Ingo Hilgendorf

Rationale: Atrial fibrillation (AF) is sustained by electrical triggers and atrial substrate, but whether AF itself generates circulating factors that acutely reinforce arrhythmogenesis is unknown. Objective: To determine whether rhythm-dependent serum bioactivity directly destabilizes atrial electrophysiology and to identify associated cellular mechanisms and circulating mediators. Methods and Results: Cardiac samples were obtained from patients with persistent atrial fibrillation (AF) during AF and after restoration of sinus rhythm (SR) using electrical cardioversion. In isolated Langendorff-perfused mouse hearts, AF serum increased the duration, frequency, and cumulative burden of spontaneous atrial depolarizations compared with paired control perfusate. In human induced pluripotent stem cell derived atrial cardiomyocytes, AF patient serum decreased Ca²⁺-transient amplitudes without significant effect on kinetics or Ca²⁺ spark activity. Moreover, AF serum reduced peak sodium current without materially altering voltage-dependent gating or paced action-potential properties. Data-independent acquisition proteomics identified rhythm-associated changes in extracellular-matrix, proteolytic, inflammatory, and signaling proteins, including MMP9, Ccathepsin G, and 14-3-3 family members. Targeted pathway perturbation differentially modified serum-induced Ca²⁺ phenotypes, indicating context-dependent, multifactorial bioactivity. Serum-induced Ca²⁺ responses were not associated with indices of atrial disease severity, including low-voltage substrate burden and left atrial pressure. Conclusions: Persistent AF is accompanied by rhythm-dependent circulating bioactivity that acutely promotes atrial electrical instability and Ca²⁺-dependent trigger formation. These findings extend the concept that “AF begets AF” beyond tissue-intrinsic remodeling and identify a potentially reversible serum-mediated feed-forward mechanism linking rhythm status and circulating proteomic signals in an atrial substrate severity independent fashion.

Background and Aims: Low-density lipoprotein cholesterol (LDL-C) targets remain unmet in many high-risk atherosclerotic cardiovascular disease (ASCVD) patients on statins (± ezetimibe). VICTORION-Challenge compared inclisiran with bempedoic acid (BPA) for LDL-C lowering and target attainment in these patients, directly. Methods: In this Phase 4, open-label study, ASCVD patients with LDL-C ≥70 mg/dl on statins (± ezetimibe) were randomized to inclisiran or BPA. The primary endpoint was a percentage change in LDL-C at Day 150; key secondary endpoints at Day 150 included percentage LDL-C change stratified by ezetimibe use. Secondary endpoints included LDL-C goal attainment and absolute change; treatment-emergent adverse events (TEAEs) were evaluated. Results: Among 402 randomized patients (mean ± standard deviation age, 63.1 ± 10.7 years; 64.2% men; baseline LDL-C 94.4 ± 28.3 mg/dl), LDL-C reduction at Day 150 was superior with inclisiran vs BPA [least squares mean −56.3% vs −15.4%; between-group difference −41.0% (95% CI −45.7 to −36.2); P < .0001]. Inclisiran achieved greater absolute LDL-C reduction at Day 150 (−53.4 vs −17.5 mg/dl) regardless of ezetimibe use, with higher LDL-C goal attainment [78.2% vs 20.3%; adjusted odds ratio 16.36 (95% CI 9.72-27.54); descriptive P < .0001]. Inclisiran showed a comparable safety profile vs BPA, with similar rates of TEAEs (63.1% vs 59.8%) and serious TEAEs (8.4% vs 11.6%). The most common TEAEs (inclisiran vs BPA) included nasopharyngitis (10.3% vs 7.5%), hypertension (4.9% vs 4.5%), and myalgia (3.4% vs 5.5%). One non-treatment-related death (inclisiran) was reported. Conclusions: Inclisiran provided superior LDL-C reduction vs BPA with a consistent safety profile, supporting its use in high-risk patients not achieving guideline-recommended goals.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular disease, but its relationship with silent brain lesions and cognitive decline in patients with atrial fibrillation (AF) is unclear. METHODS: In this prospective, multicenter cohort study, we included 1572 patients with AF enrolled between 2014 and 2017. All participants underwent deep-targeted sequencing for CHIP-associated sequence variations, brain magnetic resonance imaging, and standardized cognitive assessments. CHIP carrier status (overall, DNMT3A carrier, and non- DNMT3A carrier) was evaluated in relation to prevalent and incident silent brain lesions. Silent brain lesions were defined as large noncortical or cortical infarcts, small noncortical infarcts, microbleeds, and white matter lesions (WMLs), and were assessed at baseline and after 2 years with magnetic resonance imaging. Cross-sectional analyses were externally validated in a cohort of 199 patients with AF. Cognitive function was evaluated through 7 years using the Montreal Cognitive Assessment. Associations were analyzed using multivariable-adjusted logistic and linear regression models. RESULTS: Among 1572 patients with AF (mean±SD age, 72.5±8.3 years; 26% women), 342 (22%) carried CHIP sequence variations, most commonly in DNMT3A (49.4%) and TET2 (28.3%). CHIP carriers had significantly higher odds of cerebral microbleeds (odds ratio [OR], 1.45 [95% CI, 1.09 to 1.93]) and WMLs (OR, 1.56 [95% CI, 1.20 to 2.04]) at baseline, particularly with non- DNMT3A sequence variations (microbleeds: OR, 1.79 [95% CI, 1.25 to 2.55]; WMLs: OR, 1.80 [95% CI, 1.25 to 2.62]). A similar trend was observed in an independent AF patient cohort from Korea limited to TET2 sequence variations. Presence of multiple CHIP sequence variations further increased the odds of microbleeds (OR, 1.36 [95% CI, 1.10 to 1.69]) and WMLs (OR, 1.41 [95% CI, 1.15 to 1.75]), and large CHIP clones (variant allele frequency >10%) were associated with higher WML volumes. At 2-year follow-up, CHIP was associated with new cerebral microbleed counts and greater WML volume. Over 7 years, CHIP carriers exhibited greater cognitive decline, with a lower Montreal Cognitive Assessment score compared with noncarriers (β −0.53 [95% CI, −1.02 to −0.03]). The decline was more pronounced in DNMT3A and ASXL1 sequence variation carriers. CONCLUSIONS: In patients with AF, CHIP was independently associated with a greater burden and progression of silent brain lesions and with accelerated cognitive decline.

Background and Aims: While inflammation and (auto-)immunity are modifiers of atherosclerosis, immunological determinants of cardiovascular risk beyond the established inflammatory markers, high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) remain incompletely defined in humans. This exploratory proof-of-concept study aimed to detect immunological signals enriched in patients with increased cardiovascular risk. Methods: A nested case–control study was performed within the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort, a single-centre prospective study of 3316 patients. Forty-four individuals with and without angiographically confirmed coronary artery disease (CAD) and defined survival status were selected for comprehensive immunophenotyping employing bulk RNA, single-cell RNA (scRNA), single-cell T-cell receptor sequencing, mass cytometry, spatial imaging, and cytokine secretion in blood immune cells. Multi-omics factor analysis was applied to identify shared transcriptional programmes. Readouts were tested for their association with CAD status and cardiovascular mortality and validated in two independent cohorts. Results: The integrated analysis strategy revealed immunological signals not detectable with conventional biomarkers, including a prominent signature of cellular proliferation, linked to activation, memory formation, clonal expansion, interferon signalling, and cytokine secretion in T cells. Cell types and transcriptional programmes associated with CAD status and poor long-term survival were identified. These associations were independent of established inflammatory markers, hsCRP and IL-6 that originated from myeloid cells. Key findings were replicated across independent cohorts using 136 scRNA sequencing datasets. Cellular proliferation was confirmed by protein validation in atherosclerotic plaques, and signatures were evaluated as stratification tools to predict short-term outcomes in acute coronary syndromes. Conclusions: Multi-omic profiling of blood immune cells revealed novel immune signatures associated with CAD, short- and long-term cardiovascular disease outcomes that are independent of systemic inflammation and may be used as risk stratification tools in the future.

An increased number of macrophages in the atherosclerotic plaque is associated with plaque instability and plaque progression. Lowering systemic cholesterol levels suppresses local macrophage proliferation and leads to plaque regression. However, the pathways regulating macrophage proliferation remain poorly understood. We investigated the cellular processes that underlie lipid-triggered local macrophage proliferation in the atherosclerotic plaque in transgenic mice and in human plaque tissue samples. Macrophages from mice with genetic deficiencies in scavenger receptors Cd36 ^−/− and Msr1 ^−/− showed reduced lipid uptake, lower intracellular lipid content, and lower proliferation compared to wild type macrophages. Double knockouts for the cholesterol exporters Abca1 and Abcg1 (MAC-ABC-DKO) showed increased rates of macrophage proliferation and apoptosis. In Cd36 ^−/− , Msr1 ^−/− , and MAC-ABC-DKO mixed bone marrow chimeras, no differences in chimerism were observed in blood or aorta after 4 weeks on a high-cholesterol diet. After 12 weeks of atherogenic diet, wild type macrophages predominated in the aorta since they proliferated more than neighboring Cd36 ^−/− or Msr1 ^−/− macrophages, and were less apoptotic than ABC-DKO macrophages, respectively. Knockout of NLRP3, but not ASC, Caspase 1 or IL-1 receptor, limited macrophage proliferation; indicating an NLRP3-dependent, but inflammasome-independent, effect. Inhibition of NLRP3 by MCC950 in human carotid artery plaque tissue cultures resulted in the suppression of intra-plaque macrophage proliferation and IL-1β release consistent with murine in vivo data. We identified a novel role for NLRP3 in driving macrophage proliferation in atherosclerotic plaques. NLRP3 inhibition may represent an ideal therapeutic target in atherosclerosis by combining anti-inflammasome and anti-proliferative effects in macrophages.

Background and Aims: Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular risk, but its prognostic relevance and mechanistic role in coronary artery disease (CAD) remains incompletely understood. This study investigated the association between CHIP and all-cause mortality in CAD and explored the cellular and molecular mechanisms, focusing on TET2 mutations. Methods: Targeted deep sequencing of 13 CHIP driver genes in 8612 patients with angiographically confirmed CAD was performed. Clonal haematopoiesis of indeterminate potential carriers (variant allele frequency ≥2%) were propensity-score matched 1:1 to non-carriers. Mortality was assessed over 3 years. Mechanistic insights were derived from post-mortem high-sensitivity plaque proteomics (MISSION), RNA sequencing from carotid plaques (Athero-Express), monocyte-derived macrophage transcriptomes (STARNET), and CRISPR/Cas9-generated TET2+/− macrophages in vitro. Results: Clonal haematopoiesis of indeterminate potential was associated with increased 3-year mortality (hazard ratio 1.39, 95% confidence interval 1.16–1.65, P < .001) in 2389 matched pairs. Mutations in TET2, ASXL1, DNMT3A, JAK2, PPM1D, SF3B1, SRSF2, and U2AF1 individually conferred higher mortality risk. In human plaques, CHIP mutations were found in lesional macrophages. TET2 CHIP carriers showed increased necrotic core size, inflammation, and reduced plaque stability. Multi-omics profiling revealed up-regulation of lipid metabolism and inflammatory pathways. TET2+/− macrophages exhibited increased LDLR expression and lipid uptake, linked to enhanced chromatin accessibility at the LDLR promoter. These findings were confirmed in carotid plaques, which showed increased LDLR and inflammasome-related gene expression in TET2 CHIP carriers. Conclusions: Clonal haematopoiesis of indeterminate potential is a predictor of mortality in CAD patients. TET2 mutations promote a pro-atherogenic macrophage phenotype via LDLR up-regulation and inflammatory activation, linking epigenetic dysregulation to adverse outcomes in CAD.

Background: GLP-1 receptor agonists (GLP-1 RA) reduce major adverse cardiovascular events in patients with diabetes mellitus and atherosclerotic cardiovascular disease (ASCVD) or increased cardiovascular risk. Recently, the GLP-1 RA semaglutide was reported to reduce cardiovascular events in ASCVD patients with overweight or obesity even in the absence of diabetes mellitus. Accordingly, this was included in the current European Society of Cardiology guidelines for secondary prevention. We aimed to assess the number of inpatients with ASCVD who could qualify for therapy with GLP-1 RA. Methods: Using nationwide data from the Research Data Centre of the Federal Statistical Office of Germany, a random 10% sample of all adult inpatients in 2022 was analyzed. The proportions of ASCVD, obesity, and diabetes mellitus were examined. Results: The 10% sample included 1,446,420 patients with a mean age of 63.16 years, 52.50% were female. ASCVD was present in 229,619 inpatients (15.87%), including those with coronary artery disease, history of myocardial infarction, peripheral vascular disease or stroke. Among ASCVD patients, 79,516 individuals (34.63% of ASCVD patients) also suffered from type 2 diabetes mellitus and 15,624 individuals were diagnosed with obesity. Approximately half of those ( N = 7,256) had ASCVD and obesity without diabetes mellitus (3.16% of ASCVD patients). Overall, 37.79% of ASCVD patients also suffered from type 2 diabetes mellitus or obesity. Conclusion: In this data sampling of German inpatients, more than one-third of ASCVD patients may qualify for GLP-1 RA therapy due to concomitant diabetes mellitus or obesity. That corresponds to about 6% of inpatients in Germany.

Nach wie vor bildet die konservative Therapie das Fundament in der Behandlung des chronischen Koronarsyndroms. Die aktuellen ESC-Leitlinien betonen die Bedeutung einer individualisierten Therapie, die sich an den Pathomechanismen und den spezifischen Bedürfnissen der Patienten orientiert. Die komplexe Pathophysiologie des CCS unterstreicht die Bedeutung eines umfassenden Therapieansatzes, der konservative und interventionelle Maßnahmen integriert. CCS management, based on the 2024 ESC Guidelines, a cornerstone of contemporary cardiology, aims to prevent cardiovascular events, alleviate symptoms, and enhance quality of life through conservative and invasive strategies. Non-invasive approaches, encompassing patient education, lifestyle interventions, and optimized pharmacological treatments, have demonstrated significant benefits in prognosis and quality of life. The guidelines advocate for a patient-centered approach, tailoring therapies to pathophysiological mechanisms, comorbidities, and individual needs. Pharmacological strategies integrate antithrombotic, lipid-lowering, RAAS-blocking, anti-inflammatory, and antidiabetic agents for event prevention, alongside antianginal medications for symptom relief. Invasive interventions remain essential for high-risk patients with obstructive coronary artery disease (e.g., left main disease, three-vessel disease, or proximal LAD involvement) or refractory angina despite optimal medical therapy. However, the growing efficacy of medical management increasingly challenges the incremental benefits of early revascularization. The guidelines also highlight underdiagnosed conditions such as ANOCA (Angina with Non-Obstructive Coronary Arteries) and INOCA (Ischemia with Non-Obstructive Coronary Arteries). Recognizing diverse endotypes, including microvascular dysfunction and vasospastic angina, enables precise and individualized therapeutic approaches. Conservative therapy remains the foundation of CCS management, demanding a holistic, multidisciplinary, and patient-centered approach to optimize outcomes and improve quality of life. Article published online: 06 May 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

BACKGROUND: Immune checkpoint inhibitors (ICIs), though revolutionary in cancer treatment, may accelerate atherosclerosis by inducing arterial inflammation. Due to a lack of controlled studies, the capacity of arterial 2-deoxy-2-[ ¹⁸ F]fluoro-D-glucose ([ ¹⁸ F]FDG) uptake in patients with cancer to detect this arterial inflammation remains unclear. METHODS: Arterial [ ¹⁸ F]FDG uptake at 6 anatomic landmarks was assessed on serial positron emission tomography scans in patients with cancer treated at a German University Hospital between January 2010 and May 2023. Patients aged ≥65 years with at least 4 sequential scans within 30 months were included. Linear mixed regression analyses were used to evaluate the change in arterial tracer uptake in patients who received ICI or not. RESULTS: Of the 156 patients included, 50 (30.1%) received ICIs after the baseline scan. Baseline arterial [ ¹⁸ F]FDG uptake correlated with traditional cardiovascular risk factors, such as body mass index and male sex. Cross-sectional analyses suggested a negative effect of cholesterol-lowering medication on arterial [ ¹⁸ F]FDG uptake at follow-up. In a time-dependent interaction analysis, arterial [ ¹⁸ F]FDG uptake increased by 0.8% annually in patients without ICIs (95% CI, 0.2%–1.4%), potentially reflecting the background progression of arterial inflammation in patients with cancer. In ICI users, [ ¹⁸ F]FDG uptake increased by 2.5% annually (95% CI, 1.7%–3.3%; P =0.001 for interaction with no ICI). Higher annual increase rates in ICI users were consistent across several anatomic landmarks, preexisting cardiovascular disease status, arterial calcification status, and concomitant chemotherapy or steroid use. However, this effect did not reach statistical significance in patients with melanoma and those with prior irradiation therapy. CONCLUSIONS: This is the first controlled clinical study supporting the role of ICIs in accelerating atherosclerosis through low-grade arterial inflammation. However, although detectable by repeated [ ¹⁸ F]FDG scans, the increase in tracer uptake associated with ICI use was modest compared with individual variability, questioning whether [ ¹⁸ F]FDG captures the full pathophysiological process of ICI-induced, lymphocyte-driven inflammation.