Herrmann, Joerg

This cohort study examines the association of bruton tyrosine kinase inhibitor therapy in B-cell malignant disease with increased risk of pericardial effusion and cardiovascular outcomes.

Abstract Background Treatment with immune-checkpoint inhibitors (ICI) may be associated with adverse cardiac events. Troponin elevation is part of the diagnostic criteria for ICI related myocarditis (ICIrM) and myocardial infarction (MI), however there is limited data for causes of troponin elevation independent of MI and ICIrM and their clinical outcomes with ICI therapy. Purpose To assess the diagnostic and prognostic value of high-sensitivity troponin T (hs-TnT) in patients treated with ICI based on different etiologies and association with cardiac events. Methods All patients treated with ICI who had hs-TnT measured at a multi-center institution from 2011 to 2022 were included. Medical records were reviewed for baseline characteristics and long-term outcomes, including cardiac death and MACE (MI, stroke, heart failure [HF]), and cause of hs-TnT elevation. Risk of cardiac events and mortality were compared for the different etiologies of hs-TnT elevation. Results Of 5,423 patients treated with ICI, 1669 had post-ICI hs-TnT measurement. Mean age was 68.7±11.3 years, 58.3% were male, with follow-up through one year from ICI first administration. Elevated hs-TnT was seen in 1136 patients, with the different causes for elevation depicted in Figure 1, panel A. ICIrM patients exhibited the highest median hs-TnT value of 364 ng/L (IQR 1096), followed by a median of 98 ng/L for MI/Type 2 ischemia, 61 ng/L for infection/sepsis, 51 ng/L for pulmonary embolus, 50 ng/L for HF and 27 ng/L for indeterminate causes, Figure 1, panel B. Additionally, median time from first ICI dose to hs-TnT elevation according to each of the diagnoses are depicted in Figure 1, panel C, with ICIrM showing the shortest median time of 44 days (IQR 74). Hs-TnT elevation in patients with ICIrM had the highest risk for cardiac death (HR 52.7, 95% CI 11.7-238.0, p<0.001), followed by hs-TnT elevation due to HF (HR 15.9, 95% CI 2.9-87.0, p=0.001), MI/type 2 ischemia (HR 11.6, 95% CI 2.4-56.1, p=0.002), and infection/sepsis (HR 5.7, 95% CI 1.0-31.0, p=0.045) compared to those with no hs-TnT elevation, Figure 2, panel A. Similarly, patients with ICIrM had highest risk for MACE (HR 8.2, 95% CI 4.4-15.3, p<0.001), followed by increased hs-TnT due to MI/type 2 ischemia (HR 8.1, 95% CI 5.0-13.1, p<0.001), HF (HR 7.6, 95% CI 4.2-13.7, p<0.001), pulmonary embolism (HR 5.1, 95% CI 2.5-10.8, p<0.001), infection/sepsis (HR 4.1, 95% CI 2.4-7.0, p<0.001), and indeterminate cause (HR 2.4, 95% CI 1.5-3.8, p<0.001), Figure 2, panel B. Conclusions Hs-TnT measurements have prognostic value for cardiac events in cancer patients receiving ICI therapy, including in those without ICIrM. Patients with ICIrM demonstrated the highest median hs-TnT levels and the poorest outcomes, with a graded response observed; the worst prognosis was seen in patients with hs-TnT elevation due to ICIrM, followed by other causes, and those without hs-TnT elevation had the best prognosis.Figure 1 Figure 2

Abstract Aims Acute myocardial infarction (AMI) patients face a substantial risk of cardiovascular events and rehospitalization. The impact of the SmartHeart 12-lead electrocardiogram (ECG) telemedicine device on healthcare utilization has not been tested in a US randomized trial. Methods and results Patients with AMI were randomized at discharge to standard of care without (control group) or with the SmartHeart 12-lead ECG device (intervention group). The primary endpoint was the rate of emergency department (ED) visits, hospital readmissions, and any cardiovascular testing from discharge to 90 days of follow-up. The primary endpoint was reached in 57 (59%) patients in the control group and 53 (63%) patients in the intervention group (P = 0.61). However, in the intervention group, only 30% of patients complied with two follow-up training SmartHeart 12-lead ECG transmissions after discharge, and only 24% used the device thereafter. Among device users, ED presentations were lower in the intervention group than in the control group (8.0% vs. 29%, P = 0.04). In all patients advised to present to the ED upon device use (38%), a clinically relevant cardiovascular diagnosis was made. One patient survived a ventricular fibrillation cardiac arrest as advised to present to ED urgently after device use. Conclusion In this US-based RCT, there were no significant differences in the primary outcome in the intention-to-treat analysis. However, according to per-protocol analysis, proper use of the SmartHeart ECG device with 24/7 telemedicine support reduced inappropriate and increased appropriate ED presentations after hospitalization for AMI.

Significance: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by reactivating antitumor immunity and improving outcomes across multiple malignancies. Yet, clinical observations and preclinical studies suggest that ICIs may increase long-term cardiovascular disease risk, including hypertension, atherosclerosis, and thrombosis. The underlying mechanisms remain incompletely defined, highlighting the need for focused investigation into the vascular consequences of immune activation. Recent Advances: ICI-induced immune activation disrupts vascular and immune homeostasis through persistent production of reactive oxygen species (ROS), mitochondrial dysfunction, and accumulation of cell-free DNA (cfDNA). Sustained T-cell activation enhances ROS generation, driving DNA damage and senescence in both endothelial and immune cells. ICIs may also promote endothelial-to-mesenchymal transition (EndoMT) through chronic oxidative and inflammatory signaling, contributing to fibrosis, vascular stiffness, and chronic inflammation. Transforming growth factor-beta, although immunosuppressive in many contexts, can drive profibrotic and EndoMT programs within the vasculature. Other cytokines and regulators, including interleukin-17 and regulator of calcineurin 1, have been implicated in vascular remodeling, atherosclerosis, and hypertension. Critical Issues: The relative roles of ROS, mitochondrial dysfunction, cfDNA-driven inflammation, and EndoMT in ICI-associated vascular senescence remain unclear. While inflammation-induced vascular damage is well-recognized, direct ICI-specific mechanisms require stronger evidence. How senescent endothelial and immune cells influence therapy resistance and remodeling of the tumor microenvironment also remains to be defined. Future Directions: Mitochondrial and cytosolic ROS sources—arising from electron leakage during oxidative phosphorylation and NADPH oxidases activity—shape immune signaling and sustain T-cell activation during checkpoint blockade. The DNA damage response kinases ataxia-telangiectasia mutated and ATM- and Rad3-related, activated by oxidative and replicative stress, engage p53-dependent senescence pathways in endothelial and immune cells. Future studies should evaluate biomarkers such as cfDNA and thrombospondin-1 and explore senescence-targeting or redox-modulating interventions that may alleviate cardiovascular toxicity without diminishing antitumor efficacy. This review outlines mechanistic pathways linking ICIs to vascular dysfunction and senescence, integrating preclinical data with emerging clinical insights. It distinguishes established processes from ICI-specific hypotheses and identifies key gaps requiring clinical validation. Antioxid. Redox Signal. 00, 000–000.

Advances in cancer therapies have transformed many malignancies into chronic or manageable conditions, but have been linked to adverse, including cardiovascular, events. Vascular toxicities associated with cancer treatment range from abnormal vasoreactivity to accelerated atherosclerosis, arterial thrombotic events, vasculitis, and arterial aneurysms or dissections. 5-fluorouracil and VEGF (vascular endothelial growth factor) inhibitors are the agents most commonly linked to abnormal vasoreactivity, whereas BCR-ABL (breakpoint cluster region–Abelson murine leukemia viral oncogene homolog) inhibitors and immune checkpoint inhibitors have been associated with accelerated atherosclerosis. Arterial thrombotic events are seen with VEGF and BCR-ABL inhibitors as well as platinum drugs. Vasculitis emerged with the use of immune checkpoint inhibitors, and arterial aneurysms and dissections with VEGF inhibitors. Radiation therapy can lead to several of the outlined vascular toxicities. This review comprehensively explores the mechanisms of vascular complications associated with chemotherapy, targeted therapies, immunotherapies, and radiation therapy. Key contributors include endothelial injury and dysfunction, oxidative stress, and inflammation. An understanding of the mechanisms of vascular toxicities may facilitate optimal treatment and preventive strategies in patients with cancer.

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens.

Importance The introduction of immune checkpoint inhibitor (ICI) therapy has improved cancer outcomes but at the cost of adverse events, mainly related to the immune system. Cardiovascular (CV) toxic effects, and especially myocarditis, are of particular concern and are the subject of this position statement by the International Cardio-Oncology Society with representation of experts from oncology, hematology, and cardiology. Observations CV toxic effects of ICI therapies include inflammation-associated diseases, such as myocarditis, pericarditis, and vasculitis, as well as the aggravation of chronic inflammatory conditions, such as atherosclerosis with acute ischemic complications (myocardial infarction and stroke). Patients taking ICI therapies can also develop cardiac dysfunction, stress-induced cardiomyopathy (Takotsubo or apical ballooning syndrome), and heart failure without inflammatory cell infiltration of the myocardium. Atrial and ventricular arrhythmias can emerge in the setting of a systemic inflammatory milieu, myocarditis, or ischemia. Of all potential CV adverse effects, myocarditis remains of highest concern, although fatality rates have declined over time with a broadening spectrum of presentations ranging from troponin elevation of uncertain significance to smoldering, nonsevere, and severe or fulminant myocarditis. Conclusions and Relevance Concerns for myocarditis continue to dominate the spectrum of CV toxic effects in patients receiving ICI therapy. Recommendations for management vary according to severity. Multidisciplinary collaborations remain key for managing acute toxic effects and future cancer treatment decisions, including ICI rechallenge. Ischemic heart disease constitutes the main differential diagnosis in these patients, while pericarditis can be concomitantly present, and atrial and ventricular arrhythmias can also complicate the clinical picture. Several gaps in knowledge are identified and require further research.

BACKGROUND: The performance of estimated glomerular filtration rate (eGFR) among patients with heart failure (HF) may be worse than in the general population due to a higher prevalence of confounding factors affecting creatinine and cystatin C. Studies in this area are scarce and not stratified by type of HF. We evaluated the performance of current creatinine and cystatin C equations (eGFRcr, eGFRcys, and eGFRcrcys) compared with measured GFR (mGFR) among patients with HF stratified by ejection fraction. METHODS: We pulled data on Mayo Clinic patients with an mGFR performed for clinical indications from 2011 to 2023, with serum creatinine and cystatin C measured within 7 days and an echocardiogram performed up to 1 year before the mGFR date. HF was identified by the presence of International Classification of Diseases codes within 1 year before the mGFR and subgrouped into ejection fraction (EF) ≥50% (HFEF≥50%, n=182) or <50% (HFEF<50%, n=115) and compared with no-HF controls (n=1871). CKD-EPI (and EKFC) eGFRcr, eGFRcys, and eGFRcrcys equations were calculated and compared for bias (mGFR minus eGFR) and accuracy (1-P30, proportion of people with ≥30% difference between eGFR and mGFR). CIs were generated by bootstrapping. RESULTS: The HF groups were characterized by older age, higher proportion of males, more diabetes, higher creatinine, and higher cystatin C than controls. In terms of bias, eGFRcr overestimated mGFR to a greater extent in both HF groups compared with controls, whereas eGFRcys and eGFRcrcys showed similar bias in both HF groups and controls. In the HF groups, cystatin C-based equations were more accurate than eGFRcr, particularly within HFEF<50% (1-P30 of 28% and 34% for CKD-EPI eGFRcys and eGFRcrcys, respectively, versus 60% for eGFRcr), whereas eGFRcrcys was more accurate in controls. The CKD-EPI and EKFC equations were overall convergent, showing similar results. CONCLUSIONS: Among patients with HF, eGFRcr demonstrates inferior performance (more bias and less accuracy) compared with cystatin C-based eGFRs, with this effect being more pronounced in those with HFEF<50%.

Abstract Background Endocrine therapy has been the mainstay treatment for metastatic hormone receptor-positive / HER2-negative (HR+/HER2-) breast cancer. Given that cell cycle dysregulation and consequent uncontrolled cellular proliferation is a key mechanism behind cancer growth, agents targeting this pathway have been of major therapeutic interest.[1] The cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors palbociclib, ribociclib, and abemaciclib have shown a synergistic effect in combination with endocrine therapy.[2-3] Despite favorable results, post-approval studies have revealed potential concerns for cardiotoxicity. [4] Given this, we sought to characterize the incidence and outcomes of atrial arrhythmia among metastatic HR+/HER2- breast cancer patients who were treated with CDK 4/6 inhibitors at our institution. Purpose To investigate the incidence and risk factors of atrial arrhythmia among hormone receptor-positive/HER2-negative breast cancer patients treated with CDK4/6 inhibitors at our institution. Methods A retrospective cohort study was conducted among 2754 patients ≥18 years of age who received treatment with CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) for an established diagnosis of hormone receptor-positive, HER-2 negative breast cancer between 2015-2024. Patients with new onset atrial fibrillation and/or flutter were identified through chart review. The cumulative incidence of new-onset atrial arrhythmia was estimated using the Kaplan-Meier method. Univariable and multivariable Cox regression analyses were performed to identify predictors of atrial arrhythmia. Results A total of 2754 patients was included in the study; 97.3% were female and mean age was 61 years (13). Among these, 101 (3.6%) had a prior history of atrial arrhythmia. The 1-year and 5-year cumulative incidence of new-onset AA were 1.1% and 2.8% respectively (Figure 1). When stratified by specific CDK4/6 inhibitor agents, there was no statistically significant difference. On univariable analysis, age at treatment, hypertension, coronary artery disease, and peripheral vascular disease were associated with new-onset atrial arrhythmia. However, following multivariable adjustment, only age at treatment was statistically significant. Conclusions New-onset atrial arrhythmias may occur during or after CDK4/6 inhibitor use. Older patients appeared to have a higher risk. There were no clear differences in atrial arrhythmia risk between the three CDK4/6 inhibitors.