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Cangrelor, a potent intravenous P2Y12 platelet inhibitor, has demonstrated effectiveness in reducing ischemic events without a corresponding increase in severe bleeding during percutaneous coronary intervention, as evidenced by the CHAMPION-PHOENIX trial. Its off-label role as a bridging antiplatelet agent for patients facing high thrombotic risks who must temporarily stop oral P2Y12 inhibitor therapy further underscores its clinical utility. This is the first case series to shed light on the application of cangrelor in cancer patients needing to pause dual antiplatelet therapy for a range of medical interventions, marking it as a pioneering effort in this domain. The inclusion of patients with a variety of cancer types and cardiovascular conditions in this series underlines the adaptability and critical role of cangrelor in managing the dual challenges of bleeding risk and the need for uninterrupted antiplatelet protection. By offering a bridge for high-risk cancer patients who have recently undergone percutaneous coronary intervention and need to halt oral P2Y12 inhibitors temporarily, cangrelor presents a practical solution. Early findings indicate it can be discontinued safely 2-4 h before medical procedures, allowing for the effective reintroduction of oral P2Y12 inhibitors without adverse effects. This evidence calls for expanded research to validate and extend these preliminary observations, emphasizing the importance of further investigation into cangrelor's applications in complex patient care scenarios.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality, especially among the aging population. The “response-to-injury” model proposed by Dr. Russell Ross in 1999 emphasizes inflammation as a critical factor in atherosclerosis development, with atherosclerotic plaques forming due to endothelial cell (EC) injury, followed by myeloid cell adhesion and invasion into the blood vessel walls. Recent evidence indicates that cancer and its treatments can lead to long-term complications, including CVD. Cellular senescence, a hallmark of aging, is implicated in CVD pathogenesis, particularly in cancer survivors. However, the precise mechanisms linking premature senescence to CVD in cancer survivors remain poorly understood. This article aims to provide mechanistic insights into this association and propose future directions to better comprehend this complex interplay.

BackgroundThe deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear.MethodWe developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation.ResultOur findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS).SummaryIn this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes.

Cancer survivors undergone treatment face an increased risk of developing atherosclerotic cardiovascular disease (CVD), yet the underlying mechanisms remain elusive. Recent studies have revealed that chemotherapy can drive senescent cancer cells to acquire a proliferative phenotype known as senescence-associated stemness (SAS). These SAS cells exhibit enhanced growth and resistance to cancer treatment, thereby contributing to disease progression. Endothelial cell (EC) senescence has been implicated in atherosclerosis and cancer, including among cancer survivors. Treatment modalities for cancer can induce EC senescence, leading to the development of SAS phenotype and subsequent atherosclerosis in cancer survivors. Consequently, targeting senescent ECs displaying the SAS phenotype hold promise as a therapeutic approach for managing atherosclerotic CVD in this population. This review aims to provide a mechanistic understanding of SAS induction in ECs and its contribution to atherosclerosis among cancer survivors. We delve into the mechanisms underlying EC senescence in response to disturbed flow and ionizing radiation, which play pivotal role in atherosclerosis and cancer. Key pathways, including p90RSK/TERF2IP, TGFβR1/SMAD, and BH4 signaling are explored as potential targets for cancer treatment. By comprehending the similarities and distinctions between different types of senescence and the associated pathways, we can pave the way for targeted interventions aim at enhancing the cardiovascular health of this vulnerable population. The insights gained from this review may facilitate the development of novel therapeutic strategies for managing atherosclerotic CVD in cancer survivors.

IntroductionThis study examined the role of echocardiographic and cardiac histomorphology parameters in predicting mortality in patients with cardiac AL amyloidosis.MethodsPatients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at MD Anderson Cancer Center between 6/2011 and 6/2020 were identified. Stored echocardiographic images and endomyocardial biopsy samples were processed for myocardial strain analysis and a detailed histomorphology characterization.ResultsOf 43 patients; 44% were women and 63% white. Median age was 65 years; 51% underwent stem cell transplantation (SCT). Thirty patients (70%) died during follow up (median follow up: 4.1 years). Lower LA strain (

BackgroundCarcinoid heart disease (CnHD) is a frequent cause of morbidity and mortality in patients with neuroendocrine tumors and carcinoid syndrome. Although valve replacement surgery appears to decrease all-cause mortality in patients with advanced CnHD, few studies have investigated the outcomes of patients after valve replacement.MethodsWe conducted a multi-institution retrospective registry of patients who received both tricuspid and pulmonic bioprosthetic valve (TV/PV) replacements for advanced CnHD from November 2005 to March 2021. Patients were followed post-operatively with echocardiographic studies every 3 months. Carcinoid valvular heart disease scores were used to monitor valve degeneration. Neuroendocrine tumor treatment, their administration times, and associations with echocardiographic findings were recorded.ResultsOf 87 patients with CnHD, 22 patients underwent simultaneous surgical TV and PV replacement. In 6 patients (27.3%), increased PV Vmax was the first echocardiographic manifestation of valve degeneration in the setting of occult neurohormonal release. Post-operative telotristat ethyl and peptide receptor radionuclide therapy appeared to stabilize PV Vmax. The PV Vmax showed consistent elevation in the entire patient population when compared to baseline, while bioprosthetic TV echocardiographic parameters were relatively unchanged throughout. Post-operative warfarin therapy did not affect the rate of PV degeneration, and no major bleeding was recorded during or after post-operative anticoagulation therapy.ConclusionBioprosthetic valve degeneration is common in CnHD. Monitoring with echocardiographic studies every 3 months, focusing on PV velocities, could identify patients with occult disease that very likely promotes valve degeneration. Novel neuroendocrine tumor therapies may have a beneficial impact on valve degeneration.

IntroductionChemoradiotherapy (CRT) has been associated with increased incidence of cardiovascular (CV) adverse events (CVAE). Coronary artery calcium scoring (CAC) has shown to predict coronary events beyond the traditional CV risk factors. This study examines whether CAC, measured on standard of care, non-contrast chest CT (NCCT) imaging, predicts the development of CVAE in patients with non-small cell lung cancer (NSCLC) treated with CRT.MethodsPatients with NSCLC treated with CRT at MD Anderson Cancer Center from 7/2009 until 4/2014 and who had at least one NCCT scan within 6 months from their first CRT were identified. CAC scoring was performed on NCCT scans by an expert cardiologist and a cardiac radiologist following the 2016 SCCT/STR guidelines. CVAE were graded based on the most recent Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CVAE were also grouped into (i) coronary/vascular events, (ii) arrhythmias, or (iii) heart failure. All CVAE were adjudicated by a board-certified cardiologist.ResultsOut of a total of 193 patients, 45% were female and 91% Caucasian. Mean age was 64 ± 9 years and mean BMI 28 ± 6 kg/m2. Of 193 patients, 74% had CAC >0 Agatston units (AU), 49% CAC ≥100 AU and 36% CAC ≥300 AU. Twenty-nine patients (15%) developed a grade ≥2 CVAE during a median follow-up of 24.3 months (IQR: 10.9–51.7). Of those, 11 (38%) were coronary/vascular events. In the multivariate cox regression analysis, controlling for mean heart dose and pre-existing CV disease, higher CAC score was independently associated with development of a grade ≥2 CVAE [HR: 1.04 (per 100 AU), 95% CI: 1.01–1.08, p = 0.022] and with worse overall survival (OS; CAC ≥100 vs.

Radiation therapy (RT) to the chest increases the patients’ risk of cardiovascular disease (CVD). A complete understanding of the mechanisms by which RT induces CVD could lead to specific preventive, therapeutic approaches. It is becoming evident that both genotoxic chemotherapy agents and radiation induce mitochondrial dysfunction and cellular senescence. Notably, one of the common phenotypes observed in cancer survivors is accelerated senescence, and immunosenescence is closely related to both cancer risk and CVD development. Therefore, suppression of immunosenescence can be an ideal target to prevent cancer treatment-induced CVD. However, the mechanism(s) by which cancer treatments induce immunosenescence are incompletely characterized. We isolated peripheral blood mononuclear cells (PBMCs) before and 3 months after RT from 16 thoracic cancer patients. We characterized human immune cell lineages and markers of senescence, DNA damage response (DDR), efferocytosis, and determinants of clonal hematopoiesis of indeterminant potential (CHIP), using mass cytometry (CyTOF). We found that the frequency of the B cell subtype was decreased after RT. Unsupervised clustering of the CyTOF data identified 138 functional subsets of PBMCs. Compared with baseline, RT increased TBX21 (T-bet) expression in the largest B cell subset of Ki67–/DNMT3a+naïve B cells, and T-bet expression was correlated with phosphorylation of p90RSK expression. CD38 expression was also increased in naïve B cells (CD27–) and CD8+ effector memory CD45RA T cells (TEMRA). In vitro, we found the critical role of p90RSK activation in upregulating (1) CD38+/T-bet+ memory and naïve B, and myeloid cells, (2) senescence-associated β-gal staining, and (3) mitochondrial reactive oxygen species (ROS) after ionizing radiation (IR). These data suggest the crucial role of p90RSK activation in immunosenescence. The critical role of p90RSK activation in immune cells and T-bet induction in upregulating atherosclerosis formation has been reported. Furthermore, T-bet directly binds to the CD38 promoter region and upregulates CD38 expression. Since both T-bet and CD38 play a significant role in the process of immunosenescence, our data provide a cellular and molecular mechanism that links RT-induced p90RSK activation and the immunosenescence with T-bet and CD38 induction observed in thoracic cancer patients treated by RT and suggests that targeting the p90RSK/T-bet/CD38 pathway could play a role in preventing the radiation-associated CVD and improving cancer prognosis by inhibiting immunosenescence.

AimThis study investigated the factors predicting survival and the recurrence of pericardial effusion (PE) requiring pericardiocentesis (PCC) in patients with cancer.Materials and MethodsWe analyzed the data of patients who underwent PCC for large PEs from 2010 to 2020 at The University of Texas MD Anderson Cancer Center. The time to the first recurrent PE requiring PCC was the interval from the index PCC with pericardial drain placement to first recurrent PE requiring drainage (either repeated PCC or a pericardial window). Univariate and multivariate Fine-Gray models accounting for the competing risk of death were used to identify predictors of recurrent PE requiring drainage. Cox regression models were used to identify predictors of death.ResultsThe study cohort included 418 patients with index PCC and pericardial drain placement, of whom 65 (16%) had recurrent PEs requiring drainage. The cumulative incidences of recurrent PE requiring drainage at 12 and 60 months were 15.0% and 15.6%, respectively. Younger age, anti-inflammatory medication use, and solid tumors were associated with an increased risk of recurrence of PE requiring drainage, and that echocardiographic evidence of tamponade at presentation and receipt of immunotherapy were associated with a decreased risk of recurrence. Factors predicting poor survival included older age, malignant effusion on cytology, non-use of anti-inflammatory agents, non-lymphoma cancers and primary lung cancer.ConclusionAmong cancer patients with large PEs requiring drainage, young patients with solid tumors were more likely to experience recurrence, while elderly patients and those with lung cancer, malignant PE cytology, and non-use of anti-inflammatory agents showed worse survival.

Overlapping risks for cancer and cardiovascular diseases (CVD), the two leading causes of mortality worldwide, suggest a shared biology between these diseases. The role of senescence in the development of cancer and CVD has been established. However, its role as the intersection between these diseases remains unclear. Senescence was originally characterized by an irreversible cell cycle arrest after a high number of divisions, namely replicative senescence (RS). However, it is becoming clear that senescence can also be instigated by cellular stress, so-called stress-induced premature senescence (SIPS). Telomere shortening is a hallmark of RS. The contribution of telomere DNA damage and subsequent DNA damage response/repair to SIPS has also been suggested. Although cellular senescence can mediate cell cycle arrest, senescent cells can also remain metabolically active and secrete cytokines, chemokines, growth factors, and reactive oxygen species (ROS), so-called senescence-associated secretory phenotype (SASP). The involvement of SASP in both cancer and CVD has been established. In patients with cancer or CVD, SASP is induced by various stressors including cancer treatments, pro-inflammatory cytokines, and ROS. Therefore, SASP can be the intersection between cancer and CVD. Importantly, the conventional concept of senescence as the mediator of cell cycle arrest has been challenged, as it was recently reported that chemotherapy-induced senescence can reprogram senescent cancer cells to acquire “stemness” (SAS: senescence-associated stemness). SAS allows senescent cancer cells to escape cell cycle arrest with strongly enhanced clonogenic growth capacity. SAS supports senescent cells to promote both cancer and CVD, particularly in highly stressful conditions such as cancer treatments, myocardial infarction, and heart failure. As therapeutic advances have increased overlapping risk factors for cancer and CVD, to further understand their interaction may provide better prevention, earlier detection, and safer treatment. Thus, it is critical to study the mechanisms by which these senescence pathways (SAS/SASP) are induced and regulated in both cancer and CVD.

Objectives: To assess the clinical impact of Cardiovascular Magnetic Resonance (CMR) in clinical decision making of cancer patients with a suspected cardiomyopathy in a tertiary cancer center.Background: Cardiomyopathies of diverse etiologies are frequently encountered in a Cardio-Oncology practice. The clinical impact of CMR after a presumptive diagnosis of cardiomyopathy has not been studied in cancer patients.Methods: We reviewed data on cancer patients with presumptive diagnosis of cardiomyopathy who underwent CMR in a tertiary cancer center. The clinical impact of CMR was defined as either change in clinical diagnosis or management post CMR results. Univariate and multivariate logistic regression models were used to assess whether any of the baseline characteristics were predictive of the clinical impact of CMR.Results: A total of 110 consecutive patients were identified. Clinical impact of CMR was seen in 68 (62%) patients. Change in the clinical diagnosis and management was seen in 56 (51%) and 41 (37%) of patients, respectively. The most common change was prevention of endomyocardial biopsy in 26 patients (24%). Overall, patients with higher left ventricular ejection fraction (LVEF) by echocardiography (echo), clinical impact was influenced more by CMR (LVEF of 37.2 ± 12.3% vs. 51.5 ± 11.6%, p < 0.001). Cancer diagnosis of multiple myeloma was associated with change in the management post CMR (adjusted OR of 25.6, 95% CI 4.0–162.4, p = 0.001). Suspicion of infiltrative cardiomyopathy was associated with a higher likelihood of change in diagnosis. Having an LVEF≥40 by echo was associated with change in diagnosis and management by CMR.Conclusions: Utilization of CMR has a significant clinical impact in cancer patients with suspected cardiomyopathy. Patients with cancer diagnosis of multiple myeloma, suspicion of infiltrative cardiomyopathy and those with higher LVEF by echo seem to benefit more from CMR.

Patients with cancer and aortic stenosis (AS) are exposed to several factors that could accelerate the progression of AS. This study aimed to determine the cumulative incidence of AS progression and associated factors in these patients. This retrospective cohort study included patients with cancer, mild or moderate AS and at least two echocardiograms 6 months apart between 1996 and 2016 at MD Anderson Cancer Center. AS progression was defined by an increase in mean gradient of 20 mmHg or peak velocity of 2 m/s by spectral Doppler echocardiography or as requiring aortic valve replacement. Univariate and multivariable Fine-Gray models to account for the competing risk of death were used. One hundred and two patients were included and median follow-up was 7.3 years. Overall, 30 patients (29%) developed AS progression, while 48 (47%) died without it. Yearly rate of mean gradient change was 4.9 ± 3.9 mmHg and yearly rate of peak velocity change was 0.23 ± 0.29 m/s for patients who developed AS progression. In the univariate analysis, coronary artery disease (CAD), dyspnea, prevalent cyclophosphamide and beta-blocker use were associated with AS progression. In multivariable analysis, CAD and prevalent cyclophosphamide use for the time interval of more than 3 years of follow-up remained significantly associated with increased cumulative incidence of AS progression. In conclusion, patients with mild or moderate AS and cancer are more likely to die before having AS progression. AS progression is associated with CAD and prevalent cyclophosphamide use.

The recent surge in cancer drug approval has provided us in cardio-oncology with a new and unique era, which modern medicine has not experienced before: the diminishing availability of “conventional” evidence-based medicine. The drastic and quick changes in oncology has made it difficult, and at times even impossible, to establish a meaningful evidence-based cardio-oncology practice by simply following the oncologists' practice. For the modern cardio-oncologist, it seems that a more proactive approach and methodology is needed. We believe that only through such an approach (learn from the old, and apply to the new) the cardio-oncologist will obtain meaningful evidence to perform their every-day practice in this new era.