Differentiating type 1 from type 2 non–ST-elevation myocardial infarction (NSTEMI) is clinically challenging, particularly in patients with atrial fibrillation (AF), where the 4th Universal Definition of Myocardial Infarction (UDMI) allows classification based on presumed mechanisms without mandatory coronary angiography. Real-world data from AF cohorts undergoing systematic invasive evaluation remain limited. Between 2009 and 2020, we analyzed consecutive AF patients admitted with NSTEMI to a tertiary care center. Patients undergoing early coronary angiography were included. Infarct subtypes were adjudicated according to the 4th UDMI incorporating angiographic findings. The primary objective was to determine the prevalence of type 1 and type 2 NSTEMI. The secondary endpoint was a composite of all-cause mortality, myocardial infarction, stroke, or major bleeding. Among 536 eligible patients, 438 (81.7

Abstract Anthracycline-induced cardiotoxicity remains a major limitation of cancer therapy, and effective preventive strategies are lacking. Topoisomerase IIb has been implicated as a central driver of this toxicity, suggesting that epigenetic regulators may interfere with the pathological cardiac response. Here, we show that doxorubicin promotes topoisomerase IIb accumulation at cardiomyocyte-specific gene promoters (e.g., Actc1, Myl2 , and Myh7) overlapping myocyte enhancer factor 2 binding sites and enhances myocyte enhancer factor 2 -dependent transcription. This response is attenuated by the pan-histone deacetylase inhibitor suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid -mediated cardioprotection requires class IIa histone deacetylases, as genetic loss of HDAC4 abolishes its effect. Mechanistically, suberoylanilide hydroxamic acid induces acetylation of the chaperone 14-3-3, disrupting its interaction with HDAC4/5, promoting their nuclear accumulation, and repressing myocyte enhancer factor 2 - driven transcription. In vivo, suberoylanilide hydroxamic acid mitigates doxorubicin-induced cardiotoxicity. These findings identify histone deacetylase inhibition as a cardioprotective repurposing strategy and reveal a mechanistic link between epigenetic regulation and anthracycline-associated cardiotoxicity.

Chest pain is the leading cause of presentations to the emergency department (ED), and the number of patients presenting with this symptom may cause overcrowding. To accelerate triage in the ED, clinical decision pathways using fast diagnostic protocols and high sensitivity cTn (hs-cTn) assays are being recommended by guidelines. However, their implementation is challenging. To develop an electronic health records (EHR)–embedded clinical decision support system (CDSS) that helps to follow protocol recommendations, improve safety and effectiveness of triage and improve guideline-adherence regarding appropriate use of fast troponin-based protocols in patients presenting with suspected non-ST-elevation acute coronary syndrome (NSTE-ACS). The CDSS was designed as a knowledge-based decision support tool based on the latest version of the 2023 ESC guideline recommended clinical decision pathways, i.e. ESC 0/1 h and ESC 0/2 h algorithm, and can be programmed to consider sex-specific upper limit of normal and different commercially available hs-cTn assays. Data can be entered manually or automatically. Input variables include time since symptom onset, baseline and follow-up hs-cTn levels and time intervals between blood samples. The system’s output ultimately provides an unequivocal classification into a triage category, adjusted for the exact time elapsed between measurements. The tool further provides information on the need and timing of a second, or even a third hs-cTn, if two measurements are inconclusive. A prospective, single-centre validation study using a sequential roll-out design with alternating 2-week blocks of standard-of-care and CDSS-supported care is planned over a 24-week enrolment period. The primary endpoint is the proportion of protocol adherence. Key secondary endpoints include rates of correct triage, length of ED stay, proportion of direct discharge after rule-out in patients at low risk and the proportion of inappropriate blood draws (excessive or deferred) as an estimate for cost-effectiveness. A novel CDSS that represents a Class IIa medical software device and has already received CE mark for use in clinical routine. It is expected to improve guideline adherence, effectiveness and safety of patients admitted to an ED with suspected NSTE-ACS. A prospective pilot study for validation is planned.

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) is frequently elevated in cancer patients, but its clinical implications remain uncertain. We aimed to determine the prevalence of obstructive coronary artery disease (CAD) as a cause of hs-cTnT elevation and to evaluate the impact of cardiovascular risk factors and oncologic therapies. METHODS: Between 2016 and 2023, 810 consecutive cancer patients with elevated hs-cTnT values presenting to the cardio-oncology outpatient clinic in Heidelberg were included. All patients underwent standardized cardiovascular assessment. Further imaging or invasive evaluation was performed in cases of unexplained biomarker elevation. Logistic regression was applied to identify predictors of CAD. Oncologic therapies were categorized according to ESC cardio-oncology guidelines into low, moderate, or high cardiotoxic risk. RESULTS: Overall, 340/810 (42.0%) patients revealed alternative explanations for hs-cTnT elevation (e.g., atrial fibrillation, pulmonary embolism, and renal dysfunction). Among the remaining 470/810 (58.0%) patients evaluated for suspected CAD, 47/470 (10.0%) underwent percutaneous coronary intervention for obstructive CAD, whereas 423/470 (90.0%) showed no indication for revascularization. In multivariable analyses, younger age, female sex, preserved left ventricular ejection fraction, and normal NT-proBNP levels were independently associated with the absence of obstructive CAD. Among the 423 patients without obstructive CAD, 286/423 (67.6%) received active oncologic therapy, and 78.3% were exposed to moderate- or high-risk cardiotoxic agents. CONCLUSIONS: In cancer patients with elevated hs-cTnT, obstructive CAD is present in only a minority of cases. Traditional cardiovascular risk factors predict CAD, but therapy- and disease-related cardiac injury appear to be major contributors, highlighting the need for refined risk stratification.

Integrins, a family of transmembrane receptors that mediate cell-extracellular (ECM) interactions, play a pivotal role in the heart to maintain cardiac function and tissue integrity. As they sense extracellular signals, their expression changes in a microenvironment-dependent manner. Especially following myocardial infarction (MI), several alpha integrins are upregulated. Integrin α3 (ITGA3) expression has been found upregulated after MI, yet little is known about the function of ITGA3 in cardiac tissue. To evaluate the role of ITGA3 in vivo. we generated a mouse line with cardiomyocytes-specific ITGA3 depletion (ITGA3 KO). ITGA3 KO mice were characterized under baseline conditions and after permanent LAD ligation by echocardiography. Cardiac tissue was processed for histological staining (WGA/Sirius-Red) and molecular analysis by qPCR and WB. Identified changes were proven in vitro using coculturing model of neonatal rat cardiac fibroblasts (NRCFs) with siRNA treated neonatal rat cardiomyocytes (NRCMs) lacking ITGA3. ITGA3 KO mice did not show any disadvantageous alterations in cardiac function and structure under baseline conditions. After experimental MI, cardiac function was preserved and hypertrophic response diminished in ITGA3 KO. Development of fibrosis and the induction of pathological gene program was attenuated. Mechanistically, we identified an upregulation in Hippo signalling and activation of autophagic processes (ATG5 and p62 levels as well as enhanced LC3 II/I ratios) in ITGA3 KO mice after MI, which was confirmed by in-vitro experiments of NRCMs. Our findings show that in vivo depletion of ITGA3 in adult cardiomyocytes preserves cardiac function and reduces pathological remodelling after MI. Thus, interference with ITGA3 might be a novel translational approach to improve cardiac remodelling after ischemic injury.

Although cancer and atherosclerosis are based on shared risk factors, the impact of the acute coronary syndrome (ACS) on long-term survival in cancer patients is still unclear. We retrospectively analyzed 441 patients with initial diagnosis of cancer prior to ACS who were subjected to cardiac catheterization (CC) with a follow-up of at median 4.78 years (IQR: 0.58–9.33). These patients were compared to non-cancer ACS patients via propensity score matching according to the cardiac risk factors age, sex, arterial hypertension and diabetes. We found ACS, and overall Non-ST-elevation myocardial infarction (NSTEMI), as a relevant predictor of outcome in cancer patients with the highest mortality rates (88 deaths (40

AIMS:Patients with chronic kidney disease (CKD) display a reduced survival following myocardial infarction (MI). As the underlying mechanisms remain unclear, we examined the impact of CKD on cardiac remodeling and function post-MI using a mouse model of adenine-induced CKD. METHODS AND RESULTS:After MI, CKD mice showed a stronger cardiac dysfunction compared to non-CKD controls. While immunohistochemical and immunofluorescence analyses did not reveal changes in cardiomyocyte apoptosis, infarction size, or myofibroblast content, CKD mice exhibited an increased number of circulating myeloid cells post-infarction and more neutrophil infiltration in the heart. Combining RNAseq, untargeted kinome profiling, western blotting, and mass spectrometry revealed that post-MI, CKD enhanced cardiac oxidative stress and the acute stress complex S100A8/A9 in circulation and the heart, and enforced cardiac MAP-kinase p38 activation and NR4A1 phosphorylation as pathways underlying cardiomyocyte dysfunction. S100A8/A9 also exerted an acute detrimental impact on calcium flux and sarcomere shortening in cardiomyocytes ex vivo. Increased myeloid cell-derived S100A8/A9 expression was confirmed in the infarcted human heart by single-nucleus RNAseq, and CKD patients had higher post-infarction S100A8/A9 levels compared to patients without kidney dysfunction. Furthermore, integrating metabolomics, RNAseq, and mitochondrial analysis uncovered a disturbed cardiac metabolism with impaired glycolysis, a reduced glycerol-3-phosphate-shuttle, and a reduced Coenzyme A-bioavailability in CKD vs. non-CKD mice post-MI. These alterations were associated with poorer cardiac performance post-MI, without intrinsic defects in mitochondrial function observed. CONCLUSION:Our study reveals innate immune activation, inflammation, oxidative stress, and metabolic alterations indicative of reduced glycolytic entry and CoA bioavailability along with aggravated cardiac dysfunction post-MI in CKD compared to non-CKD conditions, independent of infarct size, and with poorer cardiac performance in CKD associated with the cardiac metabolic alterations. Combined, this could contribute to the worsened outcome of CKD patients post-MI and reveals cardiac metabolism in CKD as an interesting translational research target.

The endoplasmic reticulum (ER) is the primary site for the synthesis and folding of membrane and secretory proteins, which together comprise a large fraction of the total protein output in mammalian cells. Striated muscle cells contain a specialized membrane system, the sarcoplasmic reticulum (SR), which regulates calcium homeostasis and contraction. However, the biochemical and physiological relationship between the ER and SR, as well as the extent to which both compartments contribute to protein synthesis, remain incompletely understood. Quantification of ER- and SR-associated proteins in isolated ventricular cardiac myocytes revealed that the relative abundance of ER/SR-resident protein quality control components and ribosomes decreased during postnatal maturation, whereas SR-associated Ca2 +-handling proteins increased. Immunocytochemistry revealed that the membrane compartment prominent in early postnatal stages exhibits predominantly ER characteristics and diminishes during postnatal development. In adult cardiac myocytes, the SR becomes the dominant membrane network throughout the cell, while ER markers remain enriched in the perinuclear region. Immunocytochemistry further indicated that the ER and SR perform overlapping yet distinct specialized functions, with excitation-contraction coupling localized to the SR, and initiation of secretion concentrated within the ER. In adult ventricular cardiac myocytes, ribosomes and mRNA localize adjacent to both the ER and SR, indicating their roles as direct sites of localized protein synthesis and homeostasis. These findings demonstrate that molecular differentiation and structural organization of the ER/SR during cardiac muscle development culminate in a specialized protein synthesis network within the sarco/endoplasmic reticulum of adult myocytes. KEY POINTS: Although the sarcoplasmic reticulum (SR) is the established centre for calcium regulation in striated muscle, its role in membrane and secreted protein synthesis has remained unknown. It has remained unclear whether the endoplasmic reticulum (ER) and SR coexist as distinct membrane networks in cardiac myocytes or whether they form a single system that fulfills both calcium-handling and protein synthesis functions. We found that postnatal cardiac maturation involves a major reorganization in which the centralized, ER-dominant network of neonatal myocytes is replaced by an expansive, SR-dominant network in the adult cell periphery, while ER markers become largely confined to the perinuclear region. Using stimulated emission depletion super resolution microscopy and electron microscopy, we demonstrated that active ribosomes and mRNA associate with the longitudinal SR but are spatially excluded from ryanodine receptor 2-rich junctional zones. Our results establish that the SR functions as a specialized, distributed protein synthesis network that enables adult cardiac myocytes to maintain their highly organized cellular architecture through localized translation.

Background:A significant number of patients with atrial fibrillation (AF) on direct oral anticoagulants (DOACs) receives off-label or inappropriate doses. This study examines the prevalence, dosages, and clinical outcomes in AF-patients on DOAC therapy admitted to an emergency department (ED). Methods:This retrospective single-center observational study utilized data from the Heidelberg Registry of Atrial Fibrillation (HERA-FIB), consecutively including patients with AF presenting to the ED of the University Hospital of Heidelberg from June 2009 to March 2020. Rates of DOAC dosages at discharge from the ED were correlated with outcomes, focusing on a composite endpoint that included all-cause mortality, stroke, major bleeding, and myocardial infarction (MI). Resultsand Conclusions:Among 10,222 patients included in the HERA-FIB registry, 4,239 (41.5 %) were prescribed DOACs, and 3,031were eligible for the analysis. Of these, 2,199 (72.6 %) received appropriate dosages, 627 (20.7 %) were under-dosed, and 205 (6.8 %) were over-dosed. Under-dosed AF-patients demonstrated a significantly increased risk of the composite endpoint compared to those receiving appropriate dosages (HR 1.84, 95 %CI:1.55-2.18, p < 0.0001). Over-dosage had no significant effect on the HR for the composite endpoint, all-cause mortality, stroke, MI, or major bleeding compared to correct dosing but was associated with higher risks of the composite endpoint (HR 1.43, 95 %CI:1.04-1.96, p = 0.029) relative to under-dosage. This study underscores the critical importance of accurate DOAC dosing in patients with AF presenting to an ED. Both under-dosing and over-dosing are linked to significant clinical risks, highlighting the urgent need for improved dosing protocols and careful monitoring to enhance patient outcomes.

BACKGROUND:Guided by long-term safety data for AAV5 (adeno-associated virus 5) in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieves therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administration and vector dosages. METHODS:AAV-mediated cardiac gene transfer in pigs was performed by percutaneous catheter-based retrograde intravenous vector delivery, and vector genome and transgene expression levels determined by reverse transcription-polymerase chain reaction and immunoblotting. Postmyocardial infarction (MI) cardiac dysfunction porcine and murine models were generated by coronary catheter-based occlusion and ligation, respectively. The study end points left ventricular ejection fraction and left ventricular MI size, were measured by cardiac magnetic resonance imaging and echocardiography. Bulk myocardial RNA-sequencing and weighted gene correlation network analysis were used to link study end points to molecular pathway mechanisms. Safety was assessed by clinical chemistry, blood count and ECG. RESULTS:In a first biodistribution study, AAV5 (1×1013 vector genomes; vgs) with the reporter gene luciferase (luc) achieved broad and homogenous transduction of healthy pig hearts 30 days after catheter-based retrograde intravenous vector delivery without toxicity. Both its myocardial and extra-cardiac distribution patterns were advantageous compared with AAV9-luc and AAV6-luc. Using AAV5 with the cardioprotective human gene S100A1 (hS100A1; 1×1013 vgcs) by catheter-based retrograde intravenous vector delivery in a subsequent therapy study in post-MI pigs prevented left ventricular MI extension and improved left ventricular ejection fraction after 3 months without clinical toxicity. Weighted gene correlation network analysis linked novel antiinflammatory actions and cardioprotective signaling mechanisms by hS100A1 to study end point improvements, which was confirmed in a post-MI mouse model. CONCLUSIONS:Providing the clinically relevant proof of concept for AAV5 to effectively transduce healthy and dysfunctional human-sized hearts, its clinical long-term safety, scalable producibility, and low preexisting immunity in humans may predestine AAV5 as an effective and safe gene carrier for a prevalent disease such as chronic heart failure, using therapeutic genetic effectors such as hS100A1 or others.

CONTEXT: Hemolysis within blood samples can impact the accuracy of D-dimer values, potentially affecting the diagnostic threshold for ruling out pulmonary embolism (PE) in patients. AIMS: This study aimed to assess the influence of sample hemolysis on D-dimer measurements and its consequential impact on patient management, particularly concerning the general and age-adapted diagnostic rule-out thresholds. SETTINGS AND DESIGNS: Retrospective evaluation of D-dimer values was conducted in patients presenting with suspected PE, determined by the Wells score. SUBJECTS AND METHODS: The effect of a maximal bias of 3.4% was assumed as worst-case scenario, a shift from a D-D above the general (≥0.5 mg/L) or the age-adapted rule (age × 10, if age >50 years) defined as clinically relevant due to its potential to miss a PE due to overuse of computed tomography pulmonary angiography in older patient. STATISTICAL ANALYSIS USED: Semi-autonomous were analyzed using the %2-test and continuous ones using the Mann–Whitney U-test. RESULTS: Out of 293 patients (53.9% were men, and the average age was 64 ± 17 years old), 63.1% of patients had verified PE. Hemolysis appeared in 19.1% of samples, mainly mild/moderate. The 3.4% bias correction reduced one D-dimer value to below the age-adapted cutoff and one below the general one without any involvement of hemolysis in either. CONCLUSIONS: There is minimal clinical effect of hemolysis on the D-dimension rule-out of PE and rare effects of threshold shifting. Interpretation of D-dimer results is very important to prevent errors in diagnosis.

Background As the population ages, atrial fibrillation (AF) prevalence increases, but data on optimal oral anticoagulation (OAC) in patients ≥80 years remain limited. This study tested whether direct OACs offer comparable benefits to vitamin K antagonists in patients ≥80 years with AF presenting to the emergency department. Methods This single‐center retrospective all‐comer study used data from the Heidelberg Registry of Atrial Fibrillation, including patients with AF presenting to the emergency department of the University Hospital of Heidelberg from June 2009 until March 2020. Data were analyzed by age for outcomes and risk factors for predefined end points. Results Patients ≥80 years comprised 32.2% of AF cases. Hazard ratios (HRs) for the primary end point (all‐cause mortality, stroke, or myocardial infarction) and secondary end point (including major bleeding) were 3.09 (95% CI, 2.73–3.21) and 2.96 (95% CI, 2.73–3.21) for patients ≥80 years, compared with younger patients. Anticoagulation rates were slightly lower in patients ≥80 years (67.9% versus 70.5%, P=0.0070). OAC use, particularly the use of direct OACs, increased over time. Patients ≥80 years without OACs had higher HRs for primary (3.48 [95% CI, 3.07–3.94]) and secondary end points (3.23 [95% CI, 2.86–3.64]) compared with those with OACs. Vitamin K antagonist use was linked to higher HR for stroke or major bleeding events (HR, 1.25 [95% CI, 1.05–1.50]), rising to 1.64 (95% CI, 1.34–2.01) after excluding reduced direct OAC doses. Conclusions Our data highlight patients ≥80 years as an important and vulnerable subpopulation of patients with AF, where evidence for optimal OAC therapy remains conflicting. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05995561.

The transition from cardiac hypertrophy to heart failure is characterized by metabolic changes like downregulation of fatty acid metabolism in favor of increased glucose utilization. Carnitine palmitoyltransferase 1B (CPT1B) catalyzes the rate-limiting step of the carnitine shuttle and is an essential enzyme for fatty acid oxidation. Down-regulation of CPT1B activity has been associated with heart failure in patients and various experimental models, indicating an important role in metabolic remodeling. Therefore, we aimed to investigate whether CPT1B overexpression could play a therapeutic role in heart failure. Gene transfer of CPT1B using adeno-associated virus (AAV) vectors into neonatal rat cardiomyocytes significantly attenuated phenylephrine-induced hypertrophy and resulted in decreased generation of mitochondrial reactive oxygen species. In mice subjected to transverse aortic constriction, AAV-mediated cardiac overexpression of CPT1B attenuated cardiomyocyte hypertrophy, cardiac fibrosis, and systolic dysfunction in vivo. Upregulation of CPT1B expression might therefore represent a promising approach to treat or prevent heart failure.

Previous data suggests dynamic handgrip exercise (DHE) as a potential physiological, needle-free stressor feasible for cardiovascular magnetic resonance (CMR) conditions. DHE-fast Strain-ENCoded imaging (fSENC) is potentially cost-saving, ultra-fast and avoids pharmacological side effects thereby targeting the drawbacks of conventional pharmacological stress CMR. To assess the diagnostic accuracy of DHE-fSENC for detecting ischemia-related wall motion abnormalities in suspected obstructive coronary artery disease (CAD). Patients with known or suspected obstructive CAD referred for CMR stress testing were prospectively enrolled. Diagnostic accuracy was assessed in comparison to pharmacological stress CMR and in a subgroup, compared to invasive coronary angiography (ICA). The CMR protocol was extended by both-handed DHE with 80 repetitions per minute over 2minutes followed by fSENC short-axis acquisition before pharmacological stress testing. Stress-induced impairment of regional longitudinal strain was graded suspicious for obstructive CAD. Two-hundred sixty individuals with cardiovascular high-risk profile (64±13 years, 75% male) were enrolled. DHE-fSENC provided a sensitivity of 79% (95% CI: 64-89) and specificity of 87% (95% CI 82-91) compared to pharmacological stress CMR. In a subgroup of 105 patients with recent ICA, high diagnostic accuracy was found for the detection of obstructive CAD (sensitivity 82% (95% CI: 67-92), specificity 89% (95% CI: 78-95)). Exam duration of DHE-fSENC was significantly reduced compared to conventional CMR stress protocols (DHE-fSENC 207±69sec vs. adenosine-perfusion 287±82sec vs. dobutamine-cine 1132±294sec, all p< 0.001). DHE-fSENC allows for a reliable and fast detection of obstructive CAD, thereby expanding the applicability of needle-free CMR stress testing.

BACKGROUND:Previous data suggest dynamic handgrip exercise (DHE) as a potential physiological, needle-free stressor feasible for cardiovascular magnetic resonance (CMR) examinations. DHE-fast Strain-ENCoded imaging (fSENC) is potentially cost-saving, ultra-fast and avoids pharmacological side effects thereby targeting the drawbacks of conventional pharmacological stress CMR. OBJECTIVES:To assess the diagnostic accuracy of DHE-fSENC for detecting ischemia-related wall motion abnormalities in suspected obstructive coronary artery disease (CAD). METHODS:Patients with known or suspected obstructive CAD referred for CMR stress testing were prospectively enrolled. Diagnostic accuracy was assessed in comparison to pharmacological stress CMR and in a subgroup, compared to invasive coronary angiography (ICA). The CMR protocol was extended by both-handed DHE with 80 repetitions per minute over 2 min followed by fSENC short-axis acquisition before pharmacological stress testing. Stress-induced impairment of regional longitudinal strain was graded suspicious for obstructive CAD. RESULTS:Two-hundred sixty individuals with cardiovascular high-risk profile (64±13years, 75% male) were enrolled. DHE-fSENC provided a sensitivity of 79% (95% CI: 64-89) and specificity of 87% (95% CI 82-91) compared to pharmacological stress CMR. In a subgroup of 105 patients with recent ICA, high diagnostic accuracy was found for the detection of obstructive CAD (sensitivity 82% [95% CI: 67-92], specificity 89% [95% CI: 78-95]). Exam duration of DHE-fSENC was significantly reduced compared to conventional CMR stress protocols (DHE-fSENC 207±69 s vs. adenosine-perfusion 287±82 s vs. dobutamine-cine 1132±294 s, all p<0.001). CONCLUSION:DHE-fSENC allows for a reliable and fast detection of obstructive CAD, thereby expanding the applicability of needle-free CMR stress testing.

The need to perform endomyocardial biopsy (EMB) in patients with non-ischaemic dilated cardiomyopathies (DCM) is debated. Here we sought to determine the extent of left ventricular collagen volume fraction (LV-CVF) in DCM patients and to evaluate it as a prognostic marker. In this retrospective longitudinal study, we included 524 patients with suspected DCM who underwent left ventricular EMB (LV-EMB) as a part of their clinical work-up. LV-CVF was quantified using automated image processing of high-resolution scans of LV-EMB. Deep phenotyping was performed including assessment of late gadolinium enhancement on cardiac magnetic resonance imaging. Endpoints were (i) composite endpoint of heart failure-related death, sudden cardiac death, aborted sudden cardiac death (appropriate implantable cardioverter-defibrillator shock, reported sustained ventricular tachycardia, or cardiopulmonary resuscitation), or cardiac transplantation, and (ii) all-cause mortality. LV-EMB was associated with 0.76% major and 2.1% minor complications. No death occurred due to EMB. LV-CVF could be reliably quantified using Bayesian classification. During a median follow-up of 43.2 months (2084 patient-years), 48 patients with LV-CVF >32% and 14 patients with LV-CVF ≤32% reached the composite endpoint (log-rank p < 0.0001). A total of 62 patients reached the endpoint all-cause mortality, from which 38 presented with LV-CVF >32% and 17 with LV-CVF ≤32% (log-rank p = 0.009). In multivariable analyses, LV-CVF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (hazard ratio 2.03, 95% confidence interval 1.32–3.11) were independent predictors of unfavourable outcome. Left ventricular EMB is a safe diagnostic procedure. The extent of CVF in LV-EMB provides prognostic information in patients with DCM in addition to existing measures of left ventricular ejection fraction or NT-proBNP.

In transthyretin cardiac amyloidosis (ATTR-CA), misfolded transthyretin accumulates in the myocardium, leading to wall thickening and interstitial fibrosis. Recently published in vitro studies revealed direct effects of transthyretin on the structure, function, and gene expression of cardiac fibroblasts. Therefore, we hypothesized that biomarkers known to modulate myocardial remodeling might be clinically valuable in ATTR-CA and may improve risk stratification in ATTR-CA. To analyze this hypothesis, we evaluated 14 fibrosis-related biomarkers (EN-RAGE, IGFBP-1, -2, -3, -4, -6, FGF-23, MMP-2, -7, -9, -13, TIMP-2, -4, and RAGE-AGE) in 125 patients using Luminex multiplex assays. The study cohort consists of 14 asymptomatic gene carriers (ATTRv-asymp), 47 symptomatic hereditary (ATTRv-CA), 43 wild-type Transthyretin amyloidosis (ATTRwt) patients, and 21 were healthy controls (ctrl). Associations of fibrotic biomarkers and clinical routine data with clinical outcomes—cardiac decompensation (DMP) and transplantation/death (HTX)—were assessed via hierarchical cluster analysis, regression, and prediction modeling. We found that ATTR-CA patients showed distinct biomarker profiles compared to controls. Several markers (e.g., MMP-7, RAGE-AGE, IGFBP-1, FGF-23, TIMP-2) were significantly associated with both endpoints. Cluster analysis identified a high-risk phenotype (Cluster 2) with worse renal function, greater myocardial thickening, and elevated NT-proBNP, hsTNT. Prediction modeling revealed IGFPB-1, -3, -4 and -6 as well as FGF-23, TIMP-2, and RAGE/AGE as the best predictive parameters for cluster assignment. Taken together, these findings confirm our hypothesis that fibrosis-related biomarkers are associated with adverse outcomes in ATTR-CM. Profibrotic mediators such as IGFBP-1, FGF-23, and TIMP-2 may, therefore, provide additional prognostic information beyond established cardiac biomarkers and may reflect underlying fibrotic remodeling pathways.