Oscar O. Braun

Background: Progressive kidney disease is common in heart transplant recipients due to calcineurin inhibitor exposure and pre-existing comorbidities. Sodium–glucose cotransporter-2 (SGLT2) inhibitors may attenuate the decline in kidney function, but evidence in heart transplant recipients is limited. Methods: The DAPAgliflozin for Renal protection in Heart Transplant recipients (DAPARHT) trial is a multicenter, double-blind, randomized, placebo-controlled trial conducted at six heart transplant centers in Northern Europe. We randomized adult heart transplant recipients with an estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m ^² at least one year after transplantation 1:1 to receive dapagliflozin 10 mg or matching placebo once daily. The primary endpoint was the slope of the eGFR from 2 weeks after treatment initiation to the end of the 12-month blinded treatment period. Results: Between June 2022 and September 2025, we randomized 430 participants, of whom 217 were allocated to dapagliflozin and 213 were allocated to placebo. We included the 424 patients with at least one eGFR measurement after baseline in the full analysis set. Their mean age was 53 ± 14 years and 29& were women. The eGFR at baseline was 67 ± 22 mL/min/1.73 m ² . The median time from transplantation was 7 (3 – 13) years. Dapagliflozin improved the chronic slope of the eGFR compared with placebo. The change in the eGFR from 2 weeks to 12 months after treatment initiation was 2.0 (95% confidence interval [CI] 1.0 – 3.1) mL/min/1.73 m ² in the dapagliflozin group and 0.3 (95% CI -0.8 – 1.4) mL/min/1.73 m ² in the placebo group for a between-group difference of 1.7 (95% confidence interval 0.1 – 3.3) mL/min/1.73 m ^² ; p = 0.03. There were no unexpected safety signals and similar rates of adverse events, including infections, between groups. Conclusions: In heart transplant recipients, dapagliflozin, compared with placebo, improved the slope of the eGFR from 2 weeks to 12 months of treatment.

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.

Context: Glycogen storage diseases are inherited disorders of glycogen metabolism and are commonly associated with hypoglycemia, hepatic dysfunction, or skeletal and cardiac myopathy, depending on the affected enzyme. Glycogen storage disease type 15 (GSD15) is caused by pathogenic variants in GYG1, which encodes glycogenin-1, the autoglucosylating primer required for glycogen synthesis. GSD15 is characterized by cardiomyopathy and storage of abnormal glycogen and polyglucosan in cardiomyocytes. Objective: To understand the pathobiology of GSD15, we investigated the storage material in heart explants from 2 previously reported patients and described a new case of GSD15. Methods: The characteristic storage material was investigated using laser capture microdissection followed by quantitative mass spectrometry (MS) and immunohistochemistry comparing differentially abundant proteins in the storage material with normal-appearing cytoplasmic regions from the same patient. Global protein dysregulation in GSD15 was assessed by quantitative MS of whole-myocardial tissue samples from patients and normal controls. Results: The storage material was enriched in proteins involved in glycogen metabolism, including glycogen synthase, UDP-glucose pyrophosphorylase 2, glycogenin-1, glycogen phosphorylase, and glycogen debranching enzyme. Sequestosome 1 (p62) and desmin were also enriched, without evidence of increased autophagocytosis. Whole-tissue analyses revealed upregulation of cardiomyopathy-associated biomarkers and downregulation of mitochondrial proteins, suggesting impaired energy metabolism contributing to congestive heart failure. Conclusion: In GSD15, storage of abnormal glycogen in cardiomyocytes is associated with enrichment of specific proteins involved in glycogen metabolism, contributing to dysregulation of glycogen turnover. This dysregulation results in polyglucosan accumulation, disruption of sarcomeric and mitochondrial architecture, and progressive fibrosis. No disease-modifying therapy currently exists for GSD15; future strategies based on substrate reduction, enhancement of autophagy, or gene therapy require further investigation.

Aims: Advanced heart failure (AdvHF) remains a major clinical challenge, yet contemporary epidemiological real-world data on AdvHF patients are limited. The aim was to assess 20-year trends in clinical characteristics, outcomes, and use of left ventricular assist devices (LVAD) and heart transplantation (HTx) in patients with AdvHF and reduced ejection fraction (AdvHFrEF) in Sweden. Methods and results: Between 2003 and 2022, 5323 patients (median age 76 [IQR 68–82], 23% females) included in the Swedish HF Registry met adapted ESC-HFA criteria for AdvHF (NYHA III–IV, EF <30%, ≥1 HF hospitalization ≤6 months). Of these, 29% were eligible for AdvHF therapies (median age 63 [IQR 57–67] years, 18% females) according to the following additional criteria: ≤70 years old, no dialysis within ≤5 years, no active cancer within ≤3 years. Unadjusted temporal trends in 1-year outcomes (all-cause, CV and non-CV death, HTx, and LVAD implantation) were presented as estimated annual percent change (eAPC). 1-year all-cause mortality declined significantly in the overall cohort (eAPC −3.8; 95%CI −5.3 to −2.2) as well as in patients eligible for AdvHF therapies (eAPC −3.2; 95%CI −6.3 to −0.1) over the study period. These improvements were largely driven by reductions in CV mortality (overall cohort: eAPC −4.3; 95%CI −6.0 to −2.6; eligible cohort: eAPC −5.6, 95%CI −9.4 to −1.7). Use of LVAD significantly increased over the study period, while HTx showed a modest but non-significant rise. Conclusion: In a large nationwide cohort, all-cause and CV-mortality among AdvHFrEF patients markedly declined over the past 20 years, potentially reflecting improvements in treatments. Despite progress, significant opportunities remain to improve access to and adoption of advanced therapies.

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.

Aims: Cardiac allograft vasculopathy (CAV) is a significant complication that contributes to both morbidity and mortality after heart transplantation. The aim of this study was to (i) assess if quantitative cardiovascular magnetic resonance (CMR) myocardial perfusion could detect different stages of CAV and (ii) establish a myocardial perfusion reserve (MPR) cut-off for significant CAV. Methods and results: Patients with a heart transplant who had performed a clinical CMR scan and invasive angiography at two centres in Sweden were included in the study (n = 110). Quantitative short-axis perfusion maps were acquired using single-bolus gadolinium contrast, dual-sequence perfusion imaging at rest and during stress. Global myocardial perfusion (MP) was averaged across all segments at rest and stress and MPR was defined as the ratio between stress and rest MP. All invasive angiographies were reported according to the International Heart and Lung Transplantation CAV classification. Patients were classified as follows: 53% (58/110) as CAV0, 38% (42/110) as CAV1, and 9% (10/110) as CAV2–3. There was a gradual decrease of stress MP and MPR with increased CAV grade. The MPR could discriminate CAV2–3 with an area under the curve-receiver operating characteristic of 0.88, 95% confidence interval 0.78–0.98, and using a cut-off of 2.2, the sensitivity was 100%, specificity was 68%, and positive and negative predictive values were 21 and 100%. Conclusion: In this multi-centre retrospective study, MPR assessed by CMR could discriminate CAV2–3 with both high sensitivity and negative predictive value and a cut-off of MPR 2.2 is suggested.