2 Rare Syndromes in 1 Patient: Determining the Cause of Sudden Cardiac Arrest.

A 19-year-old man survived sudden cardiac arrest caused by ventricular fibrillation during physical activity. The initial suspicion that this was caused by electrolyte imbalance proved to be wrong. Cardiac computed tomography revealed congenital heart disease. Coronary imaging is an essential component of the comprehensive diagnostic workup after sudden cardiac arrest.

EASIX (endothelial activation and stress index) predicts mortality in patients with coronary artery disease.

BACKGROUND: Coronary interventions reduce morbidity and mortality in patients with acute coronary syndrome. However, the risk of mortality for patients with coronary artery disease (CAD) additionally depends on their systemic endothelial health status. The 'Endothelial Activation and Stress Index' (EASIX) predicts endothelial complications and survival in diverse clinical settings. OBJECTIVE: We hypothesized that EASIX may predict mortality in patients with CAD. METHODS: In 1283 patients undergoing coronary catheterization (CC) and having a diagnosis of CAD, EASIX was measured within 52 days (range - 1 year to - 14 days) before CC and correlated with overall survival. In an independent validation cohort of 1934 patients, EASIXval was measured within 174 days (+ 28 days to + 11 years) after CC. RESULTS: EASIX predicted the risk of mortality after CC (per log2: hazard ratio (HR) 1.29, 95% confidence interval: [1.18-1.41], p < 0.001) in multivariable Cox regression analyses adjusting for age, sex, a high-grade coronary stenosis ≥ 90%, left ventricular ejection fraction, arterial hypertension and diabetes. In the independent cohort, EASIX correlated with EASIXval with rho = 0.7. The long-term predictive value of EASIXval was confirmed (per log2: HR 1.53, [1.42-1.64], p < 0.001) and could be validated by integrated Brier score and concordance index. Pre-established cut-offs (0.88-2.32) associated with increased mortality (cut-off 0.88: HR training: 1.63; HR validation: 1.67, p < 0.0001 and cut-off 2.32: HR training: 3.57; HR validation: 4.65, p < 0.0001). CONCLUSIONS: We validated EASIX as a potential biomarker to predict death of CAD patients, irrespective of the timing either before or after catheterization.

Single-cell transcriptomics reveal distinctive patterns of fibroblast activation in heart failure with preserved ejection fraction.

Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease-specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF-specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global-longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.

A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation.

The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the 'innate and adaptive genomes', which enhance genetic and evolutionary comprehension of the human genome. The 'germ-free syndrome' challenges the traditional 'microbes as pathogens' view, advocating for the necessity of microbes for health. The 'slave tissue' concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. 'Acquired microbial immunity' positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The 'homeostatic reprogramming hypothesis' integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The 'cell-microbe co-ecology model' elucidates the symbiotic regulation affecting cellular balance, while the 'meta-host model' broadens the host definition to include symbiotic microbes. The 'health-illness conversion model' encapsulates the innate and adaptive genomes' interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.

Effect of impaired kidney function on outcomes and treatment effects of oral anticoagulant regimes in patients with atrial fibrillation in a real-world registry.

BACKGROUND: The impact of impaired kidney function on outcomes and treatment benefits of vitamin-K antagonists (VKA) versus direct oral anticoagulants (DOAC) in patients with atrial fibrillation (AF) has insufficiently been investigated in randomized controlled studies (RCTs). Most studies and registries are either biased due to incomplete enrolment of consecutive patients in large pharma industry sponsored registries, or due to short recruitment periods or incomplete assessment of important variables in national registries. METHODS: This study uses data from the Heidelberg Registry of Atrial Fibrillation (HERA-FIB), a retrospective single-center registry of 10,222 consecutive patients with AF presenting to the emergency department of University Hospital of Heidelberg from June 2009 until March 2020. Rates of all-cause mortality, stroke, major bleeding and myocardial infarction (MI) were related to the presence and severity of impaired presenting kidney function, as well as to assigned treatment with VKA vs. DOAC. RESULTS: The risks for all-cause mortality (HR: 3.26, p<0.001), stroke (HR: 1.58, p<0.001), major bleeding (HR: 2.28, p<0.001) and MI (HR: 2.48, p<0.001) were significantly higher in patients with an eGFR<60 ml/min at admission and increased with decreasing eGFR. After adjustment for variables of CHA2DS2VASc-score, presence of eGFR <60 ml/min remained as an independent predictor for all-cause mortality, major bleeding and MI. The hazard ratio (HR) for all-cause mortality, major bleedings and MI was significantly lower in patients receiving DOAC compared to VKA. CONCLUSION: Findings from our large real-life registry confirm the data from RCTs and extend our knowledge on the effectiveness and safety of DOACs to subjects that were underrepresented in RCTs.

Circulating extracellular vesicles as biomarkers in the diagnosis, prognosis and therapy of cardiovascular diseases.

Cardiovascular disease (CVD) ranks among the primary contributors to worldwide mortality. Hence, the importance of constant research on new circulating biomarkers for the improvement of early diagnosis and prognostication of different CVDs and the development and refinement of therapeutic measures is critical. Extracellular vesicles (EV) have a great potential as diagnostic and prognostic markers, as they represent their parent cell by enclosing cell-specific molecules, which can differ in quality and quantity based on cell state. Assuming that all cell types of the cardiovascular system are capable of releasing EV into circulation, an emerging body of evidence has investigated the potential role of serum- or plasma-derived EV in CVD. Comprehensive research has unveiled alterations in EV quantity and EV-bound cargo in the form of RNA, proteins and lipids in the context of common CVDs such as coronary artery disease, atrial fibrillation, heart failure or inflammatory heart diseases, highlighting their diagnostic and prognostic relevance. In numerous in vitro and in vivo models, EV also showed promising therapeutic potential. However, translation of EV studies to a preclinical or clinical setting has proven to be challenging. This review is intended to provide an overview of the most relevant studies in the field of serum or plasma-derived EV.

Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis.

Importance: Accurate risk stratification of nonischemic dilated cardiomyopathy (NIDCM) remains challenging. Objective: To evaluate the association of cardiac magnetic resonance (CMR) imaging-derived measurements with clinical outcomes in NIDCM. Data Sources: MEDLINE, Embase, Cochrane Library, and Web of Science Core Collection databases were systematically searched for articles from January 2005 to April 2023. Study Selection: Prospective and retrospective nonrandomized diagnostic studies reporting on the association between CMR imaging-derived measurements and adverse clinical outcomes in NIDCM were deemed eligible. Data Extraction and Synthesis: Prespecified items related to patient population, CMR imaging measurements, and clinical outcomes were extracted at the study level by 2 independent reviewers. Random-effects models were fitted using restricted maximum likelihood estimation and the method of Hartung, Knapp, Sidik, and Jonkman. Main Outcomes and Measures: All-cause mortality, cardiovascular mortality, arrhythmic events, heart failure events, and major adverse cardiac events (MACE). Results: A total of 103 studies including 29 687 patients with NIDCM were analyzed. Late gadolinium enhancement (LGE) presence and extent (per 1%) were associated with higher all-cause mortality (hazard ratio [HR], 1.81 [95% CI, 1.60-2.04]; P < .001 and HR, 1.07 [95% CI, 1.02-1.12]; P = .02, respectively), cardiovascular mortality (HR, 2.43 [95% CI, 2.13-2.78]; P < .001 and HR, 1.15 [95% CI, 1.07-1.24]; P = .01), arrhythmic events (HR, 2.69 [95% CI, 2.20-3.30]; P < .001 and HR, 1.07 [95% CI, 1.03-1.12]; P = .004) and heart failure events (HR, 1.98 [95% CI, 1.73-2.27]; P < .001 and HR, 1.06 [95% CI, 1.01-1.10]; P = .02). Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality (HR, 0.99 [95% CI, 0.97-1.02]; P = .47), cardiovascular mortality (HR, 0.97 [95% CI, 0.94-1.00]; P = .05), or arrhythmic outcomes (HR, 0.99 [95% CI, 0.97-1.01]; P = .34). Lower risks for heart failure events (HR, 0.97 [95% CI, 0.95-0.98]; P = .002) and MACE (HR, 0.98 [95% CI, 0.96-0.99]; P < .001) were observed with higher LVEF. Higher native T1 relaxation times (per 10 ms) were associated with arrhythmic events (HR, 1.07 [95% CI, 1.01-1.14]; P = .04) and MACE (HR, 1.06 [95% CI, 1.01-1.11]; P = .03). Global longitudinal strain (GLS) (per 1%) was not associated with heart failure events (HR, 1.06 [95% CI, 0.95-1.18]; P = .15) or MACE (HR, 1.03 [95% CI, 0.94-1.14]; P = .43). Limited data precluded definitive analysis for native T1 relaxation times, GLS, and extracellular volume fraction (ECV) with respect to mortality outcomes. Conclusion: The presence and extent of LGE were associated with various adverse clinical outcomes, whereas LVEF was not significantly associated with mortality and arrhythmic end points in NIDCM. Risk stratification using native T1 relaxation times, extracellular volume fraction, and global longitudinal strain requires further evaluation.

Prognostic Value of Circulating Fibrosis Biomarkers in Dilated Cardiomyopathy (DCM): Insights into Clinical Outcomes.

BACKGROUND: Dilated cardiomyopathy (DCM) involves myocardial remodeling, characterized by significant fibrosis and extracellular matrix expansion. These changes impair heart function, increasing the risk of heart failure and sudden cardiac death. This study investigates the prognostic value of circulating fibrosis biomarkers as a less invasive method in DCM patients. METHODS: Plasma samples from 185 patients with confirmed DCM were analyzed to measure 13 circulating biomarkers using Luminex bead-based multiplex assays and ELISA. The prognostic value of these biomarkers was evaluated concerning heart failure-associated events and all-cause mortality. RESULTS: Elevated MMP-2 levels (>1519.3 ng/mL) were linked to older age, higher diabetes prevalence, lower HDL, increased NT-proBNP and hs-TnT levels, and severe systolic dysfunction. High TIMP-1 levels (>124.9 ng/mL) correlated with elevated NT-proBNP, more atrial fibrillation, reduced exercise capacity, and larger right ventricles. Increased GDF-15 levels (>1213.9 ng/mL) were associated with older age, systemic inflammation, renal impairment, and poor exercise performance. Elevated OPN levels (>81.7 ng/mL) were linked to higher serum creatinine and NT-proBNP levels. Over a median follow-up of 32.4 months, higher levels of these biomarkers predicted worse outcomes, including increased risks of heart failure-related events and mortality. CONCLUSIONS: Circulating fibrosis biomarkers, particularly MMP-2, TIMP-1, GDF-15, and OPN, are valuable prognostic tools in DCM. They reflect the severity of myocardial remodeling and systemic disease burden, aiding in risk stratification and therapeutic intervention. Integrating these biomarkers into clinical practice could improve DCM management and patient prognosis.

Successful treatment of chronic venous in-stent restenosis using a Phoenix atherectomy device.

BACKGROUND: Although endovascular treatment of venous obstruction with percutaneous transluminal angioplasty (PTA) and stenting is a safe and effective alternative to conservative treatment, the overall prevalence of in-stent restenosis (ISR) remains high in this patient population. This study reports a novel treatment option for patients with chronic ISR (C-ISR). METHODS: At our center, all patients with ISR were treated based on the time since the initial intervention. Acute in-stent restenosis (A-ISR) was preferably treated with catheter-directed thrombolysis or a pharmacomechanical peripheral thrombectomy device and PTA. Selected patients with chronic ISR (C-ISR) (greater than 30 days) were treated with a catheter- guided unidirectional atherectomy in addition to PTA, under the assumption of a non-thrombotic mechanism in the development of C-ISR. RESULTS: We demonstrate a safe and practical treatment option for chronic ISR using a catheter- guided technical approach with the Phoenix atherectomy device in four patients. Technical success was achieved in every case, and mid-term patency was restored in three out of four patients. CONCLUSIONS: Restenosis following venous stenting is highly complex. Patients must be treated individually, with a focus on anticoagulation and antiplatelet therapy regimens, as well as the appropriate interventional treatment. Catheter- guided atherectomy is a viable option for this heterogeneous group of patients. Further studies are required to understand the etiology of chronic ISR.

Endothelial derived, secreted long non-coding RNAs Gadlor1 and Gadlor2 aggravate cardiac remodeling.

Pathological cardiac remodeling predisposes individuals to developing heart failure. Here, we investigated two co-regulated long non-coding RNAs (lncRNAs), termed Gadlor1 and Gadlor2, which are upregulated in failing hearts of patients and mice. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 knockout (KO) mice showed markedly reduced myocardial hypertrophy, fibrosis, and dysfunction, while exhibiting increased angiogenesis during short and prolonged periods of pressure overload. Paradoxically, Gadlor1/2 KO mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. Gadlor1 and Gadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene expression, are strongly secreted within extracellular vesicles (EVs). These EVs transfer Gadlor lncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, and impact pro-hypertrophic gene expression and calcium homeostasis. Therefore, we reveal a crucial lncRNA-based mechanism of EC-cardiomyocyte crosstalk during heart failure, which could be specifically modified in the future for therapeutic purposes.

Troponin Elevation in Asymptomatic Cancer Patients: Unveiling Connections and Clinical Implications.

PURPOSE OF THE REVIEW: Elevated troponin levels are well established e.g., for the diagnosis of suspected acute coronary syndrome in symptomatic patients. In contrast, troponin elevations in asymptomatic cancer patients emerge as a complex phenomenon, challenging traditional perceptions of its association solely with cardiac events. RECENT FINDINGS: Recent data support the predictive value of cardiac biomarker for all-cause mortality and cardiotoxicity in cancer patients. This review gives an overview about the current literature about cardiac troponins in prediction and identification of high-risk cancer patients. The overview is focusing on diagnostic challenges, biomarker significance, and gaps of knowledge. Latest publications highlight the relevance of cardiac troponin in risk analysis before cancer treatment as well as a potential diagnostic gatekeeper for further cardiological diagnostics and therapy.

Improved diagnostic performance of high-sensitivity cardiac troponins in muscle dystrophies using comprehensive definition criteria for cardiac involvement: A longitudinal study on 35 patients.

BACKGROUND AND PURPOSE: Sparse information is available on the correct interpretation of elevated high-sensitivity cardiac troponin (hs-cTn) in confirmed muscular dystrophies. METHODS: Serum concentrations of hs-cTn T (hs-cTnT) and hs-cTn I (hs-cTnI) were determined in 35 stable outpatients with confirmed skeletal muscle dystrophies. We calculated sensitivities, specificities, and positive and negative predictive values of hs-cTnT and hs-cTnI for identification of cardiac involvement using a comprehensive definition that included diastolic left ventricular and right ventricular function, strain analysis using two-dimensional transthoracic echocardiogram and magnetic resonance imaging, myocardial biopsies, and consideration of a variety of triggers for cardiac injury, including arrhythmias, conduction disorders, and hypoxemia due to respiratory failure. RESULTS: Cardiac involvement was diagnosed in 34 of 35 cases. Specificities of hs-cTnT increased from 12.5% to 100% (p = 0.0006) applying the comprehensive definition compared to a definition based on electrocardiography and echocardiography alone. At the recommended 99th percentile upper limit of normal, sensitivities were significantly lower for hs-cTnI than for hs-cTnT (29.4% vs. 100%, p = 0.0164). Conversely, the specificities of hs-cTnT and hs-cTnI increased to 100% when using the comprehensive definition criteria for diagnosing cardiac involvement. CONCLUSIONS: Elevated hs-cTnT but not hs-cTnI discriminates cardiac involvement in cases with confirmed skeletal muscle dystrophies with very high sensitivity and 100% specificity. Prior reports on worse performance may be explained by the use of less sensitive imaging methods or incomplete assessment of cardiac involvement.

Favorable safety profile of NOAC therapy in patients after tricuspid transcatheter edge-to-edge repair.

BACKGROUND: Transcatheter edge-to-edge repair for severe tricuspid regurgitation (TR) is a new treatment option (t-TEER). Data on optimal antithrombotic therapy after t-TEER in patients with an indication for anticoagulation are scarce and evidence-based guideline recommendations are lacking. We sought to investigate efficacy and safety of novel oral anticoagulation (NOAC) and vitamin-K-antagonists (VKA) in patients undergoing t-TEER. METHODS: Among 78 consecutive patients with t-TEER of severe TR, 69 patients were identified with concomitant indication for oral anticoagulation. Outcomes of these patients treated with NOAC or VKA were compared over a median follow-up period of 327 (177-460) days. RESULTS: Despite elevated thromboembolic and bleeding risk scores (CHA2DS2-VASc 4.2 ± 1.1, HEMORR2HAGES 3.0 ± 1.0 and HAS-BLED 2.1 ± 0.8), only one major bleeding incidence occurred under NOAC therapy. The risk for overall (NOAC 8% vs. VKA group 26%, p = 0.044) and major bleeding events (NOAC 2% vs. VKA 21%, p = 0.010) was significantly lower in the NOAC compared to the VKA group. No significant difference was found between NOAC and VKA treatment in terms of mortality (NOAC 18% vs. VKA 16%, p = 0.865) or the combined endpoint of death, heart failure hospitalization, stroke, embolism, thrombosis, myocardial infarction, and severe bleeding (NOAC 48% vs. VKA 42%, p = 0.801). A comparison between apixaban (n = 27) and rivaroxaban (n = 16) treated patients revealed no significant differences between NOAC substances (all bleeding events apixaban 7% vs. rivaroxaban 13%, p = 0.638). CONCLUSION: Results of this study indicate that NOACs may offer a favorable risk-benefit profile for patients with concomitant indication for anticoagulation therapy following t-TEER.

Community-based analysis of stroke prevention and effect of public interventions in atrial fibrillation: results from the ARENA project.

BACKGROUND: Community-based interventions may promote awareness and adherence to atrial fibrillation (AF)-related therapies, potentially reducing adverse events. The ARENA project investigated the health status, therapies and events in AF patients in the Rhein-Neckar Region, Germany. The subproject "ARENA intervention" studied the effect of community-based interventions on AF-associated outcomes. METHODS: From 2016 onward, patients with diagnosed AF were recruited for the observational ARENA registry. In 2018, an intervention period was initiated involving population-based information campaigns on AF diagnosis and therapies. The "control group" was recruited prior to initiation, and the "intervention group" afterward. Patients underwent standardized follow-up > 1 year after recruitment. Clinical outcomes, therapy and quality of life were compared between the two groups. RESULTS: A total of 2769 patients were included. This real-world cohort showed high adherence to oral anticoagulation therapy (OAC) and an increased use of NOACs over vitamin K antagonists over time. In the intervention group (n = 1362), more patients continued OAC at follow-up (87.1% vs. 81.5%, P = 0.002). However, this difference was not significant in the patient subgroup with class I/IIa indications for OAC (90.1% vs. 87.5%, P = 0.11). AF-related re-hospitalization was lower in the intervention group (6.8% vs. 12.3%, P < 0.001). There was no significant difference in quality of life. AF-related anxiety was reduced at follow-up. Of note, nearly a quarter of all patients stated that ARENA had influenced their health perception. CONCLUSION: Tailored community-based campaigns may raise awareness for AF-related health issues, supporting therapy adherence. Future public strategies to improve quality of life in AF patients should be investigated, as the ARENA project hints at a potential benefit of population-based campaigns. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02978248).

Transient Inhibition of Translation Improves Cardiac Function After Ischemia/Reperfusion by Attenuating the Inflammatory Response.

BACKGROUND: The myocardium adapts to ischemia/reperfusion (I/R) by changes in gene expression, determining the cardiac response to reperfusion. mRNA translation is a key component of gene expression. It is largely unknown how regulation of mRNA translation contributes to cardiac gene expression and inflammation in response to reperfusion and whether it can be targeted to mitigate I/R injury. METHODS: To examine translation and its impact on gene expression in response to I/R, we measured protein synthesis after reperfusion in vitro and in vivo. Underlying mechanisms of translational control were examined by pharmacological and genetic targeting of translation initiation in mice. Cell type-specific ribosome profiling was performed in mice that had been subjected to I/R to determine the impact of mRNA translation on the regulation of gene expression in cardiomyocytes. Translational regulation of inflammation was studied by quantification of immune cell infiltration, inflammatory gene expression, and cardiac function after short-term inhibition of translation initiation. RESULTS: Reperfusion induced a rapid recovery of translational activity that exceeds baseline levels in the infarct and border zone and is mediated by translation initiation through the mTORC1 (mechanistic target of rapamycin complex 1)-4EBP1 (eIF4E-binding protein 1)-eIF (eukaryotic initiation factor) 4F axis. Cardiomyocyte-specific ribosome profiling identified that I/R increased translation of mRNA networks associated with cardiac inflammation and cell infiltration. Short-term inhibition of the mTORC1-4EBP1-eIF4F axis decreased the expression of proinflammatory cytokines such as Ccl2 (C-C motif chemokine ligand 2) of border zone cardiomyocytes, thereby attenuating Ly6Chi monocyte infiltration and myocardial inflammation. In addition, we identified a systemic immunosuppressive effect of eIF4F translation inhibitors on circulating monocytes, directly inhibiting monocyte infiltration. Short-term pharmacological inhibition of eIF4F complex formation by 4EGI-1 or rapamycin attenuated translation, reduced infarct size, and improved cardiac function after myocardial infarction. CONCLUSIONS: Global protein synthesis is inhibited during ischemia and shortly after reperfusion, followed by a recovery of protein synthesis that exceeds baseline levels in the border and infarct zones. Activation of mRNA translation after reperfusion is driven by mTORC1/eIF4F-mediated regulation of initiation and mediates an mRNA network that controls inflammation and monocyte infiltration to the myocardium. Transient inhibition of the mTORC1-/eIF4F axis inhibits translation and attenuates Ly6Chi monocyte infiltration by inhibiting a proinflammatory response at the site of injury and of circulating monocytes.

Response to therapy with tafamidis 61 mg in patients with cardiac transthyretin amyloidosis: real-world experience since approval.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disease that causes heart failure due to amyloid fibril deposition. Tafamidis was approved as the first causal treatment in 2020. We here report on real-world data in patients treated with tafamidis for at least 12 months according to the recently defined European Society for Cardiology (ESC) consensus criteria for disease progression. METHODS AND RESULTS: Three hundred and eight wildtype and 31 hereditary ATTR-CM patients were prospectively enrolled after first diagnosis of ATTR-CM and initiation of tafamidis 61 mg once daily treatment. After 12 months, significant deterioration in Karnofsky Index, estimated glomerular filtration rate (eGFR), N-terminal brain natriuretic peptide (NT-proBNP), septum thickness and left ventricular ejection fraction (LVEF) could be observed, significant disease progression was only detected in 25 patients (9%) using ESC consensus criteria. Mean survival time was 37 months with no differences between responders and non-responders. NT-proBNP was the only independent predictor for poor therapy response (p = .008). CONCLUSIONS: The majority of patients showed no significant disease progression according to the ESC consensus criteria after 12 months of therapy with tafamidis. However, at 12 months, treatment response based on the ESC consensus criteria was not associated with improved survival. Moreover, higher levels of NT-proBNP at diagnosis of ATTR-CM appears to predict poorer treatment response, confirming that timely initiation of therapy is advantageous.

Interpretation of elevated baseline concentrations and serial changes of high-sensitivity cardiac troponin T in confirmed muscular dystrophies.

AIMS: Concentrations of high-sensitivity cardiac troponin T (hs-cTnT) are frequently elevated in stable patients with confirmed muscle dystrophies. However, sparse information is available on the interpretation of serial concentration changes. METHODS: Hs-cTnT was collected in 35 stable outpatients with confirmed skeletal muscle dystrophies at 0 and 1 h and after 6-12 months during scheduled outpatient visits. We simulated the effectiveness of the European Society of Cardiology (ESC) 0/1 h algorithm and assessed biological variation at 6-12 months using two established methods: reference change value (RCV) and minimal important difference (MID). RESULTS: Median baseline hs-cTnT concentrations were 34.4 ng/L [inter-quartile range (IQR): 17.5-46.2], and values > 99th percentile upper limit of normal were present in 34 of 35 patients. All patients were stable without cardiovascular adverse events during a follow-up of 6.6 months (IQR: 6-7). Median concentration change was 1.9 ng/L (IQR: 0.7-3.2) and 0.8 ng/L (IQR: 0-7.0) at 60 min and 6-9 months, respectively. Applying the criteria of the ESC 0/1 h algorithm for triage of suspected acute coronary syndrome (ACS) showed poor overall effectiveness of baseline hs-cTnT values. No patient would qualify for rule-out based on hs-cTnT less than the limit of detection, whereas five cases would qualify for rule-in based on hs-cTnT ≥ 52 ng/L. Biological variabilities at 6-12 months per MID and RCV were 1.2 ng/L [95% confidence interval (CI): 0.7-2.1] and 28.6% (95% CI: 27.9-29.6), respectively. A total of 8 (22.9%) and 25 (71.4%) cases exceeded the biological variation range, suggesting some additional myocardial damage. CONCLUSIONS: The high prevalence of elevated hs-cTnT could negatively impact the effectiveness of rule-out and rule-in strategies based on a single hs-cTnT value. Knowledge of the physiological and biological variation of hs-cTnT after 6-12 months is helpful to detect the progression of cardiac involvement or to search for cardiac complications including but not limited to arrhythmias that may trigger acute or chronic myocardial damage.

Catheter-based ablation to improve outcomes in patients with atrial fibrillation and heart failure with preserved ejection fraction: Rationale and design of the CABA-HFPEF-DZHK27 trial.

AIMS: Atrial fibrillation (AF) is common in heart failure (HF) and negatively impacts outcomes. The role of ablation-based rhythm control in patients with AF and HF with preserved (HFpEF) or mildly reduced ejection fraction (HFmrEF) is not known. The CABA-HFPEF-DZHK27 (CAtheter-Based Ablation of atrial fibrillation compared to conventional treatment in patients with Heart Failure with Preserved Ejection Fraction) trial will determine whether early catheter ablation for AF can prevent adverse cardiovascular outcomes in patients with HFpEF or HFmrEF. METHODS: CABA-HFPEF-DZHK27 (NCT05508256) is an investigator-initiated, prospective, randomized, open, interventional multicentre strategy trial with blinded outcome assessment. Approximately 1548 patients with paroxysmal or persistent AF diagnosed within 24 months prior to enrolment and HFpEF or HFmrEF will be randomized to early catheter ablation within 4 weeks after randomization or to usual care. All patients receive anticoagulation, rate control, and HF management according to current guideline recommendations. Usual care can include rhythm control in symptomatic patients. Patients will be followed until the end of the trial for the primary outcome, a composite of cardiovascular death, stroke, and total unplanned hospitalizations for HF or acute coronary syndrome. The safety outcome comprises complications of catheter ablation and death. The trial is powered for a rate ratio of 0.75 (two-sided alpha = 0.05, 1-beta = 0.8). CONCLUSION: CABA-HFPEF-DZHK27 will define the role of systematic and early catheter ablation in patients with AF and HFpEF or HFmrEF.