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier NCT00200707.

Association between plasma PCSK9 and gamma-glutamyl transferase levels in diabetic patients.

BACKGROUND: Proprotein convertase subtilisin kexin type 9 (PCSK9) is a secreted proprotein convertase acting as a natural inhibitor of the low-density lipoprotein (LDL) receptor. Here, we prospectively investigated the relationship between the circulating levels of PCSK9 and metabolic parameters in 117 diabetic patients. RESULTS: Plasma PCSK9 level was significantly higher in type 2 than in type 1 diabetes (P=0.04), in diabetic patients under statins (P<10(-4)) and in those with macrovascular complications (P=0.002). Univariable regression analysis revealed that plasma PCSK9 level correlated positively with age (P=0.003), body mass index (P=0.04), systolic blood pressure (SBP) (P=0.01), gamma-glutamyl transferase (GGT) levels (P=0.0002) and statin treatment (P=0.001). In a multivariable linear regression analysis, PCSK9 correlated positively with GGT level (beta=21.91, P=0.0019) after adjustment for gender, age, type of diabetes, statin treatment, BMI, SBP and HbA1c. CONCLUSION: PCSK9 level was independently associated with GGT level in diabetic patients, suggesting potential interaction between PCSK9 and liver function.