Helge Immo Lehmann

Background: Atrial fibrillation (AF) prevalence has risen alongside an aging US population and wider adoption of contemporary therapies, yet population‐level changes in mechanisms of death among people with AF remain incompletely characterized. We used National Death Certificate Trends in AF Mortality data to assess 25‐year trends in AF‐related mortality and the contribution of heart failure (HF), stroke, myocardial infarction (MI), and dementia. Methods: We conducted a retrospective analysis of CDC WONDER records for US decedents aged ≥ 35 years with AF listed as a contributing cause of death from 1999 to 2023, coinciding with the implementation of ICD‐10 coding in the CDC database. We quantified all‐cause and cause‐specific mortality rates per 100 000 and stratified trends by age, sex, and race. The analytic cohort included decedents with AF and at least one of four cardiovascular conditions (stroke, dementia, HF, or MI) listed as a primary or contributing cause of death. Confidence intervals were obtained from CDC WONDER outputs or calculated per CDC guidance. Results: Among 3 273 015 decedents with AF noted on the death certificate, 461 321 had HF, dementia, stroke, or MI listed as a contributing cause. HF emerged as the leading cause/contributor with a steep rise beginning in approximately 2008. Stroke rates were stable or declining, MI‐related mortality remained low and stable, while dementia, particularly stroke‐free dementia, increased significantly in adults ≥ 85 (outpacing stroke among the oldest White decedents since early 2000s). Non‐White groups exhibited higher stroke and HF mortality trends; women ≥ 85 had higher stroke‐related mortality than men. Conclusions: Over 25 years, AF‐associated mortality patterns shifted toward HF and stroke‐free dementia while ischemic stroke and MI declined or stabilized. Findings highlight the need to expand AF care beyond stroke prevention to prioritize HF prevention/management, cognitive health, equitable AF‐care pathways to ensure broad access to therapies, and additional studies of targeted interventions to mitigate disease risks.

Background: Pulsed field ablation (PFA) has been rapidly adopted for atrial fibrillation (AF) on the premise of greater safety than thermal ablation. Real-world signals of hemolysis, coronary spasm, and neurologic events have since emerged, and prior Manufacturer and User Facility Device Experience (MAUDE) analyses relied on term matching without prospective signal detection. Methods: We queried MAUDE for AF ablation catheter reports received January 2016 through June 2026 and assigned each to PFA, radiofrequency ablation (RFA), or cryoballoon ablation. We adjudicated injury and death narratives into predefined complication families and severity tiers with a large language model, checked against a larger model and by physician review. We calculated reporting odds ratios (ROR) and Bayesian shrinkage estimators compared against an empirical null, applied interrupted time series and prospective sequential detection, and repeated estimates on a 2026 hold-out. Results: Among 44,623 reports, 30.1% were PFA, 50.9% RFA, and 19.0% cryoballoon, with 91.8% model agreement on event occurrence ( κ = 0.83). PFA carried an ROR of 527 (95% CI, 33, 8,509) for hemolysis, 2.83 (2.55, 3.16) for arrhythmia, 2.83 (2.30, 3.48) for coronary, and 2.39 (2.10, 2.73) for cerebrovascular events, against 0.024 (0.008, 0.075) for esophageal and 0.34 (0.32, 0.37) for pericardial events. The cerebrovascular excess was largest for VARIPULSE, but without it the class proportional reporting ratio was 1.36 (1.13, 1.65), concordant with the 1.56 measured in EMBOL-AF . In the hold-out, the cerebrovascular, arrhythmia and hemolysis signals replicated, and coronary events kept their direction without meeting the signal rule. Prospective detection flagged cerebrovascular events 13 months before AVANT GUARD published its neurologic events. Conclusions: PFA showed disproportionate reporting of hemolysis, cerebrovascular, coronary, and arrhythmic events across sequential testing. Machine learning methods allowed for flagging these signals months before confirmatory trials, demonstrating a scalable tool for early detection of procedural risk. CLINICAL PERSPECTIVE: What is Known Pulsed field ablation has been adopted rapidly for atrial fibrillation on the premise of fewer collateral injuries than thermal ablation. Hemolysis, coronary spasm, and neurologic events have since emerged in case series, registries, and a paused trial, while prior analyses of Food and Drug Administration device reports relied largely on term matching without narrative adjudication at scale. What the Study Adds In injury and death reports adjudicated at the narrative level, pulsed field ablation was reported more often than thermal ablation for hemolysis, arrhythmia, coronary, and cerebrovascular events and less often for esophageal and pericardial injury. The cerebrovascular reporting excess was largest for the VARIPULSE catheter but persisted with that platform removed and concentrated in minor stroke and systemic embolism, suggesting an embolic signal not confined to one platform. Sequential detection run on reports adjudicated by a large language model would have flagged the cerebrovascular signal 13 months before AVANT GUARD published its neurologic events, suggesting a role for automated surveillance of new ablation technologies.

Aims: Stereotactic arrhythmia radioablation (STAR) is a promising noninvasive therapy for refractory ventricular tachycardia. Using scanned proton beams for STAR enables precisely focused, high doses of ionizing radiation. Effective mitigation of target motion is critical for safety but remains challenging due to the complex interplay between beam scanning and cardiorespiratory motion. We evaluated the safety and feasibility of accurately delivering gated scanned proton beams to a ventricular myocardial target and compared lesion outcomes of respiratory (single)‐ and cardiorespiratory (dual)‐gated proton beams. Methods: Six pigs (the first two used as a test of the protocol) underwent baseline CT for treatment planning with a single fractional dose of 35 Gy to a myocardial target in the left ventricular free wall. They were subsequently treated with either single‐ or dual‐gated delivery using scanned proton beams. Treatment response was evaluated by echocardiography, blood analysis and positron emission tomography (PET)‐CT at baseline and 14−15 weeks after irradiation. Lesions were assessed at termination, and tissues were harvested for histopathology. Results: Average target expansion for intrafractional motion was lower with dual compared to single gating (16%−23% vs. 48%−72%, N = 2 in each arm). The irradiated area was distinguishable in vivo on PET‐CT and ex vivo in necropsy at the expected location in all animals. Visual lesion transmurality was confirmed by histology. Lesion sizes were not far from the expected volumes in dual‐gated animals but were larger in single‐gated animals ( p = 0.3 for between‐group comparison, N = 2 in each arm). Conclusions: The results confirmed the feasibility of the workflow. Dual‐gated irradiation was associated with reduced radiation exposure of the myocardium outside the target volume, and with lesion sizes closer to those planned.

BACKGROUND: Extracellular vesicles (EVs) are involved in exercise-induced cardiac protection. However, the effects and underlying mechanisms of tissue-specific molecular cargo packaged within these EVs, including PIWI (P-element induced wimpy testis)-interacting RNA (piRNA), remain poorly understood. In particular, the mechanistic contribution of exercised intracardiac EV-associated piRNAs to doxorubicin-induced cardiotoxicity (DCT) has not been defined. METHODS: Transgenic reporter mice and a cardiomyocyte-specific Rab27a (RAB27A, member RAS oncogene family) knockout strategy were used to investigate the contribution of cardiomyocyte-derived EVs to exercise-induced cardioprotection against DCT. To screen functionally relevant cardioprotective piRNA cargo, heart tissues from patients with dilated cardiomyopathy and experimental DCT models were analyzed, including cardiomyocyte-specific knockout mice, human embryonic stem cell–derived cardiomyocytes, and primary murine cardiomyocytes. RESULTS: We found that cardiomyocyte-derived EVs post-exercise were enriched for a cardiac-specific protective piRNA (piR-mmu-57256903), designated as an exercise-induced protective piRNA (EPPIR). EPPIR levels were significantly reduced in heart tissue from patients with dilated cardiomyopathy and DCT models. Functionally, EPPIR protects the heart against DCT by regulating KDM6B (lysine [K]-specific demethylase 6B)-H3K27me3 (trimethylated histone H3 at lysine 27)-Dtna epigenetic axis. In addition, EPPIR acts as a cardiomyocyte-specific suppressor of Tp53 (tumor protein p53). CONCLUSIONS: We identify a previously unrecognized role for cardiomyocyte-derived EV-associated piRNA EPPIR in mediating exercise-induced cardioprotection. EPPIR exerts its protective effects through coordinated regulation of the KDM6B-Dtna axis and cardiomyocyte-specific suppressor of Tp53, providing mechanistic insight and highlighting a potential therapeutic strategy for DCT.

Stereotactic arrhythmia radioablation (STAR) is a treatment option for recurrent ventricular tachycardia/fibrillation (VT/VF) in patients with structural heart disease (SHD). The current and future role of STAR as viewed by cardiologists is unknown. The study aimed to assess the current role, barriers to application, and expected future role of STAR. An online survey consisting of 20 questions on baseline demographics, awareness/access, current use, and the future role of STAR was conducted. A total of 129 international participants completed the survey [mean age 43 ± 11 years, 25 (16.4%) female]. Ninety-one (59.9%) participants were electrophysiologists. Nine participants (7%) were unaware of STAR as a therapeutic option. Sixty-four (49.6%) had access to STAR, while 62 (48.1%) had treated/referred a patient for treatment. Common primary indications for STAR were recurrent VT/VF in SHD (45%), recurrent VT/VF without SHD (7.8%), or premature ventricular contraction (3.9%). Reported main advantages of STAR were efficacy in the treatment of arrhythmias not amenable to conventional treatment (49%) and non-invasive treatment approach with overall low expected acute and short-term procedural risk (23%). Most respondents have foreseen a future clinical role of STAR in the treatment of VT/VF with or without underlying SHD (72% and 75%, respectively), although only a minority expected a first-line indication for it (7% and 5%, respectively). Stereotactic arrhythmia radioablation as a novel treatment option of recurrent VT appears to gain acceptance within the cardiology community. Further trials are critical to further define efficacy, patient populations, as well as the appropriate clinical use for the treatment of VT.

BACKGROUND: Doxorubicin is an effective chemotherapeutic agent, but its use is limited by acute and chronic cardiotoxicity. Exercise training has been shown to protect against doxorubicin-induced cardiotoxicity, but the involvement of immune cells remains unclear. This study aimed to investigate the role of exercise-derived B cells in protecting against doxorubicin-induced cardiotoxicity and to further determine whether B cell activation and antibody secretion play a role in this protection. METHODS: Mice that were administered with doxorubicin (5 mg/kg per week, 20 mg/kg cumulative dose) received treadmill running exercise. The adoptive transfer of exercise-derived splenic B cells to μMT ^−/− (B cell–deficient) mice was performed to elucidate the mechanism of B cell regulation that mediated the effect of exercise. RESULTS: Doxorubicin-administered mice that had undergone exercise training showed improved cardiac function, and low levels of cardiac apoptosis, atrophy, and fibrosis, and had reduced cardiac antibody deposition and proinflammatory responses. Similarly, B cell pharmacological and genetic depletion alleviated doxorubicin-induced cardiotoxicity, which phenocopied the protection of exercise. In vitro performed coculture experiments confirmed that exercise-derived B cells reduced cardiomyocyte apoptosis and fibroblast activation compared with control B cells. Importantly, the protective effect of exercise on B cells was confirmed by the adoptive transfer of splenic B cells from exercised donor mice to μMT ^−/− recipient mice. However, blockage of Fc gamma receptor IIB function using B cell transplants from exercised Fc gamma receptor IIB ^−/− mice abolished the protection of exercise-derived B cells against doxorubicin-induced cardiotoxicity. Mechanistically, we found that Fc gamma receptor IIB, an important B cell inhibitory receptor, responded to exercise and increased B cell activation threshold, which participated in exercise-induced protection against doxorubicin-induced cardiotoxicity. CONCLUSIONS: Our results demonstrate that exercise training protects against doxorubicin-induced cardiotoxicity by upregulating Fc gamma receptor IIB expression in B cells, which plays an important anti-inflammatory role and participates in the protective effect of exercise against doxorubicin-induced cardiotoxicity.

Background: Acute decompensation is associated with increased mortality in heart failure (HF) patients, though the underlying etiology remains unclear. Extracellular vesicles (EVs) and their cargo may mark specific cardiovascular physiologic states. We hypothesized that EV transcriptomic cargo, including long non-coding RNAs (lncRNAs) and mRNAs, is dynamic from the decompensated to recompensated HF state, reflecting molecular pathways relevant to adverse remodeling. Methods: We examined differential RNA expression from circulating plasma extracellular RNA in acute HF patients at hospital admission and discharge alongside healthy controls. We leveraged different exRNA carrier isolation methods, publicly available tissue banks, and single nuclear deconvolution of human cardiac tissue to identify cell and compartment specificity of the topmost significantly differentially expressed targets. EV-derived transcript fragments were prioritized by fold change (−1.5 to + 1.5) and significance (in vitro , with a directionality mirroring the acute congested state. Conclusion: Circulating EV transcriptome is significantly altered during acute HF, with distinct cell and organ specificity in HFpEF vs. HFrEF consistent with a multi-organ vs. cardiac origin, respectively. Plasma EV-derived lncRNA fragments were more dynamically regulated with acute HF therapy independent of weight change (relative to mRNAs). This dynamicity was further demonstrated with cellular stress in vitro . Prioritizing transcriptional changes in plasma circulating EVs with HF therapy may be a fruitful approach to HF subtype-specific mechanistic discovery. CLINICAL PERSPECTIVE: What is new?: We performed extracellular transcriptomic analysis on the plasma of patients with acute decompensated heart failure (HFrEF and HFpEF) before and after decongestive efforts. Long non-coding RNAs (lncRNAs) within extracellular vesicles (EVs) changed dynamically upon decongestion in concordance with changes within human iPSC-derived cardiomyocytes under stress. In acute decompensated HFrEF, EV RNAs are mainly derived from cardiomyocytes, whereas in HFpEF, EV RNAs appear to have broader, non-cardiomyocyte origins. What are the clinical implications?: Given their concordance between human expression profiles and dynamic in vitro responses, lncRNAs within EVs during acute HF may provide insight into potential therapeutic targets and mechanistically relevant pathways. These findings provide a “liquid biopsy” support for the burgeoning concept of HFpEF as a systemic disorder extending beyond the heart, as opposed to a more cardiac-focused physiology in HFrEF.