AIMS:Myocardial fibrosis plays a crucial role in the pathophysiology of heart failure, increases myocardial stiffness, impairs diastolic function and is associated with adverse outcomes. Shear wave elastography (SWE) uses high frame rate echocardiography to assess shear waves in the myocardium. This technique may permit assessment of myocardial stiffness by measuring the propagation speed of myocardial shear waves. We aimed to validate the ability of SWE to assess the degree of myocardial fibrosis in patients with end-stage heart failure. METHODS AND RESULTS:We performed high frame rate echocardiography in 16 heart failure patients who were listed for heart transplantation and 16 age- and sex-matched healthy control subjects. Naturally occurring shear waves triggered by mitral valve closure (MVC) and aortic valve closure (AVC) were analyzed by tissue Doppler imaging in the interventricular septum. Septal shear wave velocities were compared with septal collagen volume fraction (CVF) in explanted hearts. Mean septal CVF in cardiac explants was 17.1 ± 7.6%. AVC and MVC wave velocities were associated with septal CVF (Spearman's correlation of mean septal values: ρ = 0.75, P = 0.02 and ρ = 0.65, P = 0.03, respectively). Similar results were observed in linear mixed-effects regression analysis by septal region (AVC wave: β = 2.2, 95% CI [0.7, 3.8], P = 0.004; MVC wave: β = 1.5, 95% CI [0.4, 2.5], P = 0.005). Shear waves could be measured in most patients but were limited by patient factors such as prosthetic valves and left ventricular assist devices. CONCLUSION:Shear wave velocities from SWE correlate with CVF. SWE therefore hold promise as a novel non-invasive method for assessing myocardial fibrosis.

Background Myocarditis is a potentially severe adverse event after COVID-19 messenger RNA (mRNA) vaccination. Validation of reported cases is essential. We aimed to determine the occurrence, clinical characteristics and short-term outcomes of vaccine-associated myocarditis (VAM) in Norway.Methods In this nationwide, population-based validation study, we used national health registry data and hospital electronic medical records from 27 December 2020 to 30 April 2022. We identified all Norwegian residents who received at least one dose of BNT162b2 or mRNA-1273. By cross-linking registries, we identified myocarditis within 90 days after vaccination. Diagnoses were validated through individual chart review using Brighton Collaboration criteria. VAM was defined as myocarditis without a more likely alternative cause.Results Among 4.1 million vaccinated individuals who received 10.9 million doses, we identified 367 potential myocarditis cases. Of 349 cases reviewed, 177 (51%) were validated as VAM, corresponding to 4.5 cases per 100 000 vaccinated individuals. In total, 110 (62%) cases occurred after the second dose. Of validated cases, 139 (79%) occurred in men. Median age was 30 (IQR 24–50) years for men and 54 (IQR 32–65) years for women. Three (2%) cases were under 18 years. The median hospital stay was 4 (IQR 3–5) days, and the median ejection fraction was 55% (IQR 53%–60%). Seven (4%) patients required intensive care and two (1%) older patients died. No patient required mechanical circulatory support or heart transplantation.Conclusions VAM occurred in 4.5 per 100 000 vaccinated individuals, based on validation of about half of registry-identified myocarditis cases. The acute clinical course was generally mild. National surveillance and systematic validation are essential for reliable estimates of vaccine-associated adverse events.Trial registration number NCT05610423.

Background B cells and B-cell activating factor (BAFF) are involved in the development of myocardial infarction (MI), but data on the regulation and role of BAFF in MI are scarce. Objectives To examine possible associations between plasma BAFF levels and outcomes in non-ST-elevation MI (NSTEMI) and STEMI. Methods We analyzed plasma BAFF at hospital admission by enzyme immunoassay in 732 patients with NSTEM and 261 patients with STEMI, and in STEMI also during follow-up. Plasma levels were related to pre-defined clinical outcomes (mortality and a composite of major adverse cardiac events [MACE]) in both groups and included infarct size and left ventricular ejection fraction (LVEF) evaluated by cardiac magnetic resonance imaging (CMR) in the STEMI group. Results Our major findings were: (i) BAFF levels at hospital admission were associated with adverse clinical outcome (i.e., mortality and MACE) in NSTEMI, also after adjustment for demographic variables, but only MACE was significant after adjustment for CRP, TnT and eGFR. (ii) In STEMI, BAFF levels increased from baseline and were highest at 4-months in patients who died during long term follow-up. Levels at 4 months were associated with all-cause death in adjusted analysis including CRP, TnT and the Thrombolysis in Myocardial Infarction (TIMI) risk score. (iii) STEMI patients with the largest infarct size and those with LVEF <50% at 4 months, had higher levels of BAFF at 4 months, compared with the other STEMI patients. Conclusion Our study supports a role for BAFF in the development of MI, potentially also in post-MI remodeling.

Importance:Transcatheter aortic valve implant (TAVI) is increasingly being performed in younger and healthier patients with severe aortic valve stenosis. Antithrombotic therapy after TAVI is a key element of optimizing valve durability and clinical outcomes. Objective:To evaluate the safety and efficacy of a factor Xa inhibitor non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy strategy vs an acetylsalicylic acid (ASA) monotherapy strategy after TAVI. Design, Setting, and Participants:Between December 2021 and June 2025, 360 participants between the ages of 65 and 80 years undergoing TAVI for severe aortic valve stenosis were enrolled in this prospective, randomized, open-label, blinded end point trial conducted at 3 Norwegian centers managing the majority of TAVI procedures nationally. The last patient completed follow-up on May 19, 2026. Intervention:A total of 360 participants were randomly assigned (1:1) to receive 12 months of monotherapy with either NOAC (intervention) or ASA (control). Main Outcomes and Measures:A predefined co-primary end point strategy was chosen to address both efficacy and safety. The primary efficacy end point was TAVI valve leaflet thrombosis defined as the presence of hypoattenuated leaflet thickening (HALT) on blinded core laboratory 4-dimensional cardiac computed tomographic (CT) scan at 12 months. The primary safety end point was a composite of adjudicated Valve Academic Research Consortium 3 (VARC-3) bleeding events, thromboembolic events, and all-cause death at 12 months. Results:Of the 360 participants randomized (mean age, 74.5 years [SD, 3.7]; 134 females [37%]), 336 completed the trial (168 in each group). The primary efficacy end point occurred in 27 participants (16.2%) allocated to the NOAC group and in 48 participants (28.6%) allocated to the ASA group (risk ratio, 0.55; 95% CI, 0.37 to 0.82, P = .004). The primary safety end point occurred in 13 participants (7.5%) in the NOAC group and in 19 participants (10.6%) in the ASA group (risk difference, -3.3%; 95% CI, -9.5% to 2.8%; P for noninferiority <.001). Conclusions and Relevance:A strategy of NOAC monotherapy after TAVI reduced the incidence of HALT and was noninferior for bleeding, thromboembolic events, or death compared with acetylsalicylic acid monotherapy. These findings suggest that anticoagulation therapy can be beneficial after TAVI in selected patients. Trial Registration:ClinicalTrials.gov Identifier: NCT05035277.

Background: Heart failure with reduced ejection fraction is a leading cause of death worldwide, characterized by impaired left ventricular systolic function. Contractile, structural, and electrophysiological changes underpin this impairment, but how these changes collectively determine ventricular function remains unclear. We hypothesize that their integrated action involves a complex mechanical interplay at the myocardial mesoscale level, intermediate between individual cardiomyocytes and the global left ventricle. Methods: We acquired high-resolution magnetic resonance images of healthy individuals and patients with myocardial infarction, and developed an analytical method to characterize in vivo contraction patterns in millimeter-sized myocardial units (i.e., at the mesoscale). Furthermore, we employed computational models to examine how mesoscale contraction patterns relate to the contraction mechanism, structure, and electrophysiology of the left ventricle. Results: At the left ventricular mesoscale, we observed that weakly contracting myocardial units are transiently elongated by the contraction of adjacent, more strongly contracting units. These mesoscale interactions generate a ?tug-of-war? that pervades the left ventricle in healthy hearts and becomes particularly prominent following myocardial infarction. This behavior is macroscopically invisible as the contraction patterns of opposing units cancel each other out, but it nevertheless shapes the efficiency of mechanical performance. In the healthy heart, recruitment of more uniformly contracting units (i.e., reduction in tug-of-war) supports augmented contractility during acute stress. However, following myocardial infarction, excessive tug-of-war contributes to impaired contractile efficiency and performance. Computational modelling showed that the ventricular contraction mechanism, structure, and electrophysiology underpin this behavior in healthy hearts and exacerbate it in disease. Conclusion: Left ventricular systolic function is characterized by a myocardial tug-of-war at the mesoscale, which contributes to the heart's adaptability in health and its vulnerability in disease. These findings introduce a new concept for understanding left ventricular function and a novel analytical approach for investigating its failure. ### Competing Interest Statement M.B.H., E.K.S.E., I.S. have filed a patent claim relating to the parametrization of myocardial tug-of-war. All other authors report no conflicts of interest. ### Funding Statement This work was supported by the KG Jebsen Center for Cardiac Research (Oslo, Norway), Familien Blix? Fond Til Fremme Av Medisinsk Forskning (Oslo, Norway), Olav Raagholt og Gerd Meidel Raagholts stiftelse for forskning (Oslo, Norway), Rakel og Otto Kristian Bruun?s Legat (Oslo, Norway) and a UK EPSRC (grant number EP/T017899/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All procedures were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All participants provided written informed consent prior to inclusion. The study was approved by the regional ethics committee (REK Sør-Øst 2016/1223 and REK Sør-Øst 2016/1961). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data supporting the findings of this study are available from the corresponding author upon reasonable request.

Background and aims:Conventional echocardiographic measurements like ejection fraction (EF) and global longitudinal strain (GLS) evaluate left ventricular (LV) function without considering concurrent loading conditions. A more comprehensive characterization of cardiac function and energetics can be achieved through pressure-volume analysis, but its clinical application is limited by the requirement for invasive measurements. We aimed to develop a clinically accessible, non-invasive method for pressure-volume loop analysis. Methods:We obtained simultaneous 3-dimensional echocardiograms and invasive LV pressures with micromanometer-tipped catheters during transcatheter aortic valve replacement (TAVR) for severe aortic stenosis. Volume-time traces from the echocardiograms were combined with invasive LV pressures and non-invasive pressure estimates to construct pressure-volume loops. We used echocardiograms before and after TAVR to evaluate changes in myocardial function via non-invasive pressure-volume studies. Results:In same-beat comparisons, stroke work calculated using non-invasive LV pressure estimations correlated well with stroke work calculated using invasive LV pressures (r = 0.95, ICC = 0.95, p < 0.0001, y = 0.90X + 1,836, mean bias -549 mmHg*mL, standard deviation 774 mmHg*mL; 95% limits of agreement: -2,006 to +967 mmHg*mL). After TAVR, stroke work fell substantially, ventricular efficiency increased, ventriculo-arterial coupling improved, and both total and resting energy consumption decreased. On the other hand, LV biplane EF and GLS remained unchanged. Conclusions:This study confirms the validity and clinical accessibility of non-invasive pressure-volume loop analysis in patients with aortic stenosis. The method identified and characterized changes in myocardial energetics, function, and ventriculo-arterial interaction, that are not typically detected by conventional echocardiography. These findings highlight the potential of non-invasive pressure-volume analysis in clinical and research practice.

BACKGROUND:The bidirectional interaction between inflammation and thrombus formation plays an important role in myocardial infarction (MI) with IL (interleukin)-6 as a central mediator. If anti-inflammatory therapy modulates coagulation factors, and platelet activation in patients with MI is not clear. METHODS:We have shown that tocilizumab, a monoclonal antibody targeting IL-6R (IL-6 receptor), improves myocardial salvage index in patients with ST-elevation MI. Herein, we measured levels of soluble markers of platelet activation (P-selectin, sCD40L [soluble CD40 ligand]) and coagulation (TF [tissue factor], TFPI [TF pathway inhibitor], PAI [plasminogen activator inhibitor]-1, and D-dimer) in 136 patients with ST-segment-elevation MI (70 tocilizumab and 66 placebo). Platelet-poor EDTA plasma samples were obtained at admission and after 24 and 168 hours. Temporal changes were related to TnT (troponin T), as well as infarct size and myocardial salvage index, assessed by cardiac magnetic resonance imaging. RESULTS:Our major findings were given as follows: (1) patients had higher sCD40L, P-selectin, TFPI, and D-dimer than 28 healthy controls, and these increased during 1-week follow-up, while TFPI decreased; (2) tocilizumab attenuated P-selectin in patients with short symptom duration at 24 hours in particular in those with high C-reactive protein, and this change correlated positively with indices of myocardial damage; (3) tocilizumab augmented TF at 168 hours, and this change correlated positively with infarct size and negatively with myocardial salvage index; (4) change in D-dimer at 168 hours correlated positively with infarct size and negatively with myocardial salvage index in particular in those with long symptom durations or treated with placebo; tocilizumab attenuated these changes; and (5) the use of heparin attenuated sCD40L levels and increased TFPI levels in admission samples and TF levels after 168 hours. CONCLUSIONS:Our findings support attenuation of platelet activation/coagulation by tocilizumab in patients with ST-segment-elevation MI. The marked rise in TF could be a hereto unrecognized side effects of tocilizumab, which need further investigation.

Importance Transcatheter aortic valve implant (TAVI) is increasingly being performed in younger and healthier patients with severe aortic valve stenosis. Antithrombotic therapy after TAVI is a key element of optimizing valve durability and clinical outcomes. Objective To evaluate the safety and efficacy of a factor Xa inhibitor non–vitamin K antagonist oral anticoagulant (NOAC) monotherapy strategy vs an acetylsalicylic acid (ASA) monotherapy strategy after TAVI. Design, Setting, and Participants Between December 2021 and June 2025, 360 participants between the ages of 65 and 80 years undergoing TAVI for severe aortic valve stenosis were enrolled in this prospective, randomized, open-label, blinded end point trial conducted at 3 Norwegian centers managing the majority of TAVI procedures nationally. The last patient completed follow-up on May 19, 2026. Intervention A total of 360 participants were randomly assigned (1:1) to receive 12 months of monotherapy with either NOAC (intervention) or ASA (control). Main Outcomes and Measures A predefined co–primary end point strategy was chosen to address both efficacy and safety. The primary efficacy end point was TAVI valve leaflet thrombosis defined as the presence of hypoattenuated leaflet thickening (HALT) on blinded core laboratory 4-dimensional cardiac computed tomographic (CT) scan at 12 months. The primary safety end point was a composite of adjudicated Valve Academic Research Consortium 3 (VARC-3) bleeding events, thromboembolic events, and all-cause death at 12 months. Results Of the 360 participants randomized (mean age, 74.5 years [SD, 3.7]; 134 females [37%]), 336 completed the trial (168 in each group). The primary efficacy end point occurred in 27 participants (16.2%) allocated to the NOAC group and in 48 participants (28.6%) allocated to the ASA group (risk ratio, 0.55; 95% CI, 0.37 to 0.82, P = .004). The primary safety end point occurred in 13 participants (7.5%) in the NOAC group and in 19 participants (10.6%) in the ASA group (risk difference, −3.3%; 95% CI, −9.5% to 2.8%; P for noninferiority <.001). Conclusions and Relevance A strategy of NOAC monotherapy after TAVI reduced the incidence of HALT and was noninferior for bleeding, thromboembolic events, or death compared with acetylsalicylic acid monotherapy. These findings suggest that anticoagulation therapy can be beneficial after TAVI in selected patients. Trial Registration ClinicalTrials.gov Identifier: NCT05035277

AIMS:Current recommendations for echocardiography-based classification of left ventricular filling pressure (LVFP) as normal or elevated, are based on an algorithm and parameter selection determined by human experts. We tested whether machine learning (ML) can improve classification of LVFP and investigated which parameters were deemed most important by different ML models. METHODS AND RESULTS:In a multicentre study, echocardiography was performed simultaneously with, or within 24 h of, heart catheterization in 250 patients. Eight different ML models were trained and tested using a nested cross-validation procedure to classify LVFP as normal or elevated. The training included a search and selection of the most useful parameters. Performance was assessed from the test sets not seen during training. The eight ML models could classify all patients regardless of missing parameter values with accuracy ranging from 82% to 86%. The 2016 ASE/EACVI guidelines algorithm left 13% unclassified due to missing values and had an accuracy of 81% in the remaining patients. On average, the eight ML models selected 13 parameters, and left atrial strain was included in three of these. The five highest ranked parameters by the ML models were mitral E/left atrial reservoir strain, log(NT-proBNP), tricuspid regurgitation velocity, septal E/e', and E/A. CONCLUSION:ML can improve classification of LVFP, particularly with a higher feasibility. The study unveiled less used parameters as some of the most valuable for evaluating LVFP.

Background Soluble ST2 (sST2) is a decoy receptor for interleukin-33 and a prognostic biomarker in heart failure, but its utility in precapillary pulmonary hypertension (PH) is not well established. Therefore, we aimed to evaluate the prognostic value of sST2 in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) at diagnosis and follow-up. Materials and methods In this prospective observational cohort study, we measured plasma sST2 by sandwich enzyme-linked immunosorbent assay in samples taken at diagnostic right heart catheterization from 202 treatment naïve Norwegian patients with precapillary PH (n = 115 with PAH, n = 87 with CTEPH). In an external validation cohort, we included 185 treatment naïve Swedish patients with precapillary PH (n = 121 with PAH, n= 64 with CTEPH). In a subset of patients, we measured sST2 levels at follow-up in the Norwegian discovery cohort (n=63) and the Swedish validation cohort (n=121). Results On univariable Cox regression, log sST2 was firmly associated with transplant-free survival in the Norwegian discovery cohort (HR 1.92, P = 0.005) and in the Swedish validation cohort (HR 2.64, P <.001). When adjusting for age and NT-proBNP, sST2 levels were no longer significantly associated with transplant-free survival in the discovery cohort, while remaining independently associated with the outcome in the validation cohort. The change in sST2 from baseline to follow-up was not associated with transplant-free survival in either cohort. Conclusion Plasma sST2 levels were univariably associated with death or lung transplantation in PAH and CTEPH but were no longer prognostic after adjustment for age and NT-proBNP. The change in sST2 from baseline to follow-up did not predict transplant-free survival.

Background It is important to reduce diagnostic delays for patients with cardiac amyloidosis (CA). Plasma biomarkers could streamline the diagnostic process and enhance prognostic accuracy. Objectives The authors aimed to identify circulating biomarkers capable of differentiating patients with CA from patients with heart failure (HF) and no amyloidosis. Additionally, we assessed whether these markers were associated with patient outcomes. Methods We performed focused protein screening in 12 patients with transthyretin CA, 5 patients with HF, and 16 healthy controls (HCs). To validate the findings, we used immunoassays to measure levels of differentially regulated proteins in a larger sample of 86 patients with transthyretin CA, 15 patients with light-chain CA, 16 patients with HF, and HCs. We compared protein levels between groups using multivariable general linear models. Associations between protein levels and all-cause mortality were assessed by receiver operating characteristic analysis. Results We identified 99 candidate proteins by proteomic screening. In the validation sample, 4 of these markers were higher in CA than in HCs. Levels of C-X-C motif chemokine ligand 9 and hepatocyte growth factor (HGF) were also higher in CA than in HF. HGF correlated with measures of cardiac function in patients with transthyretin and light chain CA. HGF had a good discriminatory ability for predicting all-cause mortality (area under the curve = 0.80, P < 0.001), similar to those of N-terminal pro-B-type natriuretic peptide and troponin T. Conclusions Plasma HGF is a promising screening tool for CA. Higher levels of HGF are associated with more severe HF and worse prognosis in patients with CA.

Abstract Introduction Estimating left ventricular filling pressure (LVFP) by echocardiography is challenging in patients with asymptomatic severe aortic stenosis (ASAS). The European Association of Cardiovascular Imaging has proposed an algorithm utilizing left atrial reservoir strain analysis (LARS) in patients with what was previously described as "undetermined LVFP". We aimed to validate this algorithm in patients with ASAS. Methods We performed right heart catheterization in 50 patients with ASAS. An end-expiratory pulmonary artery wedge pressure (PAWP) ≥ 15mmHg was used as a reference for increased LVFP. We compared indices of LVFP by echocardiography with invasive measurements to validate the algorithm in patients with ASAS. Results Nine patients (18%) had increased LVFP by RHC while 8 (16%) had increased LVFP by echocardiography. Only 2 of the 9 patients with invasively elevated LVPF were identified by echocardiography. On the other hand, among the 41 patients with normal LVFP, 35 (85%) were accurately identified as having a normal LVFP by echocardiography. Consequently, the echocardiographic algorithm had a sensitivity of 22% and a specificity of 85% in patients with ASAS (Table). As depicted in the figure, 9 patients were initially labelled as having undetermined LVFP. The addition of LARS, correctly excluded increased LVFP in 7 of these 9 patients (78 %). Conclusion LVFP estimation by echocardiography has low sensitivity for increased filling pressure in patients with ASAS. However, the inclusion of LARS significantly improves LVPF estimation correctly, particularly in patients initially classified as having undetermined pressure by conventional echocardiography.

BACKGROUND:Interleukin-6 receptor (IL-6R) inhibition by tocilizumab improves myocardial salvage index (MSI) in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect remain unclear. METHODS:This pre-defined exploratory sub-study of the ASSAIL-MI trial enumerated circulating monocytes and examined their transcriptome profile in relation to the MSI and peak troponin T (TnT) in STEMI patients randomiseded to tocilizumab (n = 101) or placebo (n = 98). RNA sequencing was performed on peripheral monocytes in 14 patients. To elaborate the in vivo findings, in vitro chemotaxis and apoptosis assays were performed on THP-1 monocytes and cardiomyocyte (HL-1) cell lines, respectively. FINDINGS:STEMI patients had increased monocyte counts at 24 h and 3-7 days after hospitalisation/PCI and this increase was attenuated by tocilizumab. Lower monocyte levels at 24 h were associated with lower TnT levels and higher MSI. Monocyte gene expression suggested that tocilizumab modulated cytokine signalling pathways related to myocardial remodelling, apoptosis, and chemotaxis, potentially through a decrease in suppressor of cytokine signalling 3 (SOCS3). In vitro, tocilizumab limited apoptosis of cardiomyocytes exposed to ischemia/reperfusion and reduced chemotaxis in monocytes exposed to IL-6. INTERPRETATION:These findings suggest that IL-6R inhibition by tocilizumab during STEMI is associated with reduced monocyte counts and cardioprotective alterations in monocyte signalling potentially linked to the downregulation of SOCS3. FUNDING:This work was supported by the South-Eastern Norway Regional Health Authority (no. 2019067) and The Research Council of Norway (no. 282867) The ASSAIL-MI main study was supported by an independent grant from ROCHE who also provided drugs/placebo for infusion.

Background:Due to overlapping symptoms and signs, it can be challenging to diagnose transthyretin amyloid cardiomyopathy (ATTR-CM) in the setting of concomitant aortic stenosis. Biomarkers may discriminate between heart failure with ATTR-CM and heart failure without ATTR-CM, but it is not known if these markers can differentiate between AS with and AS without concomitant ATTR-CM. Methods:In 9 patients with ATTR-CM and AS, 161 patients with lone AS, and 23 healthy controls, we measured 8 plasma proteins previously identified by proteomic analysis as potential candidates for diagnosing ATTR-CM. We assessed differences between groups and association with indices of heart failure and AS severity. Results:Plasma levels of dipeptidyl peptidase 4 (DPP4) were significantly higher in patients with AS and ATTR-CM than in patients with lone AS and in healthy controls. Lower levels of DPP4 were also associated with worse left ventricular function, higher New York Heart Association functional class, and low-flow, low-gradient aortic stenosis. Conclusions:Our findings suggest that DPP4 may be a marker of ATTR-CM in patients with severe AS. In all AS patients, those with and without coexisting ATTR-CM, high DPP4 levels were asociated with better cardiac function.

BACKGROUND AND AIMS:Heart transplantation is the preferred treatment for selected patients with end stage heart failure. Kidney function often declines after heart transplantation. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) slow the decline in eGFR in different populations. However, the effect of SGLT2i on kidney function in heart transplant recipients is unknown. METHODS:The Dapagliflozin for Renal protection in Heart Transplant recipients (DAPARHT) trial is an investigator initiated, double blind, randomized, placebo-controlled trial designed to assess dapagliflozin's effect on kidney function in heart transplant recipients. Adults heart transplanted at least one year prior to randomization are eligible. Exclusion criteria include an estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m2, diabetes type I, and contraindication to study medication. Four hundred and thirty patients will be randomized 1:1 to receive 12 months blinded treatment with dapagliflozin 10 mg o.d. or placebo, followed by 24-months open-label treatment. The primary endpoint is the chronic slope of the eGFR from two weeks to 12 months after starting randomized treatment. The open-label phase evaluates dapagliflozin's long-term effects on kidney function, clinical outcomes, safety, and tolerability. Enrolment began in June 2022. As of December 18, 2024, 300 patients were enrolled. The mean baseline creatinine was 104 ± 28 µmol/L with corresponding eGFR of 66 ± 22 mL/min/1.73 m2. Estimated last patient visit is in September, 2028. CONCLUSION:The DAPARHT trial will test whether dapagliflozin improves eGFR slope compared to placebo during one year of follow-up, providing the first randomized evidence of the efficacy of SGLT2i in heart transplant recipients. TRIAL REGISTRATION:Dapagliflozin for Renal protection in Heart Transplant recipients (DAPARHT), NCT05321706, clinicaltrials.gov.

The prevalences of aortic stenosis (AS) and transthyretin amyloid cardiomyopathy (ATTR-CM) increase with age. Identification of occult ATTR-CM in patients with AS can help explain out-of-proportion myocardial dysfunction, aid in prognostication and prompt initiation of disease-modifying treatment. Studies have suggested that many patients referred for transcatheter aortic valve implantation (TAVI) have concomitant ATTR-CM, but some have included unverified ATTR-CM in patients with ambiguous scintigrams. We aimed to assess the co-occurrence of ATTR-CM in patients scheduled for TAVI. In patients accepted for TAVI for severe AS, we used bone scintigraphy to screen for ATTR-CM. We defined ATTR-CM as a cardiac tracer uptake ≥ Perugini Grade 2 in the absence of abnormal monoclonal protein or abnormal free light chain ratio. We offered bioptic verification to patients with Grade 1 or ambiguous DPD uptake. We included 171 consecutive patients aged 79 ± 7 years, 57% were male. Six patients (3.5%) had cardiac bone tracer uptake ≥ Perugini Grade 2 and no abnormal monoclonal protein/free light chains. Endomyocardial biopsies confirmed the diagnosis in two additional patients (1.2%), whereas five patients with low-grade uptake did not have ATTR-CM. In total, 8/171 patients (4.7%) were diagnosed with concomitant AS and ATTR-CM. Most of the patients with concomitant ATTR-CM had low-flow low-gradient (LFLG) AS, and 25% had a history of carpal tunnel syndrome. We found concomitant AS and ATTR-CM in 5% of our TAVI patients. Carpal tunnel syndrome and LFLG AS suggest concomitant ATTR.