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British Journal of Clinical Pharmacology Jun 2024Bruton's tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of...
Cardiovascular events of Bruton's tyrosine kinase inhibitors: A real-world study based on the United States Food and Drug Administration Adverse Event Reporting System database.
AIMS
Bruton's tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs.
METHODS
Across all indications of three FDA-approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD).
RESULTS
A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13-2.93]), pulmonary oedema (ROR = 2.15 [1.19-3.88]), ventricular extrasystoles (ROR = 5.18 [2.15-12.44]), heart rate irregular (ROR = 3.05 [1.53-6.11]), angina pectoris (ROR = 3.18 [1.71-5.91]) and cardiotoxicity (ROR = 25.22 [17.14-37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications.
CONCLUSIONS
Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed.
PubMed: 38831641
DOI: 10.1111/bcp.16127 -
Cardiovascular Pathology : the Official... May 2024Constrictive pericarditis (CP) is characterised by scarring fibrosis and a loss of pericardial elasticity, which causes heart failure. IgG4 (immunoglobulin G4)-related...
AIM
Constrictive pericarditis (CP) is characterised by scarring fibrosis and a loss of pericardial elasticity, which causes heart failure. IgG4 (immunoglobulin G4)-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterised by the infiltration of IgG4-immunopositive plasmacytes and high serum IgG4 levels that frequently shape tumorous lesions. Although pericardial involvement of IgG4-RD is rare, with indications of CP, pericardial effusion and irregular masses, the clinical and pathological features remain unclear. In this study, we examined the relationship between CP and IgG4-RD.
METHODS
Among 35 thick-walled CP cases (histologically pericardial thickening ≥2 mm), eight cases were aetiology identified. Using the diagnostic criteria for IgG4-RD, 11 cases were classified as IgG4-CP, whereas the remainder were considered true idiopathic CP (16 cases) and the clinical pathological features were evaluated.
RESULTS
Compared with the other groups, the IgG4-CP group was more common in men and associated with low-grade fever and massive pericardial effusion with frequent recurrence. Deaths resulting from heart failure occurred in a few cases of the IgG4-CP group, but not in other groups. An increase in C-reactive protein and a high positivity rate of anti-nuclear antibodies frequently occurred in the IgG4-CP group. Histologically, the IgG4-CP group included lymphoid follicle, eosinophil infiltration and few calcifications.
CONCLUSIONS
Pericardial IgG4-RD occurs not only as nodular lesions, but also as thick-walled CP, and accounts for approximately 40% of thick-walled CP cases of unknown cause. The predominant clinical characteristic was refractory and recurrent pericardial effusion. Recognising IgG4-RD as a cause of CP is important to initiate appropriate therapy.
PubMed: 38825060
DOI: 10.1016/j.carpath.2024.107665 -
Optics Letters Jun 2024This investigation employs femtosecond laser-induced breakdown spectroscopy (fs-LIBS) to measure the concentrations of chromium (Cr), lead (Pb), and copper (Cu) in...
This investigation employs femtosecond laser-induced breakdown spectroscopy (fs-LIBS) to measure the concentrations of chromium (Cr), lead (Pb), and copper (Cu) in flowing aqueous solutions. The fs pulsed laser excites the water, generating plasma in a dynamic setting that prevents liquid splashing-a notable advantage over static methods. The flowing water column maintains a stable liquid level, circumventing the laser focus irregularities due to liquid-level fluctuations. Calibration curves, based on a linear function, reveal limits of detection (LODs) as low as 0.0179 μg/mL for Cr, 0.1301 μg/mL for Pb, and 0.0120 μg/mL for Cu. The reliability of the experiment is confirmed by R values exceeding 0.99. These findings offer valuable insights for the analysis of trace heavy metals in flowing aqueous solutions using fs-LIBS, demonstrating the technique's potential for environmental monitoring.
PubMed: 38824339
DOI: 10.1364/OL.526093 -
Heliyon May 2024Postoperative atrial fibrillation (POAF) is considered the most prevalent irregular heart rhythm after heart surgery. The cardiac autonomic nervous system significantly...
BACKGROUND AND AIMS
Postoperative atrial fibrillation (POAF) is considered the most prevalent irregular heart rhythm after heart surgery. The cardiac autonomic nervous system significantly affects POAF, and neuropeptide Y (NPY), an abundant neuropeptide in the cardiovascular system, is involved in this autonomic regulation. The current work aimed to examine the potential association of NPY with POAF in individuals administered isolated off-pump coronary artery bypass grafting.
METHODS
From January 1 to May 31, 2020, we examined consecutive cases administered successful isolated off-pump coronary artery bypass grafting with no previously diagnosed atrial fibrillation (AF). Clinical characteristics and plasma samples were collected before surgery. NPY was quantified by enzyme-linked immunosorbent assay (ELISA) in peripheral blood, and POAF cases were identified through a 7-day Holter monitoring.
RESULTS
Among 120 cases with no previously diagnosed AF, 33 (27.5 %) developed POAF during hospitalization. Median NPY levels were markedly elevated in the POAF group in comparison with the sinus rhythm group (31.72 vs. 27.95, P = 0.014). Multivariable logistic regression analysis revealed age (OR = 1.135, 95%CI 1.054-1.223; P = 0.001), left atrial size (OR = 1.136, 95%CI 1.004-1.285; P = 0.043), and NPY levels in peripheral blood (OR = 1.055, 95%CI 1.002-1.111; p = 0.041) independently predicted POAF. Additionally, NPY levels were positively correlated with high-frequency (HF) (r = 0.2774, P = 0.0022) and low-frequency (LF) (r = 0.2095, P = 0.0217) components of heart rate variability.
CONCLUSION
In summary, this study demonstrates an association between elevated NPY levels in peripheral blood before surgery and POAF occurrence.
PubMed: 38803941
DOI: 10.1016/j.heliyon.2024.e31251 -
Nature Communications May 2024The conformational dynamics of nucleosome arrays generate a diverse spectrum of microscopic states, posing challenges to their structural determination. Leveraging...
The conformational dynamics of nucleosome arrays generate a diverse spectrum of microscopic states, posing challenges to their structural determination. Leveraging cryogenic electron tomography (cryo-ET), we determine the three-dimensional (3D) structures of individual mononucleosomes and arrays comprising di-, tri-, and tetranucleosomes. By slowing the rate of condensation through a reduction in ionic strength, we probe the intra-array structural transitions that precede inter-array interactions and liquid droplet formation. Under these conditions, the arrays exhibite irregular zig-zag conformations with loose packing. Increasing the ionic strength promoted intra-array compaction, yet we do not observe the previously reported regular 30-nanometer fibers. Interestingly, the presence of H1 do not induce array compaction; instead, one-third of the arrays display nucleosomes invaded by foreign DNA, suggesting an alternative role for H1 in chromatin network construction. We also find that the crucial parameter determining the structure adopted by chromatin arrays is the angle between the entry and exit of the DNA and the corresponding tangents to the nucleosomal disc. Our results provide insights into the initial stages of intra-array compaction, a critical precursor to condensation in the regulation of chromatin organization.
Topics: Nucleosomes; Electron Microscope Tomography; DNA; Cryoelectron Microscopy; Nucleic Acid Conformation; Chromatin; Histones; Osmolar Concentration; Animals
PubMed: 38782894
DOI: 10.1038/s41467-024-48305-1 -
Journal of Biochemical and Molecular... May 2024According to the pathophysiological mechanisms linking particulate matter (PM) exposure and cardiovascular diseases, PM may directly translocate into the blood stream...
PM toxicity in blood impairs cardiac redox balance and promotes mitochondrial dysfunction in rat heart that further aggravates ischemia reperfusion injury by modulating PI3K/AKT/mTOR/NF-kB signaling axis.
According to the pathophysiological mechanisms linking particulate matter (PM) exposure and cardiovascular diseases, PM may directly translocate into the blood stream and remote target organs and thereby induce cardiovascular effects. The toxicity of PM is known to induce oxidative stress in pulmonary tissue, but its impact on the redox state in heart (distant organ) is unknown and how it modulates the cardiac response to ischemia reperfusion (IR) remains unclear. In the present study, we evaluated the toxic effect of PM on cardiac physiology in the presence and absence of IR after introducing PM into the blood. Female Wistar rats were injected with diesel particulate matter (DPM) via i.p & i.v routes at a concentration of 10 µg/ml. The toxic impact of PM not only adversely affects the cardiac ultra-structure (leading to nuclear infiltration, edema, irregularities in heart muscle and nuclear infiltration), but also altered the cellular redox balance, elevated inflammation and promoted the upregulation of proapoptotic mediator genes at the basal level of myocardium. The results showed alterations in cardiac ultrastructure, elevated oxidative stress and significant redox imbalance, increased inflammation and proapoptotic mediators at the basal level of myocardium. Moreover, the cardioprotective pro survival signaling axis was declined along with an increased NF-kB activation at the basal level. IR inflicted further injury with deterioration of cardiac hemodynamic indices (Heart rate [HR], Left ventricular developed pressure [LVDP], Left ventricular end-diastolic pressure [LVEDP] and rate pressure product [RPP]) along with prominent inactivation of signaling pathways. Furthermore, the levels of GSH/GSSG, NADH/NAD, NADPH/NADP were significantly low along with increased lipid peroxidation in mitochondria of PM treated IR rat hearts. This observation was supported by downregulation of glutaredoxin and peroxiredoxin genes in the myocardium. Similarly the presence of oxidative stress inducing metals was found at a higher concentration in cardiac mitochondria. Thus, the toxic impact of PM2.5 in heart augment the IR associated pathological changes by altering the physiological response, initiating cellular metabolic alterations in mitochondria and modifying the signaling molecules.
Topics: Animals; Female; Rats; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Particulate Matter; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Wistar; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 38738849
DOI: 10.1002/jbt.23718 -
European Journal of Applied Physiology May 2024Moderate-intensity aerobic exercise is safe and beneficial in atrial fibrillation (AF) and coronary heart disease (CHD). Irregular or rapid heart rates (HR) in AF and...
PURPOSE
Moderate-intensity aerobic exercise is safe and beneficial in atrial fibrillation (AF) and coronary heart disease (CHD). Irregular or rapid heart rates (HR) in AF and other heart conditions create a challenge to using HR to monitor exercise intensity. The purpose of this study was to assess the potential of breathing frequency (BF) to monitor exercise intensity in people with AF and CHD without AF.
METHODS
This observational study included 30 AF participants (19 Male, 70.7 ± 8.7 yrs) and 67 non-AF CHD participants (38 Male, 56.9 ± 11.4 yrs). All performed an incremental maximal exercise test with pulmonary gas exchange.
RESULTS
Peak aerobic power in AF ( Opeak; 17.8 ± 5.0 ml.kg.min) was lower than in CHD (26.7 ml.kg.min) (p < .001). BF responses in AF and CHD were similar (BF peak: AF 34.6 ± 5.4 and CHD 36.5 ± 5.0 breaths.min; p = .106); at the 1st ventilatory threshold (BF@VT-1: AF 23.2 ± 4.6; CHD 22.4 ± 4.6 breaths.min; p = .240). % Opeak at VT-1 were similar in AF and CHD (AF: 59%; CHD: 57%; p = .656).
CONCLUSION
With the use of wearable technologies on the rise, that now include BF, this first study provides an encouraging potential for BF to be used in AF and CHD. As the supporting data are based on incremental ramp protocol results, further research is required to assess BF validity to manage exercise intensity during longer bouts of exercise.
PubMed: 38703192
DOI: 10.1007/s00421-024-05487-2 -
Aquatic Toxicology (Amsterdam,... Jun 2024Ammonia is a respiratory gas that is produced during the process of protein deamination. In the unionised form (NH), it readily crosses biological membranes and is...
Ammonia is a respiratory gas that is produced during the process of protein deamination. In the unionised form (NH), it readily crosses biological membranes and is highly toxic to fish. In the present study we examined the effects of unionized ammonia (UIA), on the resting oxygen consumption (MO), ventilation frequency (f), heart rate (HR) and heart rate variability (HRV) in Nile tilapia (Oreochromis niloticus). Fish were either exposed to progressively increasing UIA concentrations, up to 97 µM over a 5 h period, or to a constant UIA level of 7 µM over a 24 h period. For both treatment groups resting MO, HR and f were recorded as physiological variables. Relative to the control group, the fish groups exposed to the incremental UIA levels did not exhibit significant changes in their MO, HR and f at UIA concentrations of 4, 10, 35, or 61 µM compared to control fish. Exposure to 97 µM UIA, however, elicited abrupt and significant downregulations (p < 0.05) in all three responses, as MO, HR and fv decreased by 25, 54 and 76 % respectively, compared to control measurements. Heart rate became increasingly irregular with increasing UIA concentrations, and heart rate variability was significantly increased at 61 and 97 µM UIA. Prolonged exposure elicited significant changes at exposure 7 µM UIA. Standard (SMR) and maximum metabolic rate (MMR) were significantly reduced, as was the corresponding f and HR. It is evident from this study that Nile tilapia is tolerant to short term exposure to UIA up to 61 µM but experience a significant metabolic change under conditions of prolonged UIA exposures even at low concentrations.
Topics: Animals; Ammonia; Heart Rate; Cichlids; Water Pollutants, Chemical; Oxygen Consumption
PubMed: 38692129
DOI: 10.1016/j.aquatox.2024.106932 -
Cureus Mar 2024Cardiac autonomic neuropathy (CAN) is a disorder affecting the autonomic nerves that regulate the cardiovascular system, leading to irregular heart rate and blood...
INTRODUCTION
Cardiac autonomic neuropathy (CAN) is a disorder affecting the autonomic nerves that regulate the cardiovascular system, leading to irregular heart rate and blood pressure control. It is commonly associated with diabetes mellitus but can also result from other conditions such as autoimmune disorders, chronic kidney disease, alcohol abuse, and certain medications. Screening for CAN is essential, particularly in individuals with poor glycemic control, cardiovascular risk factors, or complications. Early identification of CAN is vital for timely intervention to prevent or manage cardiovascular complications effectively. Regular screening helps detect CAN before symptoms emerge, enabling early intervention to slow or halt its progression. This study examined the relationship between sudomotor function and cardiovascular reflex tests.
MATERIAL AND METHODS
This was a cross-sectional study conducted between June 2019 and June 2020. The study included 271 subjects aged 18 years and above who provided informed consent, were diagnosed with type 2 diabetes mellitus (T2DM), and were overweight or obese. Exclusion criteria encompassed patients with other types of diabetes, pregnant women, those with recent neoplasm diagnoses, stroke sequelae, history of myocardial infarction, or pelvic limb amputations. The assessment of cardiac autonomic neuropathy involved conducting an electrocardiogram and evaluating the QTc interval in the morning before taking medication. Additionally, cardiovascular reflex tests (CART) were conducted, including assessments of heart rate variability during deep breathing, the Valsalva maneuver, and changes in orthostatic position. Simultaneously, the diagnosis of CAN was assessed by performing a sweat test using a Sudoscan assessment (Impeto Medical, Moulineaux, France). Results: More than half of the participants (52%, n=143) were female. Significant differences in statistical measures were noted between females and males regarding age, systolic blood pressure, fasting blood glucose, A1c level, total cholesterol, triglycerides, gamma-glutamyl transferase, and bilirubin levels. Within the CAN-diagnosed group (CAN+), 40.92% were classified as mild cases (n=90), 47.27% as moderate cases (n=104), and 11.81% as severe cases (n=26). Among the CAN+ group, 54% (n=119) were women. Electrochemical skin conductance was lower in the CAN+ group than the CAN- group in hands (67.34±15.51 μS versus 72.38±12.12 μS, p=0.008) and feet (73.37±13.38 μS versus 82.84 ±10.29 μS, p<0.001). The Sudoscan-CAN score significantly correlated with Ewing scores (r= 0.522, p<0.001). In multiple linear regression analysis, the Sudoscan-CAN score remained significantly associated with age, high BMI, long-standing diabetes, and Ewing score.
CONCLUSIONS
Sudoscan demonstrates potential in identifying patients with an increased risk of CAN. Its integration into clinical practice can improve patient outcomes through early detection, risk stratification, and personalized treatment approaches. Its non-invasive, portable, and user-friendly features render it suitable for utilization in outreach programs or resource-constrained settings as part of screening efforts designed to pinpoint high-risk individuals for additional assessment.
PubMed: 38686272
DOI: 10.7759/cureus.57226 -
BMC Veterinary Research Apr 2024Ventricular bigeminy due to myocardial ischemia has been reported in humans as well as in canine patients with obstructive gastrointestinal diseases. This is the first...
BACKGROUND
Ventricular bigeminy due to myocardial ischemia has been reported in humans as well as in canine patients with obstructive gastrointestinal diseases. This is the first case report of ventricular bigeminy in a dog with a colonic torsion that resolved after fluid resuscitation and restoration of myocardial perfusion.
CASE PRESENTATION
An 11-year-old, male neutered mixed breed dog presented with a one day history of vomiting, tenesmus, and lethargy. Physical examination identified an irregular heart rhythm and intermittent pulse deficits. A ventricular arrhythmia represented by ventricular premature complexes (VPCs) organized in bigeminy, was appreciated on a 3-lead electrocardiogram (ECG) with a single lead (II) view. Abdominal radiographs confirmed a colonic torsion. Prior to anesthetic induction, ventricular bigeminy was non responsive to fentanyl or lidocaine. The patient was anesthetized and intravascular volume deficit was identified by dampened plethysmographic wave amplitude (plethysomographic variability), audible softening of the Doppler sound, and more pronounced pulse deficits. Fluid resuscitation was achieved with a combination of intravenous crystalloid and colloid fluid therapy comprising 7.2% hypertonic saline and 6% hetastarch. The patient's cardiac rhythm converted to normal sinus after fluid resuscitation. The colonic torsion was surgically corrected. The patient recovered well from anesthesia and was ultimately discharged from the hospital 5 days later.
CONCLUSIONS
The present case report highlights that myocardial ischemia can lead to ventricular arrythmias, such as ventricular bigeminy. This is the first documented case of ventricular bigeminy in the canine patient with a colonic torsion. Assessment of patient volume status and appropriate fluid resuscitation along with continuous electrocardiogram (ECG) monitoring are vital to patient stability under general anesthesia.
Topics: Dogs; Animals; Male; Dog Diseases; Fluid Therapy; Myocardial Ischemia; Colonic Diseases; Electrocardiography; Ventricular Premature Complexes; Torsion Abnormality
PubMed: 38671452
DOI: 10.1186/s12917-024-04001-2