Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents.

Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.

Complete heart block is a significant predictor of mortality in immune checkpoint inhibitor myocarditis.

BACKGROUND: Immune checkpoint inhibitor (ICI) myocarditis is associated with significant mortality risk. Electrocardiogram (ECG) changes in ICI myocarditis have strong prognostic value. However the impact of complete heart block (CHB) is not well defined. This study sought to evaluate the impact of CHB on mortality in ICI myocarditis, and to identify clinical predictors of mortality and CHB incidence. METHODS: We conducted a retrospective cohort study of patients with ICI myocarditis at three Mayo Clinic sites from 1st January 2010 to 31st September 2022 to evaluate mortality rates at 180 days. Clinical, laboratory, ECG, echocardiographic, and cardiac magnetic resonance imaging (CMR) characteristics were assessed. Cox and logistic regression were performed for associations with mortality and CHB respectively. RESULTS: Of 34 identified cases of ICI myocarditis, 7 (20.6%) had CHB. CHB was associated with higher mortality (HR 7.41, p = 0.03, attributable fraction 86.5%). Among those with CHB, troponin T (TnT) < 1000 ng/dL, low white blood cell count and high ventricular rate at admission were protective. There was trend towards increased survival among patients who underwent permanent pacemaker insertion (p = 0.051), although most experienced device lead complications. Factors associated with development of CHB included prolonged PR and QRS intervals and low Sokolow Lyon Index. Where these were normal and TnT was < 1000 ng/dL, no deaths occurred. Impaired myocardial longitudinal strain was sensitive for ICI myocarditis but was not prognostically significant. CONCLUSION: There is a strong temporal association between CHB and early mortality in people with ICI myocarditis. Focusing on arrhythmogenic complications can be helpful in predicting outcomes for this group of critically ill individuals.

Safety and efficacy of transcatheter edge-to-edge repair (TEER) in patients with history of cancer.

Background: Surgical therapy has been a long-standing option for valvular heart disease, in patients with history of cancer, it carries an increased risk of complications. Objectives: Transcatheter edge-to-edge repair (TEER) for mitral regurgitation, represents a less invasive option. However, patients with history of cancer have generally been excluded from trials. Methods: A retrospective cohort analysis was performed on de-identified, aggregate patient data from the TriNetX research network. Patients 18 ≥ years of age, who had undergone TEER between January 1, 2013 and May 19, 2021, were identified using the CPT codes and divided into two cohorts based on a history of cancer. Subgroup analysis was performed based on history of systemic antineoplastic therapy. Odds ratio and log-rank test were used to compare the outcomes over 1 and 12-months. Results: In matched cohorts (503 patients in each, mean age 77.7 years, men 55 vs 58 %, white 84 vs 87 % in non-cancer and cancer cohorts respectively), the risk of heart failure exacerbation, all-cause mortality and all-cause hospitalizations were similar at 1 and 12 months among patients undergoing TEER. Risk of major complications (ischemic stroke, blood product transfusion and cardiac tamponade) were also similar. In the cancer cohort, hematologic/lymphoid malignancies were the most common (28.0 %) and 12.5 % patients had a history of metastatic cancer. There was no significant difference in heart failure exacerbation or all-cause mortality based on history of systemic antineoplastic therapy. Conclusions: Overall outcomes following TEER are similar in patients with a history of cancer and should be considered in selected patients in this population.

Impact of Social Vulnerability on Comorbid Cancer and Cardiovascular Disease Mortality in the United States.

Background: Racial and social disparities exist in outcomes related to cancer and cardiovascular disease (CVD). Objectives: The aim of this cross-sectional study was to study the impact of social vulnerability on mortality attributed to comorbid cancer and CVD. Methods: The Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database (2015-2019) was used to obtain county-level mortality data attributed to cancer, CVD, and comorbid cancer and CVD. County-level social vulnerability index (SVI) data (2014-2018) were obtained from the CDC's Agency for Toxic Substances and Disease Registry. SVI percentiles were generated for each county and aggregated to form SVI quartiles. Age-adjusted mortality rates (AAMRs) were estimated and compared across SVI quartiles to assess the impact of social vulnerability on mortality related to cancer, CVD, and comorbid cancer and CVD. Results: The AAMR for comorbid cancer and CVD was 47.75 (95% CI: 47.66-47.85) per 100,000 person-years, with higher mortality in counties with greater social vulnerability. AAMRs for cancer and CVD were also significantly greater in counties with the highest SVIs. However, the proportional increase in mortality between the highest and lowest SVI counties was greater for comorbid cancer and CVD than for either cancer or CVD alone. Adults <45 years of age, women, Asian and Pacific Islanders, and Hispanics had the highest relative increase in comorbid cancer and CVD mortality between the fourth and first SVI quartiles, without significant urban-rural differences. Conclusions: Comorbid cancer and CVD mortality increased in counties with higher social vulnerability. Improved education, resource allocation, and targeted public health interventions are needed to address inequities in cardio-oncology.

The Impact of Radiation Dose to Heart Substructures on Major Coronary Events and Patient Survival after Chemoradiation Therapy for Esophageal Cancer.

Background: There is a paucity of data regarding the association between radiation exposure of heart substructures and the incidence of major coronary events (MCEs) in patients with esophageal cancer (ESOC) undergoing chemoradiation therapy. We studied radiation dosimetric determinants of MCE risk and measured their impact on patient prognosis using a cohort of ESOC patients treated at a single institution. Methods: Between March 2005 and October 2015, 355 ESOC patients treated with concurrent chemoradiotherapy were identified from a prospectively maintained and institutional-regulatory-board-approved clinical database. Dose-distribution parameters of the whole heart, the atria, the ventricles, the left main coronary artery, and three main coronary arteries were extracted for analysis. Results: Within a median follow-up time of 67 months, 14 patients experienced MCEs at a median of 16 months. The incidence of MCEs was significantly associated with the left anterior descending coronary artery (LAD) receiving ≥30 Gy (V30Gy) (p = 0.048). Patients receiving LAD V30Gy ≥ 10% of volume experienced a higher incidence of MCEs versus the LAD V30Gy < 10% group (p = 0.044). The relative rate of death increased with the left main coronary artery (LMA) mean dose (Gy) (p = 0.002). Furthermore, a mutual promotion effect of hyperlipidemia and RT on MCEs was observed. Conclusion: Radiation dose to coronary substructures is associated with MCEs and overall survival in patients with ESOC. In this study, the doses to these substructures appeared to be better predictors of toxicity outcomes than mean heart dose (MHD) or whole-heart V30Gy. These findings have implications for reducing coronary events through radiation therapy planning.

Melting of subducted slab dictates trace element recycling in global arcs.

Arc magma acquires continental crust-like trace element signatures through selective recycling of incompatible elements from the subducted slab. The long-standing model of element recycling through aqueous fluid from altered oceanic crust (AOC) and sediment melt has been challenged by the resurgence of mélange diapir (a mix of AOC, sediment, and serpentinite) and saline aqueous fluid models. Here, we present experimental data for near-solidus sediment melts and a framework for calculating trace element concentrations in subduction fluids from metamorphosed sediment and oceanic crust. We observe that variation of element ratios in global primitive arc basalts is comparable with that of sediment and/or oceanic crustal melt, rather than (saline) aqueous fluid or mélange melt. In particular, the systematic correlation of element ratios in arc basalt corresponds to element fractionation in slab melt with temperature and therefore follows a power function. Our findings suggest that slab melt is primarily responsible for element recycling to the arc.

Predictive value of vascular response to cuff inflation-induced pain in the control arm for adverse cardiovascular events.

BACKGROUND: The high incidence rate of cardiovascular (CV) events had led to a comprehensive appraisal for identifying patients who are at risk for CV disease. However, CV traditional risk factors, such as Framingham risk score (FRS), failed exhaustively to predict CV events. METHODS: 402 participants (mean age, 58 [12] years; 45% male) using fingertip peripheral artery tonometry at Mayo Clinic in Rochester, Minnesota, were recruited in the present study. Measurements included reactive hyperemia index (RHI) and pain-induced peripheral artery tonometry (PIPAT). RESULTS: After a median follow-up of 3.8 (2.7-7.7) years, 95 CV events occurred. Both first minute PIPAT and RHI were independently associated with events (hazard ratio [HR], 0.77 [95% CI, 0.61-0.98]; P = 0.038 and HR, 0.75 [95% CI, 0.59-0.96]; P = 0.019, respectively). The C statistic values of FRS, FRS + first minute PIPAT, FRS + RHI, and FRS + RHI + first minute PIPAT were 0.704, 0.722, 0.694, and 0.726, respectively. Furthermore, the addition of first minute PIPAT, RHI, and first minute PIPAT + RHI to FRS results in net reclassification improvement (NRI) in the intermediate-risk group (18.1%, P = 0.031; 18.1%, P = 0.035; 21%, P = 0.013). CONCLUSION: First minute PIPAT is a risk marker for adverse CV. Addition of first minute PIPAT to FRS increased the discrimination in the receiver operating characteristic analysis. It also increased NRI compared with FRS alone.

Cardiorheumatology: cardiac involvement in systemic rheumatic disease.

Autoimmune rheumatic diseases can affect the cardiac vasculature, valves, myocardium, pericardium, and conduction system, leading to a plethora of cardiovascular manifestations that can remain clinically silent or lead to substantial cardiovascular morbidity and mortality. Although the high risk of cardiovascular pathology in patients with autoimmune inflammatory rheumatological diseases is not owing to atherosclerosis alone, this particular condition contributes substantially to cardiovascular morbidity and mortality-the degree of coronary atherosclerosis observed in patients with rheumatic diseases can be as accelerated, diffuse, and extensive as in patients with diabetes mellitus. The high risk of atherosclerosis is not solely attributable to traditional cardiovascular risk factors: dysfunctional immune responses, a hallmark of patients with rheumatic disorders, are thought to cause chronic tissue-destructive inflammation. Prompt recognition of cardiovascular abnormalities is needed for timely and appropriate management, and aggressive control of traditional risk factors remains imperative in patients with rheumatic diseases. Moreover, therapies directed towards inflammatory process are crucial to reduce cardiovascular disease morbidity and mortality. In this Review, we examine the multiple cardiovascular manifestations in patients with rheumatological disorders, their underlying pathophysiology, and available management strategies, with particular emphasis on the vascular aspects of the emerging field of 'cardiorheumatology'.

Ediacaran 2,500-km-long synchronous deep continental subduction in the West Gondwana Orogen.

The deeply eroded West Gondwana Orogen is a major continental collision zone that exposes numerous occurrences of deeply subducted rocks, such as eclogites. The position of these eclogites marks the suture zone between colliding cratons, and the age of metamorphism constrains the transition from subduction-dominated tectonics to continental collision and mountain building. Here we investigate the metamorphic conditions and age of high-pressure and ultrahigh-pressure eclogites from Mali, Togo and NE-Brazil and demonstrate that continental subduction occurred within 20 million years over at least a 2,500-km-long section of the orogen during the Ediacaran. We consider this to be the earliest evidence of large-scale deep-continental subduction and consequent appearance of Himalayan-scale mountains in the geological record. The rise and subsequent erosion of such mountains in the Late Ediacaran is perfectly timed to deliver sediments and nutrients that are thought to have been necessary for the subsequent evolution of sustainable life on Earth.

Continuous eclogite melting and variable refertilisation in upwelling heterogeneous mantle.

Large-scale tectonic processes introduce a range of crustal lithologies into the Earth's mantle. These lithologies have been implicated as sources of compositional heterogeneity in mantle-derived magmas. The model being explored here assumes the presence of widely dispersed fragments of residual eclogite (derived from recycled oceanic crust), stretched and stirred by convection in the mantle. Here we show with an experimental study that these residual eclogites continuously melt during upwelling of such heterogeneous mantle and we characterize the melting reactions and compositional changes in the residue minerals. The chemical exchange between these partial melts and more refractory peridotite leads to a variably metasomatised mantle. Re-melting of these metasomatised peridotite lithologies at given pressures and temperatures results in diverse melt compositions, which may contribute to the observed heterogeneity of oceanic basalt suites. We also show that heterogeneous upwelling mantle is subject to diverse local freezing, hybridization and carbonate-carbon-silicate redox reactions along a mantle adiabat.

Resuscitation with recombinant hemoglobin rHb2.0 in a rodent model of hemorrhagic shock.

BACKGROUND: Hemoglobin solutions combine volume effect, oxygen-carrying capacity, and vasoactive properties, the latter facilitating restoration of global hemodynamics but endangering microvascular resuscitation. Hemoglobin-evoked vasoconstriction probably is due to nitric oxide scavenging, which can be reduced by genetic modifications of the heme pocket. This study compares resuscitation with a nonhemoglobin colloid and two recombinant hemoglobin solutions with wild-type and reduced nitric oxide-scavenging capacity. METHODS: Twenty-seven awake Syrian golden hamsters fitted with dorsal skinfold chambers underwent a 30 min-hemorrhagic shock (mean arterial pressure [MAP] 30-35 mmHg) and resuscitation with shed blood volume of either 6% dextran 60 (Biophausia, Uppsala, Sweden), recombinant hemoglobin 1.1 (rHb1.1; wild-type nitric oxide-scavenging capacity; 10 g/dl), or recombinant hemoglobin 2.0 (rHb2.0; reduced nitric oxide-scavenging capacity; 10 g/dl; both Baxter Healthcare, Boulder, CO). Macrohemodynamic and laboratory parameters were assessed; microvascular parameters in the skinfold chamber were analyzed by intravital microscopy. RESULTS: Hemorrhagic shock reduced functional capillary density (FCD) by 70% and caused significant metabolic acidosis. Colloid resuscitation led to incomplete recovery of MAP and FCD. Infusion of rHb1.1 completely restored MAP but not FCD, with the smallest arteriolar diameters found in this group. FCD was restored best by resuscitation with rHb2.0, although MAP was lower than in rHb1.1-treated animals. Metabolic acidosis was resolved by both hemoglobin solutions, but not by dextran. CONCLUSION: After resuscitation with rHb1.1, arteriolar vasoconstriction quickly restored MAP, but this was achieved at the expense of FCD. In contrast, after resuscitation with rHb2.0, the recovery of MAP could be translated into a significantly improved FCD.

Oxidative stress-related increase in ubiquitination in early coronary atherogenesis.

The ubiquitin-proteasome system (UPS) is involved in the removal of damaged proteins and the activation of transcription factors, such as nuclear-factor-kappaB. Recent reports, however, questioned the functional activity of the UPS under conditions of increased oxidative stress, such as experimental hypercholesterolemia, which was the objective of our study. Pigs were placed on a normal chow diet (N) or on a hypercholesterolemic diet without (HC) or with vitamin C and E supplementation (HC+VIT) for 12 weeks. Compared with N, plasma concentration of total cholesterol increased in both HC and HC+VIT [76 +/- 21 vs. 400 +/- 148 (P<0.05) and 329 +/- 102 (P<0.05) mg/dL], whereas increase in lipid peroxidation, as assessed by LDL-malondialdehyde plasma concentration, was found in HC but not in HC+VIT [6.6 +/- 0.7 vs. 8.5 +/- 0.3 (P<0.05) and 6.8 +/- 0.7 nmol/mg protein]. In comparison with N, the level of ubiquitin conjugates in the coronary artery, as assessed by immunoblotting, increased by 42% in HC but not in HC+VIT and was localized predominantly to media vascular smooth muscle cells by immunostaining. There was no difference in proteasome proteolytic activity among the study groups. These results demonstrate that the UPS is functionally active in early atherogenesis despite increase in oxidative stress with important repercussions in the pathophysiology and therapy of cardiovascular diseases.