New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Sex‐based differences in cardiac resynchronization therapy upgrade and outcome for patients with pacemaker and new‐onset heart failure

BackgroundPatients with chronic right ventricular (RV) pacing are at an increased risk of heart failure. Previous studies have indicated that cardiac resynchronization therapy (CRT) is underused in this setting, and that there may be sex-based differences in both CRT use and clinical outcome.ObjectiveTo evaluate sex-based differences in CRT use and clinical outcome for patients with new-onset heart failure post RV pacing.MethodsData from the Swedish pacemaker registry was matched with data from the national death and disease registries. Patients with de novo pacemaker implant due to AV block during the period 2005–2020 were included. New-onset heart-failure within two years post-implant was evaluated, primary outcome was all-cause mortality.ResultsIn all, 30183 patients (37% female) were included. Women were on average 3 years older, but had less comorbidities than men. Median follow-up time was 4.5 [2.0–8.0] years. Women had better age- and comorbidity-adjusted survival (HR 0.78 [0.73–0.84], p < .001). For the 3560 patients (12.4% men and 10.7% women, p < .001) who were diagnosed with new-onset heart failure, 5-year mortality was similar for men and women (50% vs. 48%, p = .29). However, women were less likely to receive CRT-upgrade (3.8% vs. 9.1%, p < .001), and those who did were almost ten years younger than the men.ConclusionWomen with pacemaker due to AV block are older but have less comorbidities than men. They are less likely to develop new-onset heart failure, but also less likely to receive a CRT upgrade if they do develop heart failure. Increased awareness of the positive effects of CRT upgrade and potential sex- and age-based discrimination is warranted

Age-stratified comparison of prognosis in cardiac resynchronization therapy with or without prophylactic defibrillator for non-ischemic cardiomyopathy – a nationwide cohort study

Background and aimsPrior studies have suggested that the benefit from primary preventive defibrillator treatment for patients with non-ischemic cardiomyopathy primarily, treated with cardiac resynchronization therapy, may be age-dependent. We aimed to compare age-stratified mortality rates and mode of death in patients with non-ischemic cardiomyopathy who are treated with either primary preventive Cardiac Resynchronization Therapy-defibrillator (CRT-D) or CRT-pacemaker (CRT-P).MethodsAll patients with non-ischemic cardiomyopathy and CRT-P or primary preventive CRT-D who were implanted in Sweden during the period 2005-2020 were included. Propensity scoring was used to create a matched cohort. Primary outcome was all-cause mortality within five years.Results4027 patients were included, 2334 with CRT-P and 1693 with CRT-D. Crude 5-year mortality was 635 (27%) vs. 246 (15%), p ConclusionIn this nationwide registry-based study, patients with CRT-D have better five-year survival compared to patients with CRT-P. The interaction between age and mortality reduction not consistent, but patients with CRT-D age

AGPAT1 as a novel colonic biomarker for discriminating between ulcerative colitis with and without primary sclerosing cholangitis

INTRODUCTION: Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC-UC) is considered a unique inflammatory bowel disease (IBD) entity. PSC diagnosis in an IBD individual entails a significantly higher risk of gastrointestinal cancer; however, biomarkers for identifying patients with UC at risk for PSC are lacking. We, therefore, performed a thorough PSC-UC biomarker study, starting from archived colonic tissue. METHODS: Proteins were extracted out of formalin-fixed paraffin-embedded proximal colon samples from PSC-UC (n = 9), UC (n = 7), and healthy controls (n = 7). Patients with IBD were in clinical and histological remission, and all patients with UC had a history of pancolitis. Samples were processed by the multienzyme digestion FASP and subsequently analyzed by liquid chromatography–tandem mass spectrometry. Candidate proteins were replicated in an independent cohort (n: PSC-UC = 16 and UC = 21) and further validated by immunohistochemistry. RESULTS: In the discovery step, 7,279 unique proteins were detected. The top 5 most differentiating proteins (PSC-UC vs UC) based on linear regression analysis were selected for replication. Of these, 1-acetylglycerol-3-phosphate O-acyltransferase 1 (AGPAT1) was verified as higher in PSC-UC than UC (P = 0.009) in the replication cohort. A difference on the group level was also confirmed by immunohistochemistry, showing more intense AGPAT1 staining in patients with PSC-UC compared with UC. DISCUSSION: We present AGPAT1 as a potential colonic biomarker for differentiating PSC-UC from UC. Our findings have possible implication for future PSC-IBD diagnostics and surveillance

Development of a prognostic MRCP score (DiStrict) for patients with large-duct primary sclerosing cholangitis

Background and AimsMRCP is used for diagnosis and follow-up of patients with primary sclerosing cholangitis (PSC). Interest in the prognostic value of MRCP is increasing. The aim of our study is to develop an MRCP-score based on cholangiographic findings previously associated with outcomes and assess its reproducibility and prognostic value in PSC.MethodsThe score (DiStrict-score) was developed based on the extent and severity of cholangiographic changes of intrahepatic and extrahepatic bile ducts (range 0–8) on 3D-MRCP. In this retrospective, ethics review board approved, multicentre study, three pairs of radiologists with different levels of expertise from three tertiary centres applied the score independently. MRCP- examinations of 220 consecutive PSC-patients from a prospectively collected PSC-cohort, with median follow-up of 7.4 years, were reviewed. Interreader and intrareader agreements were assessed via intraclass correlation coefficient (ICC). After consensus, the prognostic value of the score was assessed using Cox-regression and outcome-free survival rates were assessed via Kaplan-Meier estimates. Harrell´s C-statistic was calculated.Results40 patients developed outcomes (liver transplantation or liver-related death). Interreader agreement between experienced radiologists was good (ICC=0.82; 95%CI:0.74–0.87, and ICC=0.81; 95%CI:0.70–0.87, respectively) and better than the agreement for the pair of experienced/less experienced radiologist (ICC=0.48; 95%CI:0.05–0.72). Agreement between radiologists from the three centres was good (ICC=0.76; 95%CI:0.57–0.89). Intrareader agreement was good to excellent (ICC=0.85–0.93). Harrell´s C was 0.78. Patients with DiStrict-score of 5 – 8 had 8.2 times higher risk (HR=8.2; 95%CI:2.97–22.65) for developing outcomes, and significantly worse survival (P ConclusionsThe novel DiStrict-score is reproducible and strongly associated with outcomes, indicating its value for PSC-patient prognoses in clinical practice.Lay summaryDiagnosis of primary sclerosing cholangitis (PSC) is based on magnetic resonance cholangiopancreatography (MRCP). However, the role of MRCP in the prognosis of PSC is still unclear. We developed a novel, simple, and reproducible risk-score, based on MRCP findings, that showed a strong association with PSC patient prognoses (DiStrict score). This score can be easily used in clinical practice and thus has the potential to be useful in clinical trials and in patient counselling and management

Is one month treatment with dabigatran before cardioversion of atrial fibrillation sufficient to prevent thromboembolism?

The use of direct oral anticoagulants (DOACs) in patients undergoing elective direct current (DC) cardioversion of non-acute atrial fibrillation (AF) can potentially shorten the time from initiation of anticoagulation treatment to cardioversion, compared with warfarin. The safety of this strategy needs to be investigated. Data from subgroup analysis from clinical trials with DOAC do not clarify whether 4-week treatment with DOAC is sufficient to prevent thromboembolism (TE) after cardioversion. The aim of this retrospective study was to assess the incidence of TE in anticoagulant naive patients converted after one month's pre-treatment with dabigatran

Adipocyte-specific ablation of the Ca2+pump SERCA2 impairs whole-body metabolic function and reveals the diverse metabolic flexibility of white and brown adipose tissue

Objective: Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) transports Ca2+ from the cytosol into the endoplasmic retitculum (ER) and is essential for appropriate regulation of intracellular Ca2+ homeostasis. The objective of this study was to test the hypothesis that SERCA pumps are involved in the regulation of white adipocyte hormone secretion and other aspects of adipose tissue function and that this control is disturbed in obesity-induced type-2 diabetes. Methods: SERCA expression was measured in isolated human and mouse adipocytes as well as in whole mouse adipose tissue by Western blot and RT-qPCR. To test the significance of SERCA2 in adipocyte functionality and whole-body metabolism, we generated adipocyte-specific SERCA2 knockout mice. The mice were metabolically phenotyped by glucose tolerance and tracer studies, histological analyses, measurements of glucose-stimulated insulin release in isolated islets, and gene/protein expression analyses. We also tested the effect of pharmacological SERCA inhibition and genetic SERCA2 ablation in cultured adipocytes. Intracellular and mitochondrial Ca2+ levels were recorded with dualwavelength ratio imaging and mitochondrial function was assessed by Seahorse technology. Results: We demonstrate that SERCA2 is downregulated in white adipocytes from patients with obesity and type-2 diabetes as well as in adipocytes from diet-induced obese mice. SERCA2-ablated adipocytes display disturbed Ca2+ homeostasis associated with upregulated ER stress markers and impaired hormone release. These adipocyte alterations are linked to mild lipodystrophy, reduced adiponectin levels, and impaired glucose tolerance. Interestingly, adipocyte-specific SERCA2 ablation leads to increased glucose uptake in white adipose tissue while the glucose uptake is reduced in brown adipose tissue. This dichotomous effect on glucose uptake is due to differently regulated mitochondrial function. In white adipocytes, SERCA2 deficiency triggers an adaptive increase in fibroblast growth factor 21 (FGF21), increased mitochondrial uncoupling protein 1 (UCP1) levels, and increased oxygen consumption rate (OCR). In contrast, brown SERCA2 null adipocytes display reduced OCR despite increased mitochondrial content and UCP1 levels compared to wild type controls. Conclusions: Our data suggest causal links between reduced white adipocyte SERCA2 levels, deranged adipocyte Ca2+ homeostasis, adipose tissue dysfunction and type-2 diabetes. (c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Funding Agencies|Swedish Research Council [2013-07107, 2017-00792, 2019-01239, 2020-01463]; Magnus Bergvall Foundation [2016-01711]; Novo Nordisk Foundation [NNF19OC0056601]; Swedish Diabetes Foundation [DIA2016-127, DIA2018-358, DIA2019-419, DIA2014-074, DIA2015-062, DIA2017- 273, DIA2018-354]</p

Early ICD implantation following out-of-hospital cardiac arrest: a retrospective cohort study from the Swedish Registry for Cardiopulmonary Resuscitation

Background It is unclear whether an implantable cardioverter-defibrillator (ICD) is generally beneficial in survivors of out-of-hospital cardiac arrest (OHCA).Objective We studied the association between ICD implantation prior to discharge and survival in patients with cardiac aetiology or initial shockable rhythm in OHCA.Design We conducted a retrospective cohort study in the Swedish Registry for Cardiopulmonary Resuscitation. Treatment associations were estimated using propensity scores. We used gradient boosting, Bayesian additive regression trees, neural networks, extreme gradient boosting and logistic regression to generate multiple propensity scores. We selected the model yielding maximum covariate balance to obtain weights, which were used in a Cox regression to calculate HRs for death or recurrent cardiac arrest.Participants All cases discharged alive during 2010 to 2020 with a cardiac aetiology or initial shockable rhythm were included. A total of 959 individuals were discharged with an ICD, and 2046 were discharged without one.Results Among those experiencing events, 25% did so within 90 days in the ICD group, compared with 52% in the other group. All HRs favoured ICD implantation. The overall HR (95% CI) for ICD versus no ICD was 0.38 (0.26 to 0.56). The HR was 0.42 (0.28 to 0.63) in cases with initial shockable rhythm; 0.18 (0.06 to 0.58) in non-shockable rhythm; 0.32 (0.20 to 0.53) in cases with a history of coronary artery disease; 0.36 (0.22 to 0.61) in heart failure and 0.30 (0.13 to 0.69) in those with diabetes. Similar associations were noted in all subgroups.Conclusion Among survivors of OHCA, those discharged with an ICD had approximately 60% lower risk of death or recurrent cardiac arrest. A randomised trial is warranted to study this further