Fasting and post-oral-glucose-load levels of methylglyoxal are associated with microvascular,but not macrovascular,disease in individuals with and without (pre)diabetes: The Maastricht Study

AimsReactive dicarbonyl compounds, such as methylglyoxal (MGO), rise during an oral glucose tolerance test (OGTT), particularly in (pre)diabetes. Fasting MGO levels are associated with chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with poorly controlled type 2 diabetes mellitus (T2DM). Yet, whether fasting or post-OGTT plasma MGO levels are associated with vascular disease in people with (pre)diabetes is unknown.MethodsSubjects with normal glucose metabolism (n = 1796; age: 57.9 ± 8.2 years; 43.3% men), prediabetes (n = 478; age: 61.6 ± 7.6 years; 54.0% men) and T2DM (n = 669; age: 63.0 ± 7.5 years; 67.0% men) from the Maastricht Study underwent OGTTs. Plasma MGO levels were measured at baseline and 2 h after OGTT by mass spectrometry. Prior CVD was established via questionnaire. CKD was reflected by estimated glomerular filtration rate (eGFR) and albuminuria; retinopathy was assessed using retinal photographs. Data were analyzed using logistic regression adjusted for gender, age, smoking, systolic blood pressure, total-to-HDL cholesterol ratio, triglycerides, HbA_1c, BMI and medication use. Odd ratios (ORs) were expressed per standard deviation of LN-transformed MGO.ResultsFasting and post-OGTT MGO levels were associated with higher ORs for albuminuria ≥ 30 mg/24 h [fasting: 1.12 (95% CI: 0.97–1.29); post-OGTT: 1.19 (1.01–1.41)], eGFR < 60 mL/min/1.73 m² [fasting: 1.58 (95% CI: 1.38–1.82), post-OGTT: 1.57 (1.34–1.83)] and retinopathy [fasting: 1.59 (95% CI: 1.01–2.53), post-OGTT: 1.38 (0.77–2.48)]. No associations with prior CVD were found.ConclusionFasting and post-OGTT MGO levels were associated with microvascular disease, but not prior CVD. Thus, therapeutic strategies directed at lowering MGO levels may prevent microvascular disease.     

Relationship between renal capacity to reabsorb glucose and renal status in patients with diabetes

AimsInterindividual variability in capacity to reabsorb glucose at the proximal renal tubule could contribute to risk of diabetic kidney disease. Our present study investigated, in patients with diabetes, the association between fractional reabsorption of glucose (FR_GLU) and degree of renal disease as assessed by urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR).MethodsFR_GLU [1-(glucose clearance/creatinine clearance)] was assessed in 637 diabetes patients attending our tertiary referral centre, looking for correlations between FR_GLU and UAE (normo-, micro-, macro-albuminuria) and Kidney Disease: Improving Global Outcomes (KDIGO) eGFR categories: >90 (G1); 90–60 (G2); 59–30 (G3); and < 30–16 (G4) mL/min/1.73 m². Patients were stratified by admission fasting plasma glucose (FPG) into three groups: low (<6 mmol/L); intermediate (6–11 mmol/L); and high (>11 mmol/L).ResultsMedian (interquartile range, IQR) FR_GLU levels were blood glucose-dependent: 99.90% (0.05) for low (n = 106); 99.90% (0.41) for intermediate (n = 288); and 96.36% (12.57) for high (n = 243) blood glucose categories (P < 0.0001). Also, FR_GLU increased with renal disease severity in patients in the high FPG group: normoalbuminuria, 93.50% (17.74) (n = 135); microalbuminuria, 96.56% (5.94) (n = 77); macroalbuminuria, 99.12% (5.44) (n = 31; P < 0.001); eGFR G1, 94.13% (16.24) (n = 111); G2, 96.35% (11.94) (n = 72); G3 98.88% (7.59) (n = 46); and G4, 99.11% (2.20) (n = 14; P < 0.01). On multiple regression analyses, FR_GLU remained significantly and independently associated with UAE and eGFR in patients in the high blood glucose group.ConclusionHigh glucose reabsorption capacity in renal proximal tubules is associated with high UAE and low eGFR in patients with diabetes and blood glucose levels > 11 mmol/L.     

Metabolic and psychological effects of short-term increased consumption of less-processed foods in daily diets: A Pilot Study

AimThis study evaluated whether the consumption of locally produced food without additives might have a positive effect on known risk factors for non-communicable diseases (NCDs) such as hypertension, and levels of fasting glucose and visceral adipose tissue (VAT). Attention was focused on various types of cheese, sausages, fresh pasta, pastries, biscuits and chocolate without additives to make them palatable and durable for transport.MethodsHealthy volunteers were randomized to purchase the foods under study from either local producers not using additives (group 1) or supermarkets (group 2). At baseline and after 6 months, both groups underwent evaluation for weight, blood pressure, VAT, serum sodium, potassium, fasting glucose, insulin, C-peptide and creatinine levels, and also the State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory (BDI-II) by examiners blinded to group allocation. At baseline, the state part of the STAI and Wechsler Adult Intelligence Scale IV were also performed, and body mass index, HOMA index and estimated glomerular filtration rate calculated.ResultsData for 159 subjects (89 in group 1, 70 in group 2) were analyzed. Baseline evaluations did not differ between groups. At 6 months, HOMA scores and fasting glucose levels were lower in group 1 than in group 2 (P < 0.01). Also, in group 1, VAT (P = 0.006), systolic blood pressure (P = 0.001) and BDI-II score (P = 0.0005) were decreased, whereas serum fasting glucose (P = 0.04) and C-peptide (P = 0.03) levels, and diastolic blood pressure (P = 0.02), were increased in group 2.ConclusionConsumption of the locally produced food under study improved some of the major risk factors for NCDs after 6 months.     

Effect of maternal lifestyle intervention on metabolic health and adiposity of offspring: Findings from the Finnish Gestational Diabetes Prevention Study (RADIEL)

AimTo assess in women at high risk of gestational diabetes mellitus (GDM) the effect of a lifestyle intervention on the metabolic health of their offspring around 5 years after delivery.MethodsFor the original Finnish gestational diabetes prevention study (RADIEL), 720 women with a prepregnancy body mass index (BMI) ≥ 30 kg/m² and/or previous GDM were enrolled before or during early pregnancy and allocated to either an interventional (n = 126) or conventional (n = 133) care group. The present 5-year follow-up substudy assessed the metabolic health outcomes of their offspring. Age- and gender-standardized residuals of metabolic health components (waist circumference, mean arterial pressure, high-density lipoprotein and triglyceride levels, and fasting insulin/glucose ratio) were also combined to determine the accumulation of metabolic effects. Body composition was assessed by electrical bioimpedance.ResultsOffspring of women in the intervention group had a less optimal metabolic profile after the 5-year follow-up compared with offspring in the usual care group (P = 0.014). This difference in metabolic health was primarily related to lipid metabolism, and was more prominent among boys (P = 0.001) than girls (P = 0.74). Neither GDM, gestational weight gain, prepregnancy BMI, offspring age nor timing of randomization (before or during pregnancy) could explain the detected difference, which was also more pronounced among the offspring of GDM pregnancies (P = 0.010). Offspring body composition was similar in both groups (P > 0.05).ConclusionThe lifestyle intervention aimed at GDM prevention was associated with unfavourable metabolic outcomes among offspring at around 5 years of age.     

Higher liver stiffness scores are associated with early kidney dysfunction in patients with histologically proven non-cirrhotic NAFLD

AimThe association between Liver fibrosis (LF), as assessed by either histology or Liver stiffness measurement (LSM), and the presence of Early kidney dysfunction (EKD) was investigated in this study, as was also the diagnostic performance of LSM for identifying the presence of EKD in patients with Non-alcoholic fatty liver disease (NAFLD).Materials and methodsA total of 214 adults with non-cirrhotic biopsy-proven NAFLD were recruited from two independent medical centres. Their histological stage of LF was quantified using Brunt's criteria. Vibration-controlled Transient elastography (TE), using M-probe (FibroScan®) ultrasound, was performed in 154 patients and defined as significant when LSM was ≥ 8.0 kPa. EKD was defined as the presence of microalbuminuria with an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m². Logistic regression modelling was used to estimate the likelihood of having EKD with NAFLD (LSM–EKD model).ResultsThe prevalence of EKD was higher in patients with vs without LF on histology (22.14% vs 4.82%, respectively; P < 0.001) and, similarly, EKD prevalence was higher in patients with LSM ≥ 8.0 kPa vs LSM < 8.0 kPa (23.81% vs 6.59%, respectively; P < 0.05). The area under the ROC curve of the LSM–EKD model for identifying EKD was 0.80 (95% CI: 0.72–0.89). LF detected by either method was associated with EKD independently of established renal risk factors and potential confounders.ConclusionLF was independently associated with EKD in patients with biopsy-proven NAFLD. Thus, TE-measured LSM, a widely used technique for quantifying LF, can accurately identify those patients with NAFLD who are at risk of having EKD.     

Minimal agreement between basophil activation test and immunoassay in diagnosis of penicillin allergy

IntroductionBasophil activation test (BAT) and immunoassays are the most widely used in vitro tests to diagnose IgE-mediated allergic reactions to penicillin. However, studies to determine if one test is interdependent from another are limited.ObjectiveThe present study aimed to measure the agreement between BAT and immunoassay in diagnosis of penicillin allergy.MethodBAT was performed using penicillin G (Pen G), penicillin V (Pen V), penicilloyl-polylysine (PPL), minor determinant mix (MDM), amoxicillin (Amx) and ampicillin (Amp) in 25 patients. Immunoassay of total IgE (tIgE) and specific IgE (sIgE) antibodies to Pen G, Pen V, Amx and Amp were quantified. Skin prick test (SPT) using PPL-MDM, Amx, Amp and Clavulanic acid were also performed.ResultsMinimal agreement was observed between BAT and immunoassay (k = 0.25). Of two BAT-positive patients, one patient is positive to Amx (59.27%, SI = 59) and Amp (82.32%, SI = 82) but sIgE-negative to all drug tested. This patient is also SPT-positive to both drugs. Another patient is BAT-positive to Pen G (10.18%, SI = 40), Pen V (25.07%, SI = 100) and Amp (19.52%, SI = 79). In sIgE immunoassay, four patients were sIgE-positive to at least one of the drugs tested. The sIgE level of three patients was between low and moderate and they were BAT-negative. One BAT-positive patient had a high level of sIgE antibodies (3.50–17.5 kU/L) along with relatively high specific to total IgE ratio ≥0.002 (0.004–0.007).ConclusionsThe agreement between BAT and immunoassay is minimal. Performing both tests provides little increase in the sensitivity of allergy diagnosis work-up for immediate reactions to penicillin.     

Transcatheter edge-to-edge repair following surgical valve repair with ring implantation: Results from the multicentre “Clip-in-Ring” registry

BackgroundManagement of mitral regurgitation recurrence after failed surgical valve repair with ring implantation is controversial.AimTo describe the French experience regarding midterm safety and efficacy of transcatheter edge-to-edge mitral valve repair (TEER) in patients with failed surgical valve repair with ring implantation.MethodsThe “Clip-in-Ring” registry is a multicentre registry conducted in 11 centres in France, approved by local institutional review boards, of consecutive TEER following surgical valve repair with ring implantation. Outcomes were Mitral Valve Academic Research Consortium (MVARC) technical success, modified 30-day device and procedural success (where 10 mmHg is considered as a cut-off for significant mitral stenosis) and MVARC complications.ResultsTwenty-three patients were studied: mean age, 69 ± 10 years; male sex, 74%; EuroSCORE II, 16 ± 17; left ventricular ejection fraction, 53 ± 12%; mitral regurgitation grade 3+/4+, 17%/78%; New York Heart Association class III/IV, 47%/22%; median surgery to TEER delay, 23 (6–94) months. Technical success was 100%. At discharge, residual mitral regurgitation grade was ≤ 2+ in 87% and median transmitral gradient was 4 (3–5) mmHg. Thirty-day modified MVARC device and procedural success was 82%: four patients (17%) had residual mitral regurgitation grade > 2+, including two patients who needed complementary surgery. No patient had a 30-day transmitral gradient > 7 mmHg. No patient died or had a stroke or any life-threatening complications. One patient presented a vascular access complication requiring transfusion. No other MVARC-2 adverse event was reported.ConclusionsTEER in patients with failed mitral ring is feasible and safe. Further studies should delineate its exact role in the therapeutic armamentarium for this medical issue.     

Clinical significance of myocardial contraction fraction in significant primary mitral regurgitation

BackgroundThe optimal timing for mitral valve (MV) surgery in asymptomatic patients with primary mitral regurgitation (MR) remains a matter of debate. Myocardial contraction fraction (MCF) − the ratio of the left ventricular (LV) stroke volume to that of the myocardial volume − is a volumetric measure of LV myocardial shortening independent of size or geometry.AimTo assess the relationship between MCF and outcome in patients with significant chronic primary MR due to prolapse managed in contemporary practice.MethodsClinical, Doppler-echocardiographic and outcome data prospectively collected in 174 patients (mean age 62 years, 27% women) with significant primary MR and no or mild symptoms were analysed. The impact of MCF< or ≥30% on cardiac events (cardiovascular death, acute heart failure or MV surgery) was studied.ResultsDuring an estimated median follow-up of 49 (22–77) months, cardiac events occurred in 115 (66%) patients. The 4-year estimates of survival free from cardiac events were 21 ± 5% for patients with MCF <30% and 40 ± 6% for those with ≥30% (P < 0.001). MCF <30% was associated with a considerable increased risk of cardiac events after adjustment for established clinical risk factors, MR severity and current recommended class I triggers for MV surgery (adjusted hazard ratio: 2.33, 95% confidence interval: 1.51−3.58; P < 0.001). Moreover, MCF < 30% improved the predictive performance of models, with better global fit, reclassification and discrimination.ConclusionsMCF < 30% is strongly associated with occurrence of cardiac events in patients with significant primary MR due to prolapse. Further studies are needed to assess the direct impact of MCF on patient management and outcomes.     

Comparative non-persistence in the first year of treatment with oral anticoagulants in patients with atrial fibrillation: A French comprehensive nationwide study

BackgroundDirect oral anticoagulants (DOACs) were developed as an alternative to vitamin K antagonists (VKAs) and are commonly used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Unlike VKAs, DOACs do not require Internal Normalized Ratio (INR) monitoring, but regular intake is as important for effective anticoagulation.ObjectivesThis study examined treatment persistence among patients receiving oral anticoagulants (OACs) for NVAF.MethodsWithin the French healthcare claims database (SNDS), we assessed and compared the rates of non-persistence (≥ 30-day treatment gap) among patients with NVAF initiating an OAC between January 2014 and December 2016. The time-to-event of non-persistence was computed and plotted using a cumulative incidence function accounting for the competing risk of mortality. After adjusting on confounding factors, the risk for non-persistence was compared between apixaban and each other OACs using a Cox proportional hazard model, or Fine and Gray models.ResultsIn a cohort of 321,501 OAC-naive patients with NVAF, the cumulative incidence of non-persistence at 12 months considering competing risk was 44.3%, 31.0%, 41.3% and 46.8% for VKAs, apixaban, rivaroxaban and dabigatran, respectively. Median therapy duration before non-persistence ranged between 70 and 121 days. Non-persistence was lower with apixaban compared with VKAs (HR = 0.63, 95%CI = [0.62–0.64]), rivaroxaban (HR = 0.71, 95%CI = [0.70–0.73]), and dabigatran (HR = 0.60, 95%CI = [0.59–0.62]).ConclusionsIn this nationwide observational study, non-persistence rates of oral anticoagulant treatment were high in patients treated for NVAF. Apixaban-treated patients seem to experience lowest discontinuation rates 12 months after treatment initiation compared to patients treated with any other OAC.     

Clustering of patients with inconclusive non-invasive stress testing referred for vasodilator stress cardiovascular magnetic resonance

BackgroundInconclusive non-invasive stress testing is associated with impaired outcome. This population is very heterogeneous, and its characteristics are not well depicted by conventional methods.AimsTo identify patient subgroups by phenotypic unsupervised clustering, integrating clinical and cardiovascular magnetic resonance data to unveil pathophysiological differences between subgroups of patients with inconclusive stress tests.MethodsBetween 2008 and 2020, consecutive patients with a first inconclusive non-invasive stress test referred for stress cardiovascular magnetic resonance were followed for the occurrence of major adverse cardiovascular events (defined as cardiovascular death or myocardial infarction). A cluster analysis was performed on clinical and cardiovascular magnetic resonance variables.ResultsOf 1402 patients (67% male; mean age 70 ± 11 years) who completed the follow-up (median 6.5 years, interquartile range 5.6–7.5 years), 197 experienced major adverse cardiovascular events (14.1%). Three distinct phenogroups were identified based upon unsupervised hierarchical clustering of principal components: phenogroup 1 = history of percutaneous coronary intervention with viable myocardial infarction and preserved left ventricular ejection fraction; phenogroup 2 = atrial fibrillation with preserved left ventricular ejection fraction; and phenogroup 3 = coronary artery bypass graft with non-viable myocardial scar and reduced left ventricular ejection fraction. Using survival analysis, the occurrence of major adverse cardiovascular events (P = 0.007), cardiovascular mortality (P = 0.002) and all-cause mortality (P < 0.001) differed among the three phenogroups. Phenogroup 3 presented the worse prognosis. In each phenogroup, ischaemia was associated with major adverse cardiovascular events (phenogroup 1: hazard ratio 2.79, 95% confidence interval 1.61–4.84; phenogroup 2: hazard ratio 2.59, 95% confidence interval 1.69–3.97; phenogroup 3: hazard ratio 3.16, 95% confidence interval 1.82–5.49; all P < 0.001).ConclusionsCluster analysis of clinical and cardiovascular magnetic resonance variables identified three phenogroups of patients with inconclusive stress testing, with distinct prognostic profiles.     

The relationship of family history and risk of type 2 diabetes differs by ancestry

AimType 2 diabetes (T2DM) in a first-degree relative is a risk factor for incident diabetes. Americans of African ancestry (AA) have higher rates of T2DM than Americans of European ancestry (EA). Thus, we aimed to determine whether the presence, number and kinship of affected relatives are associated with race-specific T2DM incidence in a prospective study of participants from the Genetic Study of Atherosclerosis Risk (GeneSTAR), who underwent baseline screening including a detailed family history.MethodsNondiabetic healthy siblings (n = 1405) of patients with early-onset coronary artery disease (18–59 years) were enrolled (861 EA and 544 AA) and followed for incident T2DM (mean 14 ± 6 years).ResultsBaseline age was 46.2 ± 7.3 years and 56% were female. T2DM occurred in 12.3% of EA and 19.1% of AA. Among EA, 32.6% had ≥ 1 affected first-degree relatives versus 53.1% in AA, P < 0.0001. In fully adjusted Cox proportional hazard analyses, any family history was related to incident T2DM in EA (HR = 2.53, 95% CI: 1.58–4.06) but not in AA (HR = 1.01, 0.67–1.53). The number of affected relatives conferred incremental risk of T2DM in EA with HR = 1.82 (1.08–3.06), 4.83 (2.15–10.85) and 8.46 (3.09–23.91) for 1, 2, and ≥ 3 affected, respectively. In AA only ≥ 3 affected increased risk (HR = 2.45, 1.44–4.19). Specific kinship patterns were associated with incident T2DM in EA but not in AA.ConclusionsThe presence of any first-degree relative with T2DM does not discriminate risk in AA given the high race-specific prevalence of diabetes. Accounting for the number of affected relatives may more appropriately estimate risk for incident diabetes in both races.     

A suggested protocol for the endocrine postoperative management of patients undergoing pituitary surgery

PurposeEndocrine disorders are the most frequent postoperative complications in patients undergoing pituitary surgery. Given the absence of recent guidelines on the postoperative care following pituitary surgery, this article summarizes the available evidence on the topic.MethodWe conducted a systematic search of PubMed up to 2021 and updated the search in December 2022. We retrieved 119 articles and included 53 full-text papers.ResultsThe early postoperative care consists of the assessment for cortisol deficiency and diabetes insipidus (DI). Experts suggest that all patients should receive a glucocorticoid (GC) stress dose followed by a rapid taper. The decision for GC replacement after discharge depends on the morning plasma cortisol level on day 3 after surgery. Experts suggest that patients with a morning plasma cortisol < 10 mcg/dL should receive GC replacement at discharge, and those with 10–18 mcg/dL a morning dose only, with formal assessment of the hypothalamic-pituitary-adrenal axis at week 6 postoperatively. When the cortisol level is > 18 mcg/dL, the patient can be discharged safely without GC, as suggested by observational studies. Postoperative care also includes a close monitoring of water balance. If DI develops, desmopressin is used only in case of uncomfortable polyuria or hypernatremia. The assessment of other hormones is indicated at 3 months postoperatively and beyond.ConclusionThe evaluation and treatment of patients following pituitary surgery are based on expert opinion and a few observational studies. Further research is needed to provide additional evidence on the most appropriate approach.     

Unsupervised clustering of patients with severe aortic stenosis: A myocardial continuum

BackgroundTraditional statistics, based on prediction models with a limited number of prespecified variables, are probably not adequate to provide an appropriate classification of a condition that is as heterogeneous as aortic stenosis (AS).AimsTo investigate a new classification system for severe AS using phenomapping.MethodsConsecutive patients from a referral centre (training cohort) who met the echocardiographic definition of an aortic valve area (AVA) ≤ 1 cm² were included. Clinical, laboratory and imaging continuous variables were entered into an agglomerative hierarchical clustering model to separate patients into phenogroups. Individuals from an external validation cohort were then assigned to these original clusters using the K nearest neighbour (KNN) function and their 5-year survival was compared after adjustment for aortic valve replacement (AVR) as a time-dependent covariable.ResultsIn total, 613 patients were initially recruited, with a mean ± standard deviation AVA of 0.72 ± 0.17 cm². Twenty-six variables were entered into the model to generate a specific heatmap. Penalized model-based clustering identified four phenogroups (A, B, C and D), of which phenogroups B and D tended to include smaller, older women and larger, older men, respectively. The application of supervised algorithms to the validation cohort (n = 1303) yielded the same clusters, showing incremental cardiac remodelling from phenogroup A to phenogroup D. According to this myocardial continuum, there was a stepwise increase in overall mortality (adjusted hazard ratio for phenogroup D vs A 2.18, 95% confidence interval 1.46–3.26; P < 0.001).ConclusionsArtificial intelligence re-emphasizes the significance of cardiac remodelling in the prognosis of patients with severe AS and highlights AS not only as an isolated valvular condition, but also a global disease.     

Prolongation of the heart rate-corrected QT interval is associated with cardiovascular diseases: Systematic review and meta-analysis

BackgroundConflicting findings have described the association between prolonged heart rate-corrected QT interval (QTc) and cardiovascular disease.AimsTo identify articles investigating the association between QTc and cardiovascular disease morbidity and mortality, and to summarize the available evidence for the general and type 2 diabetes populations.MethodsA systematic search was performed in PubMed and Embase in May 2022 to identify studies that investigated the association between QTc prolongation and cardiovascular disease in both the general and type 2 diabetes populations. Screening, full-text assessment, data extraction and risk of bias assessment were performed independently by two reviewers. Effect estimates were pooled across studies using random-effect models.ResultsOf the 59 studies included, 36 qualified for meta-analysis. Meta-analysis of the general population studies showed a significant association for: overall cardiovascular disease (fatal and non-fatal) (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.33–2.12; I² = 69%); coronary heart disease (fatal and non-fatal) in women (HR 1.27, 95% CI 1.08–1.50; I² = 38%; coronary heart disease (fatal and non-fatal) in men (HR 2.07, 95% CI 1.26–3.39; I² = 78%); stroke (HR 1.59, 95% CI 1.29–1.96; I² = 45%); sudden cardiac death (HR 1.60, 95% CI 1.14–2.25; I² = 68%); and atrial fibrillation (HR 1.55, 95% CI 1.31–1.83; I² = 0.0%). No significant association was found for cardiovascular disease in the type 2 diabetes population.ConclusionQTc prolongation was associated with risk of cardiovascular disease in the general population, but not in the type 2 diabetes population.     

Impact of left atrial and diastolic ventricular dysfunction on mortality in patients with aortic stenosis

BackgroundDiastolic dysfunction (DD) is common in severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF ≥ 50%).AimTo determine the impact of American Society of Echocardiography/European Association of Cardiovascular Imaging-recommended DD grading and left atrial strain on mortality in a cohort of patients with severe AS and preserved LVEF.MethodsWe studied patients with severe AS (aortic valve area indexed < 0.6 cm²/m² and/or aortic valve area < 1 cm²), LVEF ≥ 50% and no or mild AS-related symptoms. The endpoint was all-cause mortality.ResultsA total of 387 patients (median age 76 years; 53% women) were studied. During a median follow-up of 57 (interquartile range 37; 83) months, 158 patients died. After adjustment for prognostic factors, patients with grade II or III DD had an increased mortality risk versus patients with grade I DD (adjusted hazard ratio (aHR) 1.62, 95% confidence interval (CI) 1.11–2.38; P = 0.013; aHR 4.73, 95% CI 2.49–8.99; P < 0.001; respectively). Adding peak atrial longitudinal strain (PALS) ≤ 14% to a multivariable model including DD grade improved predictive performance, with better global model fit, reclassification and discrimination. Patients with grade III DD or grade II DD + PALS ≤ 14% displayed an increased mortality risk versus patients with grade I DD + PALS > 14% (aHR 4.17, 95% CI 2.46–7.06; P < 0.0001). Those with grade I DD + PALS ≤ 14% or grade II DD + PALS > 14% were at intermediate risk (aHR 1.63, 95% CI 1.07–2.49; P = 0.024).ConclusionsOur results demonstrate the strong relationship between DD and mortality in patients with severe AS and preserved LVEF. Patients with grade III or grade II DD and impaired PALS are at very high risk. These data demonstrate the importance of a comprehensive assessment of diastolic function in patients with severe AS.     

Ductular reaction and hepatocyte ballooning identify patients with fibrosing cholestatic hepatitits after liver transplantation

IntroductionDiagnosis of severe hepatitis C recurrence is based on analytical and histological criteria but there is little information about their correlation.AimTo assess the accuracy of laboratory criteria for the diagnosis of fibrosing cholestatic hepatitis (FCH).Patients and methodsRetrospective analysis of prospectively collected data form HCV positive patients who underwent liver transplantation (LT) between 2000 and 2014 in two European university hospitals. Patients were classified according to laboratory criteria such as FCH, cholestatic hepatitis (CH) and non-cholestatic acute hepatitis (NCAH). Histological characteristics were also evaluated.ResultsSeventy patients with acute HCV recurrence within the first year after LT with an available liver biopsy were included in the study. Most patients were male (70%) with a median age of 58 years (50–64) and infected with genotype 1b (71.4%). Median time from LT to diagnosis of recurrence was 2.96 months (2.1–5.3). Thirty-nine patients were classified as FCH, 21 as CH and 10 as NCAH. Marked hepatocyte ballooning and ductular reaction were associated with the presence of FCH with an OR of 4.66 (p = 0.047) and 20.58 (p = 0.025), respectively. Considering liver biopsy as the gold standard, the sensitivity, specificity, positive and negative predictive values of the analytical criteria were 0.8, 0.5, 0.3 and 0.9, respectively. However, correlation between histological and analytical criteria was poor (k = 0.033).DiscussionAnalytical criteria may be used to rule out the presence of FCH, but a biopsy is mandatory to confirm the diagnosis. Ductular reaction and hepatocyte ballooning were independent predictors of FCH.     

Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10)

AimsSUSTAIN 10 compared the efficacy and safety of the anticipated most frequent semaglutide dose (1.0 mg) with the current most frequently prescribed liraglutide dose in Europe (1.2 mg), reflecting clinical practice.MethodsIn this phase 3b, open-label trial, 577 adults with type 2 diabetes (HbA_1c 7.0–11.0%) on 1–3 oral antidiabetic drugs were randomized 1:1 to subcutaneous once-weekly semaglutide 1.0 mg or subcutaneous once-daily liraglutide 1.2 mg. Primary and confirmatory secondary endpoints were changes in HbA_1c and body weight from baseline to week 30, respectively.ResultsMean HbA_1c (baseline 8.2%) decreased by 1.7% with semaglutide and 1.0% with liraglutide (estimated treatment difference [ETD] –0.69%; 95% confidence interval [CI] -0.82 to -0.56, P < 0.0001). Mean body weight (baseline 96.9 kg) decreased by 5.8 kg with semaglutide and 1.9 kg with liraglutide (ETD -3.83 kg; 95% CI -4.57 to -3.09, P < 0.0001). The proportions of subjects achieving glycaemic targets of < 7.0% and = 6.5%, weight loss of = 5% and = 10%, and a composite endpoint of HbA_1c < 7.0% without severe or blood glucose-confirmed symptomatic hypoglycaemia and no weight gain were greater with semaglutide vs liraglutide (all P < 0.0001). Both treatments had similar safety profiles, except for more frequent gastrointestinal disorders (the most common adverse events [AEs]) and AEs leading to premature treatment discontinuation with semaglutide vs liraglutide (43.9% vs 38.3% and 11.4% vs 6.6%, respectively).ConclusionSemaglutide was superior to liraglutide in reducing HbA_1c and body weight. Safety profiles were generally similar, except for higher rates of gastrointestinal AEs with semaglutide vs liraglutide.     

Platelet activation and coronavirus disease 2019 mortality: Insights from coagulopathy,antiplatelet therapy and inflammation

BackgroundCoronavirus disease 2019 (COVID-19) is associated with an inflammatory cytokine burst and a prothrombotic coagulopathy. Platelets may contribute to microthrombosis, and constitute a therapeutic target in COVID-19 therapy.AimTo assess if platelet activation influences mortality in COVID-19.MethodsWe explored two cohorts of patients with COVID-19. Cohort A included 208 ambulatory and hospitalized patients with varying clinical severities and non-COVID patients as controls, in whom plasma concentrations of the soluble platelet activation biomarkers CD40 ligand (sCD40L) and P-selectin (sP-sel) were quantified within the first 48 hours following hospitalization. Cohort B was a multicentre cohort of 2878 patients initially admitted to a medical ward. In both cohorts, the primary outcome was in-hospital mortality.ResultsIn cohort A, median circulating concentrations of sCD40L and sP-sel were only increased in the 89 critical patients compared with non-COVID controls: sP-sel 40,059 (interquartile range 26,876–54,678) pg/mL; sCD40L 1914 (interquartile range 1410–2367) pg/mL (P < 0.001 for both). A strong association existed between sP-sel concentration and in-hospital mortality (Kaplan-Meier log-rank P = 0.004). However, in a Cox model considering biomarkers of immunothrombosis, sP-sel was no longer associated with mortality, in contrast to coagulopathy evaluated with D-dimer concentration (hazard ratio 4.86, 95% confidence interval 1.64–12.50). Moreover, in cohort B, a Cox model adjusted for co-morbidities suggested that prehospitalization antiplatelet agents had no significant impact on in-hospital mortality (hazard ratio 1.05, 95% CI 0.80–1.37; P = 0.73).ConclusionsAlthough we observed an association between excessive biomarkers of platelet activation and in-hospital mortality, our findings rather suggest that coagulopathy is more central in driving disease progression, which may explain why prehospitalization antiplatelet drugs were not a protective factor against mortality in our multicentre cohort.     

Insulin clearance is altered in women with a history of gestational diabetes progressing to type 2 diabetes

Background and aimsInsulin clearance is a relevant process in glucose homeostasis. In this observational study, we aimed to assess insulin clearance (Cl_INS) in women with former gestational diabetes (fGDM) both early after delivery and after a follow-up.Methods and resultsWe analysed 59 fGDM women, and 16 women not developing GDM (CNT). All women underwent an oral glucose tolerance test (OGTT) yearly, and an insulin-modified intravenous glucose tolerance test (IVGTT) at baseline and at follow-up end (until 7 years). Both IVGTT and OGTT Cl_INS was assessed as insulin secretion to plasma insulin ratio. We also defined IVGTT first (0–10 min) and second phase (10–180 min) Cl_INS. We found that 14 fGDM women progressed to type 2 diabetes (PROG), whereas 45 women remained diabetes-free (NONPROG). At baseline, IVGTT Cl_INS showed alterations in PROG, especially in second phase (0.88 ± 0.10 l·min⁻¹ in PROG, 0.60 ± 0.06 in NONPROG, 0.54 ± 0.07 in CNT, p ≤ 0.03). Differences in Cl_INS were not found from OGTT. Cox regression analysis showed second phase Cl_INS as significant type 2 diabetes predictor (hazard ratio = 1.90, 95% confidence interval 1.09–3.30, p = 0.02).ConclusionThis study showed that insulin clearance derived from an insulin-modified IVGTT is notably altered in women with history of GDM progressing towards type 2 diabetes.