J. Gustav Smith

Background: Accumulating evidence suggests that the gut microbiota is implicated in cardiovascular disease. We investigated how the gut microbiome associates with incident major adverse cardiovascular events (MACE), and cardiovascular and all-cause mortality (ACM) in a large, prospective, population-based study. The findings were tested for replication in four independent cohorts. Methods: Gut microbiome composition was assessed via shallow shotgun sequencing in the FINRISK 2002 cohort, with up to 18 years of follow-up. Associations of microbial taxa with incident MACE were investigated using time-to-event analyses. Significant associated microbial features were tested for replication in four European cohorts (HUNT, HELIUS, SIMPLER, and SCAPIS) followed by a meta-analysis. Results: In the FINRISK 2002 cohort (1167 incident MACE events), nine taxa were significantly associated with incident MACE and sustained adjustments for traditional risk factors and multiple comparisons. The meta-analysis of replication cohorts (N=30,228; 1,938 participants with incident MACE) confirmed robust associations for several identified taxa. Specifically, higher abundance of genera Scardovia (HR=1.17 [95% CI 1.08-1.26], p= 0.0001) and Limosilactobacillus (HR=1.16 [95%CI 1.09-1.23], p= 1E-06) was associated with increased MACE risk, and increased risk of cardiovascular mortality and all-cause mortality. The species ER4 sp900317525 (HR=0.89 [95%CI 0.83-0.95], p=0.0005) was associated with lower hazard of MACE and all-cause mortality. Conclusions: The gut metagenome showed robust associations with incident MACE, which were replicated in four independent European cohorts. Key microbial taxa also associated with incident MACE and mortality, suggesting their potential relevance as candidate risk markers for further studies.

Background: Pulmonary congestion in heart failure (HF) is challenging to quantify. Recent advances in cardiovascular magnetic resonance (CMR) using routine clinical perfusion scans make it possible to calculate the pulmonary blood volume indexed to body surface area (PBVi) as a prognostic marker of congestion. The aims were to assess if PBVi normalizes after onset of treatment and if PBVi differs in different HF subtypes compared to healthy controls. Methods: In this prospective cohort study, a total of 115 subjects (22 healthy controls, 93 HF patients of which 19 newly diagnosed) underwent CMR at 1.5T. PBVi was calculated as the transit time for a contrast bolus from the right to the left side of the heart during a perfusion scan, multiplied by the cardiac output from 2D aortic flow. Results: Patients with newly diagnosed HF showed signs of pulmonary congestion in terms of an increased PBVi compared to controls (394 vs 302 ml/m2 p = 0·004). After treatment, PBVi normalized to similar levels as controls (296 ml/m2, p > 0·99). There were no differences in PBVi between controls and chronic out-patients with preserved (HFpEF, n = 19, p > 0·999), mildly reduced (HFmrEF, n = 24, p > 0·999) or reduced ejection fraction (HFrEF, n = 31, p = 0·146). Conclusion: This proof-of-concept study demonstrates for the first time that non-invasive PBVi normalizes following initiation of guideline-directed medical therapy, while PBVi remained within normal range in treated patients with HFpEF or HFmrEF. Assessment by CMR may provide incremental clinical value as a marker of pulmonary congestion in suspected HF and for evaluating response to decongestive treatment.

Aims/hypothesis: Heart failure (HF) is a common complication of diabetes, associated with a high mortality rate and a substantial healthcare burden. Residual HF risk persists despite achieving current treatment targets, suggesting a role for additional mechanisms beyond conventional risk factors. We sought to prospectively assess HF incidence and independent risk factors in individuals with new-onset diabetes. Methods: We used a prospective inception cohort (ANDIS, n =19,892) that included all individuals with newly diagnosed diabetes from southern Sweden between 2008 and 2021. Baseline clinical, biochemical and questionnaire data were linked to the Region Scania Care Database to obtain data on cardiovascular events and to the National Diabetes Registry to gather further data on cardiovascular risk factors that were not collected in the ANDIS study protocol. All-cause HF included all cases of HF regardless of underlying aetiology, whereas non-ischaemic HF was defined as HF occurring in individuals without prior acute myocardial infarction at baseline or during follow-up before the HF diagnosis. Cardiovascular disease incidence was estimated using the Kaplan–Meier method, and the associations with risk factors and incident HF were assessed using Cox proportional hazards regression. Results: The median age of the overall population was 62.5 years (IQR 52.6–70.3), while the median age among individuals who developed incident all-cause HF was 69.8 years (IQR 62.7–76.7). A total of 819 individuals (4.1%) with prevalent HF were excluded. During up to 14 years of follow-up (median 5.0), the cumulative incidence of HF was 4.8%, exceeding that of myocardial infarction (3.0%). No individuals with type 1 diabetes developed HF, but the incidence was similar across those with type 2 diabetes, latent autoimmune diabetes in adults, and secondary diabetes. A lower eGFR and higher HOMA2-IR, were associated with increased risk of all-cause and non-ischaemic HF, independently of the presence of conventional risk factors. Insulin resistance predicted all-cause HF independently of the established SCORE2-Diabetes risk score. The hazard ratio (HR) per 1 SD increase in HOMA2-IR was highest in the low-risk group (HR 1.89; 95% CI 1.02, 3.48; p =4.3 × 10 ⁻² ), with concordant results observed for non-ischaemic HF. Conclusions/interpretation: The HF incidence was high, with approximately 1 in 20 individuals developing HF within 5 years after diagnosis of diabetes other than type 1, highlighting a notably high risk of developing HF soon after diabetes diagnosis. Beyond conventional risk factors, higher HOMA2-IR and lower renal function, but not hyperglycaemia or autoantibodies, were independent risk factors for HF. Measuring HOMA2-IR also provided prognostic information in addition to that provided by the SCORE2-Diabetes risk score, supporting its value in HF risk stratification.

BACKGROUND: Lipidomics, the comprehensive profiling of circulating lipid species, has emerged as a powerful tool to investigate metabolic alterations underlying coronary atherosclerosis. Understanding the mechanisms driving high-risk vulnerable plaque formation and progression to myocardial infarction remains a key therapeutic priority. This study investigates associations between circulating lipid metabolites and imaging-defined features of vulnerable coronary plaque. METHODS: Following revascularization, patients with myocardial infarction underwent 3-vessel coronary artery imaging with near-infrared spectroscopy and intravascular ultrasound to assess nonflow-limiting plaques for lipid core burden index and plaque burden. Multivariable models evaluated associations between 424 lipid metabolites in plasma, quantified by mass spectrometry, pan-coronary lipid, pan-coronary plaque burden, and high-risk vulnerable plaque measures (maximum lipid core burden index within any 4-mm segment across the entire lesion ≥324.7 and plaque burden ≥70%) in 877 patients. Findings were validated in the SCAPIS study (Swedish Cardiopulmonary Bioimage Study) using coronary computed tomography angiography–based measures of coronary artery calcium score and segment involvement score. RESULTS: We identified 156 significant associations ( P <0.05) between lipid metabolites and coronary plaque characteristics across 39 metabolic pathways. Sphingomyelins were inversely associated with all plaque metrics, and 1-palmitoyl-2-oleoyl-GPE (16:0/18:1), a phosphatidylethanolamine, was positively associated with all plaque metrics. After correcting for multiple testing, 27 lipid species across 7 pathways remained significant (q<0.05). The majority were linked to pan-coronary lipid burden, with the strongest inverse association observed for sphingomyelin d18:1/22:1, d18:2/22:0, and d16:1/24:1. Similar inverse patterns were seen for select dihydrosphingomyelins and fatty acid dicarboxylates. In contrast, 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) remained positively associated with pan-coronary lipid. In the SCAPIS validation cohort, 19 of the 27 significant lipid associations were successfully replicated (q<0.05). CONCLUSIONS: This study is the first to demonstrate that sphingomyelins are negatively and 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) positively associated with vulnerable coronary plaque features based on multimodality intracoronary imaging in patients with myocardial infarction. Moreover, these associations were validated in a large cohort using coronary computed tomography angiography–derived measures of plaque burden. These novel results may enable the development of new diagnostic and therapeutic strategies.

Aims: To build a comprehensive biobank integrated in the Swedish Heart Failure Registry (SwedeHF) comprising comprehensive clinomic data, proteomic, transcriptomic and genomic information in combination with clinical and diagnostic characteristics and additional ICD-code registry data. Methods: Blood and urine samples will be biobanked at SwedeHF registration with an optional second sampling after six months in patients with HF attending routine clinical visits at nine hospitals with access to healthcare integrated biobanking. Circulating and urine biomarkers will be investigated by proteomic, metabolomic, transcriptomic profiling, explored with genetic data. Sample size assessments were based on the BIOSTAT-CHF cohort and doubled to fulfil all aims targeting 5000 patients. Results: The first 1348 enrolled patients were median 72 years, 30% females, 65% HFrEF and 11% HFpEF. Median NT-proBNP was 1240 (interquartile range 470 - 2830) pg/ml. This was comparable to the 8506 patients with an index registration in SwedeHF during 2023 with 52% HFrEF and 20% HFpEF, age 75 years, 36% females and NT-proBNP 1560 [629 - 3617] pg/ml. Conclusions: We are building a high-quality detailed biobank linked to SwedeHF, the world’s largest continuous HF registry, consisting of plasma, serum, whole blood and urine samples. The Biobank will enable studies exploring underlying disease mechanisms in HF and response to HF treatment, paving the way for precision medicine and novel drug targets. It will also generate a structure for biobanking in Registry-based Randomized Controlled Trials within the national SwedeHF registry.

BACKGROUND: NPs (natriuretic peptides) are bioactive hormones crucial for regulating blood pressure, glucose homeostasis, and lipid metabolism. Despite the high heritability of circulating NP levels, the genetic determinants of NP regulation, particularly across ancestries and sexes, remain poorly understood. The objective of the current study was to identify genetic variants associated with NT-proBNP (N-terminal pro-B-type NP) levels in a multiancestry study population. METHODS: Whole genome sequencing and array-based data from 81 213 individuals without heart failure were analyzed from the Trans-Omics for Precision Medicine cohorts, UK Biobank, All of Us Research Program, and REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to identify common, rare, and structural variants associated with NT-proBNP levels. The main outcome of the study was rank-based inverse normal and standardized NT-proBNP levels. Genetic associations with NT-proBNP were examined, followed by gene prioritization, transcriptome-wide association studies, colocalization, and rare variant analyses. RESULTS: Nine novel loci and 3 previously reported loci were identified to be associated with NT-proBNP levels. Novel structural variants were detected across 12 loci. Similar effect sizes were observed for both common and rare variants. Key genes such as BAG3 (10q26.11) and SLC39A8 (4q24) were identified through gene prioritization, with prior animal models supporting their therapeutic relevance. Rare variant analysis identified 6 masks with significant associations, specifically non-coding masks, suggesting regulatory modulation of NT-proBNP. CONCLUSIONS: This study identifies novel common, rare, and structural variants associated with NT-proBNP levels, highlighting the contribution of both coding and regulatory non-coding variation. These findings advance our understanding of the genetic architecture of NT-proBNP and may inform future cardiometabolic therapeutic strategies.

Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of CMKLR1 and LTBP4 in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor β signaling in AS.

Objectives We aimed to describe clinical and diagnostic characteristics of primary care patients with heart failure and physicians’ adherence to guideline-directed medical therapy (GDMT) for treating chronic heart failure. Design Cross-sectional study based on baseline data from the prospective primary care-based study Heart failure in Southern Sweden (HISS). Setting Patients with heart failure were included from 20 primary healthcare centres in the southernmost region of Sweden (Skåne). Participants Between 2020 and 2023, patients were included in HISS, resulting in a total of 587 participants. Of these, 558 patients (95% of the HISS participants) had available data on left ventricular ejection fraction and were included in this study. Adult patients aged 18 years or older diagnosed with heart failure (International Classification of Diseases, 10th Revision codes I50, I11.0, I42, I43) were considered eligible for inclusion in HISS. Community-dwelling patients with assisted care were excluded. Primary and secondary outcomes The primary outcome measures were distribution of heart failure subtypes and prescribed medications. The secondary outcomes were temporal trends in GDMT and the association between physicians’ adherence to GDMT and clinical characteristics of patients, using logistic regression models. Results Heart failure with preserved ejection fraction (HFpEF) was the most prevalent subtype (42%), followed by mildly reduced (30%) and reduced ejection fraction (HFrEF, 28%). Among patients with HFrEF, 20% were prescribed the recommended GDMT according to the European Society of Cardiology (ESC) 2021 guidelines, which consisted of a renin-angiotensin system inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and a sodium-glucose 2 inhibitor. We observed no significant change in the prescribing trends for the quadruple therapy in patients with HFrEF when comparing the 2 years before and after the publication of the ESC 2021 guidelines. Similarly, we observed no association between patient characteristics and the prescription of GDMT according to ESC 2021 for patients with HFrEF. Conclusion HFpEF was the most prevalent subtype, with conclusive and recent echocardiography data among two-thirds of the cohort. Temporal trends in prescription patterns showed no appreciable increase in the use of GDMT for HFrEF during the two years following guideline publication compared with the two preceding years. These findings indicate a need for inclusion of primary care patients as a basis for intensified medical recommendations and implementation strategies. Trial registration number NCT04129658.

Background: Heart failure (HF) is characterized by hemodynamic derangements that are likely to mediate systemic metabolic perturbations but limited data are available. Plasma metabolite profiling provides opportunities for comprehensive investigation of such perturbations. Here, we aimed to characterize plasma profiles that associate with HF and their relationship with central hemodynamics, symptom burden, and response to restoration of cardiac function by heart transplantation. Methods: Untargeted metabolite profiling was conducted with mass spectrometry in 2 independent case–control samples. Results: In total, 89 of 797 studied metabolites were significantly associated with HF in both cohorts with concordant directionality. Amino acid, carbohydrate, and nucleotide metabolites were enriched for association with HF and were consistently increased in HF cases. A subset of patients with advanced HF subsequently underwent heart transplantation, after which 17 of the 89 metabolites returned significantly toward healthy control levels. These 17 metabolites represent increased catecholamine and heme metabolism, conjugated bile acids, kynurenine pathway mediators, spermidine metabolism, and allantoin, as well as tricarboxylic acid cycle and glycolysis intermediates. Most of these metabolites associated with symptom burden and at least 1 of 12 central hemodynamic parameters, primarily relating to either increased systemic or pulmonary venous congestion, lower cardiac output, or lower left ventricular stroke work. Conclusions: We comprehensively identified metabolite profiles associated with HF and central hemodynamics that reverse by cardiac transplantation. Increased levels of most metabolites also associated with higher symptom burden. Our findings provide perspectives on the metabolic consequences of HF with potential implications for noninvasive monitoring and tailored therapy.

Aims: Peak oxygen uptake (VO2peak) is closely related to total heart volume (THV) in healthy individuals. This study aimed to investigate (i) the association between VO2peak and THV in subjects with sub-clinical diastolic dysfunction, athletes, healthy controls, and patients with established heart failure with and without preserved ejection fraction (HFpEF and HFrEF), and (ii) whether VO2peak/THV-index can distinguish between subjects with sub-clinical diastolic dysfunction, HFpEF, HFrEF, and healthy controls. Methods and results: Seventy participants were included: 15 with sub-clinical diastolic dysfunction (defined as showing only 1–2 echocardiographic signs of diastolic dysfunction, not meeting clinical diagnostic criteria), 10 athletes, 15 healthy controls, and 30 heart failure patients (15 HFpEF and 15 HFrEF). VO2peak was assessed by cardiopulmonary exercise testing and THV by cardiovascular magnetic resonance imaging. In sub-clinical diastolic dysfunction, THV was a weak determinant of VO2peak (R2 = 0.41, P = 0.01), and even weaker in heart failure (R2 = 0.16, P = 0.03). However, THV strongly predicted VO2peak in athletes and controls combined (R2 = 0.87, P < 0.0001). VO2peak/THV did not distinguish healthy controls from sub-clinical diastolic dysfunction but could reliably discriminate between healthy controls and patients with heart failure. Conclusion: Subjects with sub-clinical diastolic dysfunction may have an altered relationship between VO2peak and THV, approaching that of patients with established heart failure. Thus, this proof-of-concept study indicates that sub-clinical diastolic dysfunction constitutes a group of patients that may be of interest to follow over time to prevent continued deterioration of cardiac function. Furthermore, the VO2peak/THV ratio can be used to distinguish between healthy controls and overt heart failure.