Christoph Nowak

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

The type 1 diabetes community is coalescing around the benefits and advantages of early screening for disease risk. To be accepted by healthcare providers, regulatory authorities and payers, screening programmes need to show that the testing variables allow accurate risk prediction and that individualised risk-informed monitoring plans are established, as well as operational feasibility, cost-effectiveness and acceptance at population level. Artificial intelligence (AI) has the potential to contribute to solving these issues, starting with the identification and stratification of at-risk individuals. ASSET (AI for Sustainable Prevention of Autoimmunity in the Society; www.asset.healthcare) is a public/private consortium that was established to contribute to research around screening for type 1 diabetes and particularly to how AI can drive the implementation of a precision medicine approach to disease prevention. ASSET will additionally focus on issues pertaining to operational implementation of screening. The authors of this article, researchers and clinicians active in the field of type 1 diabetes, met in an open forum to independently debate key issues around screening for type 1 diabetes and to advise ASSET. The potential use of AI in the analysis of longitudinal data from observational cohort studies to inform the design of improved, more individualised screening programmes was also discussed. A key issue was whether AI would allow the research community and industry to capitalise on large publicly available data repositories to design screening programmes that allow the early detection of individuals at high risk and enable clinical evaluation of preventive therapies. Overall, AI has the potential to revolutionise type 1 diabetes screening, in particular to help identify individuals who are at increased risk of disease and aid in the design of appropriate follow-up plans. We hope that this initiative will stimulate further research on this very timely topic. Graphical Abstract

Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m², 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9–3.3], 2.0 (1.9–2.1), 4.5 (4.2–4.9), 2.8 (2.7–3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43–50) within 3 months] after adjustment for other CVD subtype incidence. Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed. Hazard ratios (HRs) [and 95% confidence intervals [CIs]) for the risk of kidney failure with replacement therapy (KFRT) associated to developing heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF) or stroke, across 81 global cohorts and graphically depicted using the Optum Labs Data Warehouse database.

Human gut microbiota produce a variety of molecules, some of which enter the bloodstream and impact health. Conversely, dietary or pharmacological compounds may affect the microbiota before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health. In this cross-sectional study, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for a detailed characterization of the gut microbiota and plasma metabolome, respectively, of 8583 participants invited at age 50 to 64 from the population-based Swedish CArdioPulmonary bioImage Study. Here, we find that the gut microbiota explain up to 46% of the variance of individual plasma metabolites and we present 997 associations between alpha diversity and plasma metabolites and 546,819 associations between specific gut metagenomic species and plasma metabolites in an online atlas (https://gutsyatlas.serve.scilifelab.se/). We exemplify the potential of this resource by presenting novel associations between dietary factors and oral medication with the gut microbiome, and microbial species strongly associated with the uremic toxinp-cresol sulfate. This resource can be used as the basis for targeted studies of perturbation of specific metabolites and for identification of candidate plasma biomarkers of gut microbiota composition.

Aims: The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an ‘Add-on’ to incorporate CKD measures into these algorithms, using a validated approach. Methods: In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets. Results: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004–0.008) and 0.016 (0.010–0.023), respectively, for SCORE2 and 0.012 (0.009–0.015) and 0.024 (0.014–0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062–0.138) for SCORE2] compared to the qualitative approach in the ESC guideline. Conclusion: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD.

Aims: The interplay between pain of different chronicity and cardiovascular disease (CVD) is incompletely understood. We aimed to investigate the association between different levels of chronic or nonchronic pain and risk of CVD. Methods and results: Participants in the UK Biobank who reported pain at baseline were divided into three groups according to pain duration and widespreadness. Participants reporting no pain were controls. Multivariable Cox regression was used to investigate the association between pain and incidence of myocardial infarction, heart failure, stroke, cardiovascular mortality, and composite CVD (defined as any of the before-mentioned cardiovascular events). Of 475 171 participants, 189 289 reported no pain, 87 830 reported short-term pain, 191 716 chronic localized pain, and 6336 chronic widespread pain (CWP). During a median of 7.0 years’ follow-up, participants with chronic localized pain and CWP had, after adjustment for age, sex, established cardiovascular risk factors, physical activity, anxiety, depression, cancer, chronic inflammatory/painful disease, pain/anti-inflammatory medication, socioeconomic status, a significantly increased risk for composite CVD [hazard ratio (HR) 1.14, confidence interval (CI) 1.08–1.21, P < 0.001; and HR 1.48, CI 1.28–1.73, P < 0.001, respectively] compared with controls, with similar results when using the different specific CVDs as outcomes. Population attributable risk proportion for chronic pain as a risk factor for composite CVD was comparable with that of diabetes (8.6 vs. 7.3%, respectively). Conclusion: Chronic pain is associated with an increased risk for myocardial infarction, stroke, heart failure, and cardiovascular death independent of established cardiovascular risk factors, socioeconomic factors, comorbidities and medication. Our study, the largest to date, confirms and extends our understanding of chronic pain as an underestimated cardiovascular risk factor with important public health implications.

Aims Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). Methods DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 μg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. Results We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. Conclusions Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis, and to explore relevant clinical correlates. METHODS: We conducted a cross-sectional study of 8973 participants aged 50 to 65 without overt atherosclerotic disease from the population-based Swedish Cardiopulmonary BioImage Study (SCAPIS). Coronary atherosclerosis was measured using coronary artery calcium score (CACS) and coronary computed tomography angiography (CCTA). Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of stool samples, and their association with coronary atherosclerosis was evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3% of participants, and 5.4% had at least one stenosis with more than 50% occlusion. Sixty-four species were associated with CACS independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and S. oralis subsp . oralis ( P -5 ). Associations were largely similar across CCTA-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations and 16 with neutrophil counts. Oral species in the gut were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid beta-oxidation and amino acid degradation was associated with CACS. CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp. and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation. Further longitudinal and experimental studies are warranted to explore the potential implication of a bacterial component in atherogenesis. CLINICAL PERSPECTIVE: WHAT IS NEW?: Shotgun metagenomics identified associations between gut species and subclinical atherosclerosis assessed with computed tomography-derived coronary artery calcium score (CACS) in 8973 participants, with an overrepresentation of the Streptococcus and Oscillobacter genera. The relative abundance of CACS-associated oral species detected in fecal samples was negatively associated with indole propionate, while positively associated with secondary bile acids and imidazole propionate. Gut Streptococcus spp. were positively associated with circulating biomarkers of systemic inflammation and infection response, and with the same species located in the mouth, which were in turn associated with oral pathologies. WHAT ARE THE CLINICAL IMPLICATIONS?: We describe the link between gut microbiota composition, especially species commonly found in the mouth, with subclinical coronary atherosclerosis and biomarkers of inflammation in the largest cardiovascular and metagenomics study to date. The effects of gut and oral Streptococcus spp. on risk for coronary artery disease merit further longitudinal and experimental studies.