Three-year cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia or small cell lymphocytic lymphoma treated with Bruton tyrosine kinase inhibitors acalabrutinib or ibrutinib: a real-world analysis.

Bruton tyrosine kinase (BTK) inhibitors play an important role in targeted treatment of B-cell lymphoproliferative disorders. However, adverse events may limit the proper course of treatment in many patients. The purpose of this study is to compare the risk of cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia (CLL) or small cell lymphocytic lymphoma (SLL) treated with the first-generation BTK inhibitor ibrutinib versus second-generation acalabrutinib, using real-world data from a collaborative multinational network. We used data from the network (TriNetX), which encompasses more than 100 healthcare organizations worldwide. We queried the database for patients aged ≥ 18 years with chronic lymphocytic leukemia or small-cell lymphomas treated with ibrutinib or acalabrutinib in the past ten years before the analysis. We used propensity score matching to balance the cohorts. The 3-year cumulative incidences and hazard ratios for the following outcomes were calculated: atrial flutter or fibrillation, other arrhythmias, heart failure, ischemic stroke or peripheral embolism, acute coronary syndrome, bleeding, and sepsis. We compared 2,107 patients in each group. Atrial fibrillation or flutter occurred in 150 (7.1%) patients with acalabrutinib and 310 (14.7%) patients with ibrutinib during the 3-year follow-up (hazard ratio, 0.68, 95% CI 0.55-0.84). New-onset hypertension occurred in 342 (16.3%) patients in the acalabrutinib group and 584 (27.7%) patients in the ibrutinib group (hazard ratio 0.81, 95% CI 0.66-0.98). Sepsis was diagnosed in 136 (6.5%) patients in the acalabrutinib group versus 239 (11.3%) patients in the ibrutinib group (hazard ratio 0.77, 95 CI 0.60-0.98). The two groups had no significant differences concerning the other adverse events. In a large retrospective cohort using real-world data from electronic medical registers, patients with CLL or SLL treated with acalabrutinib had a better cardiovascular and non-cardiovascular safety profile than those treated with ibrutinib, with lower risks of atrial flutter or fibrillation, new-onset arterial hypertension, and sepsis.

Five-year cardiovascular outcomes in patients with chronic myeloid leukemia treated with imatinib, dasatinib, or nilotinib: A cohort study using data from a large multinational collaborative network.

Background: Breakpoint cluster region-Abelson gene (BCR-ABL) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, concern has arisen about the cardiac safety profile of these drugs. Objectives: This study aims to compare long-term risks of adverse cardiovascular and cerebrovascular events (ACE), heart failure or left ventricular ejection fraction (LVEF) < 50%, and venous thromboembolic events (VTE) in patients with CML treated with BCR-ABL TKIs, using data from a large multinational network. Methods: Patients aged ≥ 18 years with CML treated with imatinib, dasatinib, or nilotinib without prior cardiovascular or cerebrovascular disease were included. We used propensity score matching to balance the cohorts. The 5-year cumulative incidences and hazard ratios were calculated. Results: We identified 3,722 patients with CML under treatment with imatinib (n = 1,906), dasatinib (n = 1,269), and nilotinib (n = 547). Patients with imatinib compared to dasatinib showed a higher hazard ratio (HR) for ACE (HR 2,13, 95% CI 1.15-3.94, p = 0.016). Patients with imatinib presented a lower HR than nilotinib for ACE (HR 0.50, 95% CI 0.30-0.83, p = 0.0074). In relation to heart failure or LVEF < 50%, patients with imatinib had a higher HR than dasatinib (HR 9.41, 95% CI 1.22-72.17, p = 0.03), but no significant difference was observed between imatinib and nilotinib (HR 0.48, 95% CI 0.215-1.01, p = 0.064). Conclusion: In this retrospective study with a large number of patients with CML, those treated with nilotinib had a higher 5-year ratio of ACE, while patients with dasatinib showed a lower ratio than patients with imatinib. The ratio of heart failure was higher in patients with imatinib than in patients with dasatinib, but not when compared to nilotinib.

Percutaneous coronary intervention or medical therapy in patients with severe aortic stenosis and coronary artery disease undergoing transcatheter aortic valve implantation: a real-world analysis using data from an international network.

Patients undergoing transcatheter aortic valve implantation (TAVI) due to severe aortic stenosis have a high prevalence of coronary artery disease (CAD). As many of them have high surgical risk, CAD treatment in this group has typically been carried out with optimal medical treatment or paired with percutaneous coronary intervention (PCI). However, the best approach in this scenario is not well established. We aimed to evaluate 5-year cardiovascular outcomes in patients with aortic stenosis and chronic CAD treated with medical treatment alone compared to PCI coupled with medical therapy before or during TAVI. We used data from a large multinational electronic health record network (TriNetX). Patients aged 18 years or older with severe aortic stenosis and CAD who underwent TAVI in the last 10 years before the analysis were considered eligible. Five-year Kaplan-Meier curves and hazard ratios were calculated. We identified 19 058 patients undergoing isolated TAVI and 2277 patients undergoing TAVI and PCI. Using propensity matching scores, 2277 patients in each group were compared. The 5-year cumulative incidence of MACE was 22.92% in the isolated TAVI group, vs. 25.91% in the PCI-TAVI group. The probability of the composite primary outcome was not significantly different between the isolated TAVI group vs. the PCI-TAVI group [53.1 vs. 47.6%, adjusted hazard ratio (HR) 0.92, 95% confidence interval (CI), 0.80-1.05]. In a real-world study of patients with CAD and severe aortic stenosis, the 5-year probability of death, acute coronary syndrome and ischemic stroke did not differ between patients undergoing isolated TAVI compared to patients undergoing PCI before or during TAVI.

Cardiopulmonary Resuscitation in Prone Position

Abstract Mechanical ventilation in prone position is an alternative strategy for patients with acute respiratory discomfort syndrome (ARDS) to improve oxygenation in situations when traditional ventilation modalities have failed. However, due to the significant increase in ARDS cases during the SARS-CoV-2 pandemic and the experimental therapeutic use of potentially arrhythmogenic drugs, cardiopulmonary resuscitation in this unusual position could be needed. Therefore, we will review the available scientific evidence of cardiopulmonary resuscitation in prone position.

Genetic associations of bradykinin type 2 receptor, alpha-adrenoceptors and endothelial nitric oxide synthase with blood pressure and left ventricular mass in outpatients without overt heart disease.

BACKGROUND: Physiological pathways such as bradykinin, renin-angiotensin, neurohormones and nitric oxide have been shown to play an important role in the regulation of cardiovascular function. Genetic variants of these pathways may impact blood pressure and left ventricular (LV) mass in different populations. To evaluate associations of genetic polymorphisms of bradykinin B2 receptor (BDKRB2), alpha-adrenergic receptors (ADRA) and endothelial nitric oxide synthase (eNOS) on the modulation of the blood pressure and the left ventricular mass. METHODS: We enrolled 758 individuals without overt heart disease. Blood pressure was estimated by auscultatory method during the clinical examination. Left ventricular (LV) mass was assessed by echocardiography. Genotypes for ADRA1A rs1048101, ADRA2A rs553668, ADRA2B rs28365031, eNOS rs2070744, eNOS rs1799983, and BDKRB2 rs5810761 polymorphisms were assessed by high-resolution melting analysis. RESULTS: BDKRB2 polymorphism rs5810761 was associated with blood pressure. Carriers of DD genotype had higher levels of SBP and DBP than carrier of II genotype (p = 0.013 and p = 0.007, respectively). eNOS polymorphism rs1799983 was associated with DBP. Carriers of GT genotype had lower levels of DBP than carriers of GG genotype (p = 0.018). eNOS polymorphism rs2070744 was associated with LV mass. Carriers of TC genotype had higher LV mass than carriers of TT genotype (p = 0.028). CONCLUSIONS: In a cohort of individuals without overt heart disease, the BDKRB2 rs5810761 polymorphism (DD genotype carriers) were associated higher systolic and diastolic blood pressures, and the eNOS rs1799983 polymorphism (T allele carriers) were associated with lower diastolic blood pressure. The eNOS rs2070744 polymorphism (C allele carriers) was associated with higher left ventricular mass. These data suggest that eNOS and bradykinin receptor genetic variants may be potential markers of common cardiovascular phenotypes.

Gender-related associations of genetic polymorphisms of α-adrenergic receptors, endothelial nitric oxide synthase and bradykinin B2 receptor with treadmill exercise test responses.

BACKGROUND: Treadmill exercise test responses have been associated with cardiovascular prognosis in individuals without overt heart disease. Neurohumoral and nitric oxide responses may influence cardiovascular performance during exercise testing. Therefore, we evaluated associations between functional genetic polymorphisms of α-adrenergic receptors, endothelial nitric oxide synthase, bradykinin receptor B2 and treadmill exercise test responses in men and women without overt heart disease. METHODS: We enrolled 766 (417 women; 349 men) individuals without established heart disease from a check-up programme at the Heart Institute, University of São Paulo Medical School. Exercise capacity, chronotropic reserve, maximum heart-rate achieved, heart-rate recovery, exercise systolic blood pressure (SBP), exercise diastolic blood pressure (DBP) and SBP recovery were assessed during exercise testing. Genotypes for the α-adrenergic receptors ADRA1A Arg347Cys (rs1048101), ADRA2A 1780 C>T (rs553668), ADRA2B Del 301-303 (rs28365031), endothelial nitric synthase (eNOS) 786 T>C (rs2070744), eNOS Glu298Asp (rs1799983) and BK2R (rs5810761) polymorphisms were assessed by PCR and high-resolution melting analysis. RESULTS: Maximum SBP was associated with ADRA1A rs1048101 (p=0.008) and BK2R rs5810761 (p=0.008) polymorphisms in men and ADRA2A rs553668 (p=0.008) and ADRA2B rs28365031 (p=0.022) in women. Maximum DBP pressure was associated with ADRA2A rs553668 (p=0.002) and eNOS rs1799983 (p=0.015) polymorphisms in women. Exercise capacity was associated with eNOS rs2070744 polymorphisms in women (p=0.01) and with eNOS rs1799983 in men and women (p=0.038 and p=0.024). CONCLUSIONS: The findings suggest that genetic variants of α-adrenergic receptors and bradykinin B2 receptor may be involved with blood pressure responses during exercise tests. Genetic variants of endothelial nitric oxide synthase may be involved with exercise capacity and blood pressure responses during exercise tests. These responses may be gender-related.

Exercise-induced muscle vasodilatation and treadmill exercise test responses in individuals without overt heart disease.

BACKGROUND: The beneficial effects of exercise on cardiovascular health may be related to the improvement in several physiologic pathways, including peripheral vascular function. The aim of this study was to evaluate the relationship between cardiovascular responses during the treadmill exercise test and exercise-induced muscle vasodilatation in individuals without overt heart disease. METHODS: The study included 796 asymptomatic subjects (431 females and 365 males) without overt heart disease. We evaluated the heart rate (chronotropic reserve and heart rate recovery), blood pressure (maximum systolic and diastolic blood pressure as well as systolic blood pressure recovery) and exercise capacity during symptom-limited treadmill exercise testing. Exercise-induced muscle vasodilatation was studied with venous occlusion plethysmography and estimated by forearm blood flow and vascular conductance responses during a 3-min handgrip maneuver. RESULTS: Forearm blood flow increase during the handgrip exercise was positively associated with heart rate recovery during treadmill exercise testing (p < 0.001). Forearm vascular conductance increase during the handgrip exercise was inversely associated with exercise diastolic blood pressure during exercise treadmill testing (p = 0.038). No significant association was found between exercise capacity and exercise-induced muscle vasodilation. CONCLUSION: In a sample of individuals without overt heart disease, exercise-induced muscle vasodilatation was associated with heart rate and blood pressure responses during treadmill exercise testing, but was not associated with exercise capacity. These findings suggest that favorable hemodynamic and chronotropic responses are associated with better vasodilator capacity, but exercise capacity does not predict muscle vasodilatation.

High-sensitivity C-reactive protein levels and treadmill exercise test responses in men and women without overt heart disease.

BACKGROUND: C-reactive protein (CRP) is a marker of systemic inflammatory activity and may be modulated by physical fitness. Treadmill exercise testing is used to evaluate cardiovascular health through different variables including exercise capacity, heart rate and blood pressure responses. It was hypothesized that CRP levels are associated with these variables in men and women without overt heart disease. METHODS: A total of 584 asymptomatic subjects (317 [54.3%] women and 267 [45.7%] men) were enrolled in the present study and underwent clinical evaluation. CRP levels in men and women were examined relative to clinical characteristics and to variables of treadmill exercise testing: peak heart rate, exercise systolic blood pressure, exercise time, chronotropic reserve and heart rate recovery at the first and second minutes after exercise. Multivariate analysis was performed using a log-linear regression model. RESULTS: In women, exercise time on the treadmill exercise test (P=0.009) and high-density lipoprotein cholesterol levels (P=0.002) were inversely associated with CRP levels. Body mass index (P<0.001) and total cholesterol levels (P=0.005) were positively associated with CRP levels. In men, exercise time on the treadmill exercise test was inversely associated with CRP levels (P=0.015). Body mass index (P=0.001) and leukocyte count (P=0.002) were positively associated with CRP levels. CRP levels were not associated with peak heart rate, chronotropic reserve, heart rate recovery at the first and second minutes, or exercise systolic blood pressure. CONCLUSIONS: These findings contribute to the evidence that CRP is lower in individuals with better exercise capacity and demonstrate that this relationship is also apparent in individuals without overt heart disease undergoing cardiovascular evaluation through the treadmill exercise test. Lowering inflammatory markers may be an additional reason to stimulate sedentary individuals with low exercise capacity in the treadmill exercise test to improve physical conditioning through regular exercise.