Elevated IL-6 and Tumor Necrosis Factor-α in Immune Checkpoint Inhibitor Myocarditis.

INTRODUCTION: The impact of peripheral cytokine levels on the prognosis and treatment of immune checkpoint inhibitor (ICI) myocarditis has not been well studied. OBJECTIVES: This study aimed to identify cytokines that can prognosticate and direct the treatment of ICI myocarditis. METHODS: This was a single-center, retrospective cohort study of patients with ICI myocarditis who had available peripheral cytokine levels between January 2011 and May 2022. Major adverse cardiovascular events (MACEs) were defined as a composite of heart failure with/without cardiogenic shock, arterial thrombosis, life-threatening arrhythmias, pulmonary embolism, and sudden cardiac death. RESULTS: In total, 65 patients with ICI myocarditis had cytokine data available. Patients were mostly males (70%), with a mean age of 67.8 ± 12.7 years. Interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were the most common cytokines to be elevated with 48/65 (74%) of patients having a peak IL-6 above normal limits (>5 pg/mL) and 44/65 (68%) of patients with peak TNF-α above normal limits (>22 pg/mL). Patients with elevated peak IL-6 had similar 90-day mortality and MACE outcomes compared to those without (10.4% vs. 11.8%, p = 0.878 and 8.8% vs. 17.7%, p = 0.366, respectively). Similarly, those with elevated peak TNF-α had similar 90-day mortality and MACEs compared to those without (29.6% vs. 14.3%, p = 0.182 and 13.6% vs. 4.8%, p = 0.413, respectively). Kaplan-Meier survival analysis also showed that there was not a significant difference between MACE-free survival when comparing elevated and normal IL-6 and TNF-α levels (p = 0.182 and p = 0.118, respectively). MACEs and overall survival outcomes were similar between those who received infliximab and those who did not among all patients and those with elevated TNF-α (p-value 0.70 and 0.83, respectively). CONCLUSION: Peripheral blood levels of IL-6 and TNF-α are the most commonly elevated cytokines in patients with ICI myocarditis. However, their role in the prognostication and guidance of immunomodulatory treatment is currently limited.

Prevalence, mortality, cost, and disparities in transcatheter mitral valve repair and replacement in cancer patients: Artificial intelligence and propensity score national 5-year analysis of 7495 procedures.

INTRODUCTION: We conducted the first comprehensive evaluation of the therapeutic value and safety profile of transcatheter mitral edge-to-edge repair (TEER) and transcatheter mitral valve replacement (TMVR) in individuals concurrently afflicted with cancer. METHODS: Utilizing the National Inpatient Sample (NIS) dataset, we analyzed all adult hospitalizations between 2016 and 2020 (n = 148,755,036). The inclusion criteria for this retrospectively analyzed prospective cohort study were all adult hospitalizations (age 18 years and older). Regression and machine learning analyses in addition to model optimization were conducted using ML-PSr (Machine Learning-augmented Propensity Score adjusted multivariable regression) and BAyesian Machine learning-augmented Propensity Score (BAM-PS) multivariable regression. RESULTS: Of all adult hospitalizations, there were 5790 (0.004%) TMVRs and 1705 (0.001%) TEERs. Of the total TMVRs, 160 (2.76%) were done in active cancer. Of the total TEERs, 30 (1.76%) were done in active cancer. After the comparable rates of TEER/TMVR in active cancer in 2016, the prevalence of TEER/TMVR was significantly less in active cancer from 2017 to 2020 (2.61% versus 7.28% p < 0.001). From 2017 to 2020, active cancer significantly decreased the odds of receiving TEER or TMVR (OR 0.28, 95%CI 0.13-0.68, p = 0.008). In patients with active cancer who underwent TMVR/TEER, there were no significant differences in socio-economic disparities, mortality or total hospitalization costs. CONCLUSION: The presence of malignancy does not contribute to increased mortality, length of stay or procedural costs in TMVR or TEER. Whereas the prevalence of TMVR has increased in patients with active cancer, the utilization of TEER in the context of active cancer is declining despite a growing patient population.

Navigating P2Y12 inhibition in the labyrinth of cardio-oncology care: cangrelor bridging in patients with cancer.

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.

Evaluation of Midodrine Utilization in Patients with Cancer and Heart Failure.

PURPOSE: The purpose of this study was to evaluate safety and cardiovascular outcomes as well as overall survival of cancer patients with concomitant heart failure (HF) treated with midodrine for hypotension. METHODS: Adult patients diagnosed with cancer and HF who were treated with midodrine at a tertiary cancer center from 03/2013 to 08/2021 were identified. Demographic and clinical parameters were collected retrospectively. RESULTS: A total of 85 patients were included with a median age of 68 years (IQR: 60, 74; 33% female and 85% White). Of those, 31% had HFpEF (EF ≥ 50%), 42% HF with mildly reduced EF (HFmrEF; EF 41-49%), and 27% HFrEF (EF ≤ 40%). The most common indication for midodrine use was orthostatic hypotension (49%). Midodrine was continued for at least one month in 57% of the patients. Supine hypertension was the only side effect reported in 6% of patients. No statistically significant changes in NYHA class, guideline-directed medical therapy, cardiac biomarkers (NT-proBNP or troponin T), echocardiographic findings or cardiovascular hospitalizations were observed between patients who continued treatment with midodrine compared to those who stopped using midodrine over a median follow-up of 38 months. In the multivariable cox regression analysis, continuation of midodrine, compared to discontinuation, and use of midodrine for orthostatic hypotension, as opposed to other causes of hypotension, were not associated with an increased risk of mortality (HR 0.41, 95% CI 0.24-0.69, p < .0001; HR 0.34, 95% CI 0.18-0.64, p < .001, respectively). In contrast, elevated creatinine (> 1.3 for males and > 1.1 for females) was associated with an increased risk of mortality (HR 1.83, 95% CI 1.07-3.14). LVEF was not significantly associated with lower or higher risk of mortality. CONCLUSIONS: In our study, midodrine use in patients with cancer and HF was not associated with significant adverse effects, worse cardiovascular outcomes, or increased risk of mortality. Larger, prospective studies are needed to confirm these findings.

Coronary Revascularization in Patients With Cancer.

Purpose of review: The treatment of coronary artery disease (CAD) in cancer patients is an evolving landscape. Recent data emphasizes the importance of aggressive management of cardiovascular risk factors and diseases in improving cardiovascular health in this unique group of patients regardless of cancer type or stage. Recent findings: Novel cancer therapeutics such as immune therapies and proteasome inhibitors have been associated with CAD. Recent stent technologies may safely allow for shorter duration (< 6 months) of dual antiplatelet therapy post-percutaneous coronary interventions. Intracoronary imaging may be useful in the decision making process in terms of stent positioning and healing. Summary: Large registry studies have partially filled a gap left by the lack of randomized controlled trials in the treatment of CAD in cancer patients. Cardio-oncology is gaining traction as a major sub-specialty in the cardiology field given the release of the first European Society of Cardiology - Cardio-oncology guidelines in 2022.

Effect of Carbonyl Iron Particle Types on the Structure and Performance of Magnetorheological Elastomers: A Frequency and Strain Dependent Study.

Magnetorheological elastomers (MREs) are smart viscoelastic materials in which their physical properties can be altered when subjected to a varying magnetic field strength. MREs consist of an elastomeric matrix mixed with magnetic particles, typically carbonyl iron particles (CIPs). The magnetic field-responsive property of MREs have led to their wide exposure in research. The potential development and commercialization of MRE-based devices requires extensive investigation to identify the essential factors that can affect their properties. For this reason, this research aims to investigate the impact of CIPs' type, concentration and coating on the rheological and mechanical properties of MREs. Isotropic MREs are fabricated with four different CIP compositions differing between hard or soft, and coated or uncoated samples. Each MRE composition have three different concentrations, which is 5%, 10%, and 20% by volume. The dynamic properties of the fabricated samples are tested by compression oscillations on a dynamic mechanical analyzer (DMA). Frequency and strain dependent measurements are performed to obtain the storage and loss modulus under different excitation frequencies and strain amplitudes. The emphasis is on the magnetorheological (MR) effect and the Payne effect which are an intrinsic characteristics of MREs. The effect of the CIPs' type, coating, and concentration on the MR and Payne effect of MREs are elucidated. Overall, it is observed that, the storage and loss modulus exhibit a strong dependence on both the frequency excitations and the strain amplitudes. Samples with hard and coated CIPs tend to have a higher MR effect than other samples. A decrease in the storage modulus and non-monotonous behavior of the loss modulus with increasing strain amplitude are observed, indicating the Payne effect. The results of this study can aid in the characterization of MREs and the proper selection of CIPs grades based on the application.

Evaluation of contemporary echocardiographic and histomorphology parameters in predicting mortality in patients with endomyocardial biopsy-proven cardiac AL amyloidosis.

Introduction: This study examined the role of echocardiographic and cardiac histomorphology parameters in predicting mortality in patients with cardiac AL amyloidosis. Methods: Patients 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. Results: Of 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 (<13.5%) and absence of SCT as a time-varying covariate were significantly associated with increased risk of death in the multivariate cox regression analysis. Higher LV mass and lower RV tricuspid annular plane systolic excursion were associated with increased odds of having ≥5% interstitial amyloid deposition on biopsy in the multivariate logistic regression analysis. Conclusion: Lower LA strain independently predicted mortality in our cohort, and its performance in the routine assessment of AL amyloidosis may be beneficial. Furthermore, SCT for cardiac AL amyloidosis was associated with improved OS. These findings need to be confirmed by larger studies in the era of contemporary systemic therapies.

Inflammation of the periodontium associates with risk of future cardiovascular events.

BACKGROUND: While growing evidence suggests a link between periodontal disease (PD) and cardiovascular disease (CVD), the independence of this association and the pathway remain unclear. Herein, we tested the hypotheses that: (1) inflammation of the periodontium (PDinflammation ) predicts future CVD independently of disease risk factors shared between CVD and PD, and (2) the mechanism linking the two diseases involves heightened arterial inflammation. METHODS: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) imaging was performed in 304 individuals (median age 54 years; 42.4% male) largely for cancer screening; individuals without active cancer were included. PDinflammation and arterial inflammation were quantified using validated 18 F-FDG-PET/CT methods. Additionally, we evaluated the relationship between PDinflammation and subsequent major adverse cardiovascular events (MACE) using Cox models and log-rank tests. RESULTS: Thirteen individuals developed MACE during follow-up (median 4.1 years). PDinflammation associated with arterial inflammation, remaining significant after adjusting for PD and CVD risk factors (standardized ß [95% CI]: 0.30 [0.20-0.40], P < 0.001). PDinflammation predicted subsequent MACE (standardized HR [95% CI]: 2.25 [1.47 to 3.44], P <0.001, remaining significant in multivariable models), while periodontal bone loss did not. Furthermore, mediation analysis suggested that arterial inflammation accounts for 80% of the relationship between PDinflammation and MACE (standardized log odds ratio [95% CI]: 0.438 [0.019-0.880], P = 0.022). CONCLUSION: PDinflammation is independently associated with MACE via a mechanism that may involve increased arterial inflammation. These findings provide important support for an independent relationship between PDinflammation and CVD.

Impact of Chronic Thrombocytopenia on Outcomes After Transcatheter Valvular Intervention and Cardiac Devices Implantation (From a National Inpatient Sample).

To evaluate the impact of chronic thrombocytopenia (cTCP) on outcomes of transcatheter valvular procedures such as aortic valve implantation (TAVI), MitraClip, permanent pacemaker (PPM), implantable-cardioverter defibrillator (ICD), cardiac resynchronization therapy (CRT), left atrial appendage closure, and pericardiocentesis. Impact of cTCP on clinical outcomes following TAVI, Mitraclip, PPM, ICD, CRT, left atrial appendage closure, and pericardiocentesis procedures is not well described. Utilizing the National Inpatient Sample and (ICD-9-CM) procedural codes, we evaluated patients (age ≥18 years) who underwent these procedures, from January 1, 2009 to December 31, 2014, with or without cTCP as a chronic condition variable indicator. Propensity score matching model implemented to derive 2 matched groups. Propensity score matching created 47,292 and 47,351 hospitalizations matched pairs with and without cTCP, respectively. Patients with cTCP were older (mean age, 74.27 vs 72.26 years; absolute standardized differences [ASD] = 15.6) and less likely to be female (36.76% vs 43.74%, ASD = -14.31). They experienced higher in-hospital mortality (3.0% vs 2.0%; odds ratio [OR], 1.53; 95% confidence interval [CI], 1.27 to 1.83) and higher odds of vascular injury requiring surgery (2.63% vs 1.10%; OR, 2.43; 95% CI, 1.93 to 3.05). Postoperative hematoma and bleeding were 2-fold higher (4.57% vs 2.24%; OR, 2.08; 95% CI, 1.77 to 2.45) and 3-fold higher (6.34% vs 2.45%; OR, 2.69; 95% CI, 2.31 to 3.13) respectively among cTCP patients. They had greater health-care cost ($47,163 vs $35,763, p <0.0001) and longer hospital stay (mean 9.26 days vs 6.84 days, p <0.0001). In conclusion, cTCP patients had higher risk of complications after TAVI, MitraClip, PPM, ICD, CRT, left atrial appendage closure, and pericardiocentesis, including a 1.5-fold increased risk of in-hospital mortality.

Liver stiffness measurement and spleen diameter as predictors for the presence of esophageal varices in chronic hepatitis C patients.

Although it is an invasive and unpleasant procedure, esophagogastroduodenoscopy (EGD) is still the gold standard for esophageal varices (EV) detection. The aim of this study was to investigate liver stiffness measurement (LSM) and spleen diameter as simple noninvasive tools for EV prediction in chronic hepatitis C patients (CHC).A total of 123 Egyptian patients with CHC have been included and were classified based on screening EGD result into 2 groups; group A (without EV) and group B (with EV). Group (B) was subclassified according to EV grade into 4 subgroups: (B1, grade I), (B2, grade II), (B3, grade III), and (B4, grade IV). LSM was taken for each patient on the next day by an independent Fibroscan operator and correlated to the EGD result. Demographic, clinical, and biochemical data were recorded and analyzed using advanced data-mining computational technology.Mean LSM was 9.94 ±â€Š6 kPa for group A and 33.32 ±â€Š14 kPa for group B, whereas it was 21.22 ±â€Š3, 25.72 ±â€Š6, 33.82 ±â€Š8, and 46.1 ±â€Š15 kPa for subgroups B1, B2, B3, and B4, respectively. Mean spleen diameter was 11.09 ±â€Š1.7 cm for group A and 16.58 ±â€Š1.6 cm for group B. However, LSM ≥17 kPa was the only independent factor for EV prediction; splenic longitudinal span ≥15 cm was a complementary predictor when LSM was <17 kPa. The overall accuracy was 98.33 ±â€Š3.33, Mikro = 98.26%.LSM ≥17 kPa and spleen diameter ≥15 cm is a simple noninvasive algorithm that could be used for prediction of EV and discrimination among its different grades.

Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study.

BACKGROUND: Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events. METHODS: Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent 18F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses. FINDINGS: 293 patients (median age 55 years [IQR 45·0-65·5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7-4·8). Amygdalar activity was associated with increased bone-marrow activity (r=0·47; p<0·0001), arterial inflammation (r=0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27-1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (r=0·70; p=0·0083). Perceived stress was associated with amygdalar activity (r=0·56; p=0·0485), arterial inflammation (r=0·59; p=0·0345), and C-reactive protein (r=0·83; p=0·0210). INTERPRETATION: In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings. FUNDING: None.

FDG PET/CT Imaging of Carotid Atherosclerosis.

Atherosclerosis is a complex inflammatory process and an integral component of myocardial infarction and stroke. Atherosclerotic plaques can be detected using ultrasonography, myocardial perfusion imaging, coronary angiography, multidetector computed tomography (CT), and MR imaging. These modalities assess the luminal encroachment of the plaques or the structural features. Imaging plaque biology in concert with plaque structure may provide important insights. PET scanning using (18)F fluorodeoxyglucose. ((18)F FDG-PET) is commonly combined with CT scanning to characterize oncological processes. This review examines the role of (18)F FDG-PET/CT imaging in the characterization of atherosclerotic plaque biology.

Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study.

3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.