Adverse Cardiovascular Effects Research Articles

Acute electrophysiological effects of energy drink, energy gum and coffee: a double-blind randomized placebo-controlled crossover study

Abstract Background Energy drink consumption is highly prevalent in young adults, especially in males, and has been associated with adverse cardiovascular events, including QT prolongation and atherothrombosis. A proposed mechanism underlying these adverse cardiovascular effects is caffeine, but this has not been systematically evaluated. Therefore, the purpose of this study was to compare the acute electrophysiological effects of energy drink consumption with other forms of caffeine consumption in young males. Methods We performed a randomized, double-blind, placebo-controlled, crossover study in 16 young healthy males. Each participant underwent electrocardiography assessment at pre- and post-treatment (1-hour and 2-hours) in response to 4 beverage and gum combinations: 1) energy drink + placebo gum (ED); 2) coffee + placebo gum (C); 3) placebo beverage + caffeinated energy gum (EG); and 4) placebo beverage + placebo gum (P). Caffeine content was the same in all treatment combinations and a washout period of at least 1-week was allowed among treatments. Results At 1-hour post-treatment, heart rate increased in response to ED while it decreased in response to EG (p<0.05 for ED vs. EG; Figure 1A). At 2-hours post-treatment, the increase in heart rate after ED and Coffee was significantly greater compared to the change in heart rate in response to the other treatments (p<0.05). The increase in QRS duration 1-hour post-treatment was significantly greater after ED compared to EG and Placebo (p <0.05). Corrected QT (QTc) duration was significantly reduced at 1-hour post-treatment in response to EG vs. ED (p<0.05), but was not different compared to the other treatments. At 2-hours post-treatment, QTc duration was significantly reduced in response to EG and was increased in response to Coffee (p < 0.05 for EG vs. ED and C, Figure 1C). The most prominent increase from baseline in the percentage of participants experiencing ventricular ectopy was in response to ED (Figure 1D). Conclusions The acute electrophysiological effects of energy drink, energy gum and coffee do not appear to be mediated by caffeine content. Further investigations are warranted to better understand the cardiovascular effects of these caffeinated products.

Abstract 15188: Mid-Cavity Takotsubo Cardiomyopathy Post CAR T-cell Therapy

Introduction: CAR T-cell therapy has been reported to have cardiovascular (CV) adverse effects mostly in context of cytokine reconstitution syndrome (CRS). Although pathophysiology of CAR T-cell cardiotoxicity (CTCC) is not fully understood, it is thought to be IL-6 mediated which has been implicated as a mediator of myocardial depression in infectious and inflammatory states. Another mechanism is direct cardiotoxicity from potential cross-reactivity with unrelated peptides expressed by normal tissue. We present a case of Takotsubo cardiomyopathy following CAR T cells. Case: 61 year old male with h/o Waldenstrom's macroglobulinemia, DMT2, HLD was admitted for CAR T cell therapy. Following infusion, he developed chills, diaphoresis, tachypnea, tachycardia, chest tightness lasting several hours. EKG had dynamic ST depressions in inferolateral leads with elevated hstroponin (6000 pg/ml). Despite severe pancytopenia, heparin was started for acute coronary syndrome. Pain resolved with morphine and he received tocilizumab for CRS. Echo showed a mid-cavitary variant of Takotsubo involving right and left ventricles with depressed systolic function (LVEF 30-35%; Image). Coronary angiogram was deferred due to bleeding risk. Repeat echo in 2 days showed persistent mid-cavity hypokinesis with slight improvement in LVEF (40%) after initiating beta blocker. The temporal relation of acute mid-cavity dysfunction to CAR T-cells indicates most likely CTCC. Heparin was stopped and he was managed conservatively with plan to reassess LVEF in 2 months. Conclusion: Patients undergoing CAR T-cell therapy should be assessed for CV symptoms using biomarkers and imaging for early detection of cardiotoxicity and prompt initiation of supportive treatment. We present a case of acute mid-cavity left ventricular dysfunction (a Tako-tsubo variant) that was temporally related to CAR T cell infusion. Further studies are needed to determine the frequency of this acute form of CTCC.

Abstract 15693: Weekend Sleep Extension (Catch-up Sleep) is Associated With Lower Incidence of Coronary Calcium Score: The Elsa-Brasil Study

Background: Insufficient sleep is a worldwide public health problem with potential cardiovascular consequences. Therefore, strategies aiming at improving sleep patterns are highly desired. Cross-sectional studies showed that weekend sleep extension (catch-up sleep) is associated with better glucose metabolism and cognitive function profiles, but longitudinal studies are lacking. Hypothesis: Catch-up sleep may have protective effects on subclinical atherosclerosis. Methods: In this prospective cohort study, we performed a 7-days wrist actigraphy for monitoring sleep duration and a sleep study to detect sleep apnea. Catch-up-sleep was measured by calculating weekend sleep duration (Friday-Saturday nights) minus weekday sleep duration (Sunday-Thursday nights). Coronary artery calcium, CAC (64-slice multi-detector computed tomography) was measured at two different time points throughout the study (baseline, between 2010-2014, and follow-up, between 2016-2018). Incidence of subclinical atherosclerosis was defined as baseline CAC=0 followed by CAC>0 at a 5-year follow-up visit. The association of incident CAC outcome was assessed using logistic regression adjusting for age, sex, race, body mass index, hypertension, diabetes mellitus, smoking, low- and high-density lipoprotein, use of statin, sleep apnea and interscan period). Analysis of incidence was Inverse probability censoring weighted. Results: We analyzed 1,832 participants with available CAC scores at baseline (age: 48.8±8.0years; 57.8% women; 32.1% with sleep apnea). The mean sleep duration was 6.6±1.0 hours. Catch-up-sleep >90 minutes was observed in 28.0%. Incidence of CAC was 27/141 (19.1%) among subjects with catch-up-sleep >90 minutes and 326/1029 (31.7%) among those with catch-up-sleep ≤90 minutes (P<0.001). In covariate-adjusted analyses (n=1,170, follow-up=5.4±0.90 years), we found a lower incidence of CAC in those participants with weekend sleep extension >90 minutes (OR=0.62; 95% CI 0.52-0.74). Conclusion: Catch-up sleep is independently associated with a lower incidence of CAC. These results underscore that catch-up sleep may mitigate the adverse cardiovascular effects of weekdays sleep restrictions frequently observed in our Society.

Abstract 12391: Correlation of Admission Heart Rate With MACE Among ST-segment Elevation Myocardial Infarction Patients (killip1) Undergoing Primary Percutaneous Coronary Intervention

Introduction: Different admission heart rate (AHR) levels are frequently observed in ST-segment elevation myocardial infarction (STEMI) patients. However, it is not clear whether AHR is related to the occurrence of major adverse cardiovascular effects (MACE) after pPCI. Hypothesis: We aim to explore the possible correlation between AHR and MACE after STEMI patients receive the primary percutaneous coronary intervention (pPCI). Methods: The Chinese STEMI pPCI Registry was registered with ClinicalTrials.gov (NCT04996901). We analyzed 5586 patients with STEMI who underwent pPCI in a multi-center study in China, and patients were grouped according to the AHR greater or less than 70 bpm. Patients’ in-hospital MACE referred to new-onset heart failure and death. The association between AHR and in-hospital MACE was assessed in Logistic regression analysis. Results: 4004 patients were enrolled ultimately, including 1105 patients with AHR< 70 bpm and 2899 patients with AHR≥ 70 bpm. After multivariate adjustment for age, gender, DBP, HR, smoking, hypertension, et al., the OR of MACE in patients with AHR ≥ 70 bpm was 1.573-1.581 times that of the other group in calibration Model I to IV. Subgroup analysis showed that it was also observed in the young (<60 years old) or the old (≥60 years old), male or female, Left anterior descending (LAD), and Right circumflex artery (RCA) patients (all P <0.05). We still found that AHR was a risk factor for in-hospital MACE after excluding those patients with a history of MACE, RCA occlusion and AHR less than 50 bpm or greater than 90 bpm in sensitivity analysis. ROC curve of AHR in predicting the occurrence of MACE after pPCI was 0.699. The cubic spline also confirmed that the risk of MACE decreased significantly with the reduction of AHR. Conclusions: In STEMI patients undergoing pPCI, elevated AHR (≥70 bpm) identifies those at increased risk of in-hospital MACE. AHR less than 70 bpm may be a protective factor to avoid the occurrence of MACE.

Abstract 16081: Cardiovascular Outcomes of Individuals With Sleep Deprivation; a Retrospective Population-Based Analysis

Introduction: Inadequate sleep quality and duration have been linked to adverse cardiovascular effects. Examining the cardiovascular outcome profile of the inpatient population with sleep deprivation (SD) has been relatively scarce. We aimed to study the outcomes in this setting. Hypothesis: We hypothesize that SD is associated with adverse cardiovascular outcomes, and studying the effect will help inform clinical care and prevention strategies. Methods: We used the ICD-10 code to identify all hospitalizations aged 18-85 with a primary or secondary SD diagnosis from the Nationwide Inpatient Database (NIS) 2016-2020. We excluded individuals with sleep apnea and those with established SD due to medical or psychiatric illnesses. A multivariate logistic regression model was used to account for confounders (including demography, smoking history, hospital setting, and insurance type) and estimate the probability of outcomes. Our outcomes of interest were hypertension (HTN), dyslipidemia (DysL), and obesity. Results: There were 27,294,891 hospitalizations aged 18-85 during the study period, and 2.6% (718,083) had a sleep deprivation diagnosis, mean age of 57.7 years ± 17. Of these, 74.8% (519497) were Caucasians, 12.1% (84463) were Blacks, and 8.1% (56316) were Hispanics. Individuals with SD had a higher likelihood of HTN, adjusted odds ratio (aOR) =1.28 (1.27-1.30, p<0.0001), DysL 1.3 (1.2-1.3, p<0.0001), and obesity 1.02 (1.01-1.02, p<0.0001). Conclusions: Our analysis showed that sleep deprivation was associated with a higher likelihood of hypertension, dyslipidemia, and obesity. Encouraging lifestyle modification, including adequate sleep hygiene, cannot be overstated.

Abstract 16751: Novel Psoriasis Agents Associated Cardiotoxicity: Analysis of FAERS

Introduction: Psoriasis is a chronic skin condition characterised by hyper-proliferation of epidermal keratinocytes, resulting in erythematous and scaling lesions. The US Food and Drug Administration (FDA) has approved nine biological agents to address the burden of psoriasis, but their cardiovascular risks remain poorly studied. Methods: This retrospective pharmacovigilance study utilised the FDA Adverse Event Reporting System database to analyse adverse events associated with newly approved therapeutic agents for psoriasis. We employed disproportionally signal analysis, calculating the reporting odds ratio (ROR) with a 95% confidence interval. Results: Among the vast FAERS database, which contained more than 25 million adverse events, a total of 334,399 events were associated with newly approved therapeutic agents for psoriasis. Cardiac adverse events accounted for 3,852 cases, including pericarditis, atrial fibrillation, and coronary artery disease. Secukinumab had the highest number of reported adverse events, followed by brodalumab, while tildrakizumab had the lowest. Coronary artery disease was the most reported adverse event (1,438 cases), followed by pericarditis (572 cases) and atrial fibrillation (384 cases). Secukinumab had the highest incidence of coronary artery disease, pericarditis, and atrial fibrillation. Risankizumab showed a significant association with an increased risk of coronary artery disease and atrial fibrillation, while tildrakizumab and Ixekizumab were associated with atrial fibrillation. Secukinumab was associated with an elevated risk of pericarditis. Conclusions: The study uncovers unknown cardiovascular adverse effects related to biologic agents used in psoriasis treatment. These findings emphasise the importance of monitoring and evaluating the cardiovascular safety profiles of biologic agents used in psoriasis treatment.

Abstract 18449: Myocarditis in Patients With Cancer Undergoing Combination Checkpoint Inhibitor Therapy

Introduction: Immune checkpoint inhibitors (ICI) have improved the clinical outcomes of several cancers but have also been associated with a greater risk of cardiovascular adverse effects. Hypothesis: The use of combination ICI therapy is associated with an increased risk of myocarditis, compared to use of a single ICI. Methods: A cohort study was conducted using medical and pharmacy claims data (2011 to 2022) in the Optum Clinformatics database. Cox regression models quantified the comparative risk of myocarditis between cancer patients receiving combination therapy (nivolumab and ipilimumab) and those taking a single ICI. Results: Among 53,018 patients to whom ICI were dispensed there were 148 cases of myocarditis (0.3%): 33 (0.7%) in patients on combination therapy and 115 (0.2%) in patients on monotherapy. The crude risk of myocarditis per 1,000 patients was 7.40 in the combination therapy group and 2.37 in the monotherapy group (risk ratio= 3.12; 95% CI: 2.12 to 4.60) over an average follow-up period of 226 days (IQR 93-495 days). After propensity score-matching the hazard ratio comparing myocarditis in the combination therapy versus monotherapy groups was 3.67 (1.76 to 7.67; p<0.01). 76% of all myocarditis events in both groups occurred within six months of commencing treatment (figure). Conclusions: Simultaneous combination therapy with nivolumab and ipilimumab was associated with an increased risk of myocarditis compared to the use of single agents. Myocarditis was infrequent and occurred most often within six months of treatment start.

Cardiovascular and Respiratory Effects of Increased Intra-Abdominal Pressure with and without Dexmedetomidine in Anesthetized Dogs.

Intra-abdominal pressure (IAP) elevation during capnoperitoneum can cause adverse cardiovascular and respiratory effects. This study aimed to determine if a sequentially increased IAP affects cardiovascular and respiratory variables in anesthetized dogs and evaluate the effects of the constant-rate infusion of dexmedetomidine (Dex) on cardiovascular and respiratory variables with increased IAP. Five dogs were anesthetized and instrumented, and a Veress needle was equipped to adjust the IAP using a carbon dioxide insufflator. Stabilization was conducted for 1 h, and physiological variables were measured at IAPs of 0, 5, 10, 15, and 20 mmHg and after desufflation. After the washout period, the dogs underwent similar procedures along with a constant-rate infusion of dexmedetomidine. The cardiovascular effects of increased IAP up to 20 mmHg were not significant in healthy beagle dogs and those administered with dexmedetomidine. When comparing the control and dexmedetomidine groups, the overall significant effects of dexmedetomidine were noted on heart rate, cardiac output, and systemic vascular resistance during the experiment. Respiratory effects were not observed during abdominal insufflation when compared between different IAPs and between the two groups. Overall, an increased IAP of up to 20 mmHg did not significantly affect cardiovascular and respiratory variables in both the control and dexmedetomidine groups. This study suggests that the administration of a dexmedetomidine infusion is applicable in laparoscopic procedures in healthy dogs.

Cardiovascular Outcomes Associated With Exposure To Radiation Therapy In Thoracic Malignancies: An Insight Study Using the National Inpatient Database.

Background Thoracic irradiation is a widely used therapeutic and palliative treatment option for thoracic neoplasms. However, short- and long-term cardiovascular adverse effects of radiation exposure remain a major concern. The short-term adverse effects are observed within months of exposure such as pericardial diseases; meanwhile, the long-term complications are usually insidious and manifest over decades, such as congestive heart failure, coronary artery disease, cardiomyopathy, conduction disorders, constrictive pericarditis, and valvular heart disease. Hence, long-term cardiovascular adverse effects are challenging to predict, and the association with radiation exposure remains difficult to establish. Methodology This retrospective, observational study was conducted using data from the National Inpatient Sample (NIS) database from 2016 to 2019. Adult patients with primary thoracic malignancieswho underwent radiation therapy (RT) were defined using principal and secondary International Classification of Diseases, Tenth Revision codes. Other malignancies that can be treated with RT and all secondary malignancies were excluded from the primary comparison group. Cardiac outcomes were defined as the prevalence of congestive heart failure, coronary artery disease, cardiomyopathy, conduction disorders, pericardial diseases, and valvular heart diseases in the primary group. The multivariate logistic and the linear regression analyses were used to adjust for confounders. Results When compared to the general population, adults with thoracic malignancies exposed to RT had higher odds of developing chronic pericarditis (adjusted odds ratio (aOR) = 2, 95% confidence interval (CI) = 1.9-2.2, p < 0.001), acute pericarditis (aOR = 2.3, 95% CI = 1.9-2.9, p < 0.001), constrictive pericarditis (aOR = 2.8, 95% CI = 2.1-3.7, p < 0.001), conduction disorders (aOR = 1.3, 95% CI = 1.2-1.35, p < 0.001), coronary artery disease (aOR = 1.24, 95% CI = 1.2-1.27, p < 0.001), heart failure (aOR = 1.44, 95% CI = 1.4-1.5, p < 0.001), and valvular heart disease (aOR = 1.37, 95% CI = 1.3-1.4, p < 0.001). There was no difference in the odds of developing cardiac arrest (aOR = 1, 95% CI = 0.9-1.10, p = 0.6) or acute myocardial infarction (aOR = 1.1, 95% CI = 1-1.15, p < 0.001). When compared to adults with thoracic malignancies not exposed to RT, adults with thoracic malignancies who were exposed to RT had higher odds of developing acute myocardial infarction (aOR = 1.14, 95% CI = 1.1-1.18, p < 0.001), chronic pericarditis (aOR = 1.3, 95% CI = 1.2-1.3, p < 0.001), acute pericarditis (aOR = 1.6, 95% CI = 1.2-2.1, p < 0.001), constrictive pericarditis (aOR = 2.2, 95% CI = 1.5-3.2, p < 0.001), conduction disorders (aOR = 1.1, 95% CI = 1.08-1.13, p < 0.001), coronary artery disease (aOR = 1.14, 95% CI = 1.12-1.16, p < 0.001), heart failure (aOR = 1.2, 95% CI = 1.17-1.23, p < 0.001), and valvular heart disease (aOR = 1.3, 95% CI = 1.2-1.35, p < 0.001). The odds were similar between the two groups for developing cardiac arrest (aOR = 0.86, 95% CI = 0.8-0.98, p = 0.05). Conclusions Adults with thoracic malignancies who were treated with RT have higher odds of developing chronic pericarditis, acute pericarditis, constrictive pericarditis, conduction disorders, coronary artery disease, heart failure, and valvular heart disease while similar odds of developing cardiac arrest or acute myocardial infarction compared to the general adult population.

Exploration of Tilmicosin Cardiotoxicity in Rats and the Protecting Role of the Rhodiola rosea Extract: Potential Roles of Cytokines, Antioxidant, Apoptotic, and Anti-Fibrotic Pathways.

Tilmicosin (TIL) is a common macrolide antibiotic in veterinary medicine. High doses of TIL can have adverse cardiovascular effects. This study examined the effects of Rhodiola rosea (RHO) that have anti-inflammatory, antioxidant, and anti-fibrotic effects on tilmicosin (TIL)-induced cardiac injury targeting anti-inflammatory, antioxidant, apoptotic, and anti-apoptotic signaling pathways with anti-fibrotic outcomes. Thirty-six male Wistar albino rats were randomly divided into groups of six rats each. Rats received saline as a negative control, CARV 1 mL orally (10 mg/kg BW), and RHO 1 mL orally at 400 mg/kg BW daily for 12 consecutive days. The TIL group once received a single subcutaneous injection (SC) dose of TIL (75 mg/kg BW) on the sixth day of the experiment to induce cardiac damage. The standard group (CARV + TIL) received CARV daily for 12 consecutive days with a single TIL SC injection 1 h after CARV administration only on the sixth day of study and continued for another six successive days on CARV. The protective group (RHO + TIL) received RHO daily for the same period as in CARV + TIL-treated rats and with the dosage mentioned before. Serum was extracted at the time of the rat's scarification at 13 days of study and examined for biochemical assessments in serum lactate dehydrogenase (LDH), cardiac troponin I (cTI), and creatine phosphokinase (CK-MB). Protein carbonyl (PC) contents, malondialdehyde (MDA), and total antioxidant capacity (TAC) in cardiac homogenate were used to measure these oxidative stress markers. Quantitative RT-PCR was used to express interferon-gamma (INF-γ), cyclooxygenase-2 (COX-2), OGG1, BAX, caspase-3, B-cell lymphoma-2 (Bcl-2), and superoxide dismutase (SOD) genes in cardiac tissues, which are correlated with inflammation, antioxidants, and apoptosis. Alpha-smooth muscle actin (α-SMA), calmodulin (CaMKII), and other genes associated with Ca2+ hemostasis and fibrosis were examined using IHC analysis in cardiac cells (myocardium). TIL administration significantly increased the examined cardiac markers, LDH, cTI, and CK-MB. TIL administration also increased ROS, PC, and MDA while decreasing antioxidant activities (TAC and SOD mRNA) in cardiac tissues. Serum inflammatory cytokines and genes of inflammatory markers, DNA damage (INF-γ, COX-2), and apoptotic genes (caspase-3 and BAX) were upregulated with downregulation of the anti-apoptotic gene Bcl-2 as well as the DNA repair OGG1 in cardiac tissues. Furthermore, CaMKII and α-SMA genes were upregulated at cellular levels using cardiac tissue IHC analysis. On the contrary, pretreatment with RHO and CARV alone significantly decreased the cardiac injury markers induced by TIL, inflammatory and anti-inflammatory cytokines, and tissue oxidative-antioxidant parameters. INF-γ, COX-2, OGG1, BAX, and caspase-3 mRNA were downregulated, as observed by real-time PCR, while SOD and Bcl-2 mRNA were upregulated. Furthermore, the CaMKII and α-SMA genes' immune reactivities were significantly decreased in the RHO-pretreated rats.

Iodine-Induced Hypothyroidism and Long-Term Risks of Incident Heart Failure.

Background Although most individuals can adapt to a large iodine load and remain euthyroid, hypothyroidism can develop after iodine exposure. Hypothyroidism is associated with adverse cardiovascular consequences, including heart failure. This study was performed to investigate the relationships between iodine-induced hypothyroidism and incident heart failure. Methods and Results This cohort study of the US Veterans Health Administration (1998-2021) included adults aged ≥18 years with a serum thyroid-stimulating hormone (thyrotropin) <60 days of iodine contrast administration, and <1 year of a baseline normal serum thyroid-stimulating hormone. Cox proportional hazards regression ascertained risk of incident heart failure following iodine-induced hypothyroidism, adjusting for age, sex, race and ethnicity, body mass index, and history of coronary heart disease, dyslipidemia, diabetes, and hypertension. Of 45 470 veterans (mean±SD age, 61.1±14.1 years; 88% men), 3361 (7.4%) developed iodine-induced hypothyroidism. Heart failure developed in 5685 (12.5%) individuals over a median follow-up of 3.6 years (interquartile range, 1.9-7.2 years). Adjusted for risk factors, iodine-induced hypothyroidism was associated with increased risk of heart failure, compared with those who remained euthyroid after iodine exposure (adjusted hazard ratio [HR], 1.11 [95% CI, 1.01-1.22]). Women were at greater risk than men (adjusted HR: women, 1.65 [95% CI, 1.13-2.40]; men, 1.08 [95% CI, 0.98-1.19]; P for interaction, 0.02). Conclusions In the largest US study of this topic, hypothyroidism following iodine exposure was associated with an increased risk of incident heart failure, particularly in women. These findings support the need for further research to address the clinical significance of this issue, including the possible sex-specific risks of incident heart failure in more diverse data sets and study populations.

Cardiovascular adverse effects associated with the use of anti-HER2 in breast cancer treatment.

Background: Cancer represents an important public health problem with increasing incidence, prevalence, and mortality, affecting the entire Western population, especially in developed and developing countries. The use of monoclonal antibodies has revolutionized the treatment of cancer, but this treatment can cause adverse cardiovascular effects (AE). Objective: The objective of this paper is to identify and classify AE in breast cancer patients in the use of Trastuzumab in two health institutions. Methods: Retrospective study of medical records of patients with breast cancer Her 2+ submitted the therapy with trastuzumab in early and advanced stage of the disease. Review conducted in a university hospital and a private clinic, both located in Rio de Janeiro State, Brazil. Results: Cardiovascular events were late for trastuzumab, with predominance of moderate reactions. There was a predominance of dyspnea, increased blood pressure, fatigue and reduced left ventricular ejection. Conclusion: The results resemble similarities in the pattern of the institutions' reactions. Identify possible AE and know the toxicity profile of trastuzumab can contribute to a safer therapy.

Cardiovascular Adverse Effects of Chemotherapy: Evidence-based Prevention and Treatment Strategies

Cardiovascular Adverse Effects of Chemotherapy: Evidence-based Prevention and Treatment Strategies

Repeated witness social stress causes cardiomyocyte contractile impairment and intracellular Ca2+ derangement in female rats

The impact of psychosocial stressors on cardiovascular health in women is of growing interest in both the popular and scientific literature. Rodent models are useful for providing direct experimental evidence of the adverse cardiovascular consequences of psychosocial stressors, yet studies in females are scarce. Here, we investigated the effects of repeated exposure to witness social defeat stress (WS) on cardiomyocyte contractile function and intracellular Ca2+ homeostasis in young adult wild-type Groningen female rats. Female rats bore witness to an aggressive social defeat episode between two males for nine consecutive days or were exposed to a control procedure. Stress-related behaviors were assessed during the first and last WS/control exposure. Twenty-four hours after the last exposure, plasma corticosterone levels were measured, and cardiomyocytes were isolated for analyses of contractile properties and Ca2+ transients, and expression levels of proteins involved in intracellular Ca2+dynamics. The results show an impairment of the intrinsic cardiac mechanical properties and prolonged intracellular Ca2+decay in WS female rats showing social stress-related behavioral (larger amounts of burying behavior) and neuroendocrine (elevated plasma corticosterone levels) phenotypes. Further, the results implicate alterations in the sarcoplasmic reticulum Ca2+-ATPase/phospholamban complex in the contractile defects described in cardiomyocytes of WS female rats. In conclusion, this study highlights the utility of the WS model as an ethologically relevant social stressor for investigating pathophysiological processes that occur in the heart of female subjects and may increase vulnerability to social stress-related cardiovascular risk.

Adverse cardiovascular effects of long-term exposure to diethyl phthalate in the rat aorta

Phthalates are classified as priority environmental pollutants, since they are ubiquitous in the environment, have endocrine disrupting properties and can contribute to impaired health. Used primarily in personal care products and excipients for pharmaceuticals, diethyl phthalate (DEP) is a short-chain alkyl phthalate that has been linked to decreased blood pressure, glucose tolerance, and increased gestational weight gain in humans, while in animals it has been associated with atherosclerosis and metabolic syndrome. Although all these findings are related to risk factors or cardiovascular diseases, DEP's vascular impacts still need to be clarified. Thus, performing ex vivo and in vitro experiments, we aimed to understand the vascular DEP effects in rat. To evaluate the vascular contractility of rat aorta exposed to different doses of DEP (0.001–1000 μM), an organs bath was used; and resorting to a cell line of the rat aorta vascular smooth muscle, electrophysiology experiments were performed to analyse the effects of a rapid (within minutes with no genomic effects) and a long-term (24 h with genomic effects) exposure of DEP on the L-type Ca2+ current (ICa,L), and the expression of several genes related with the vascular function. For the first time, vascular electrophysiological properties of an EDC were analysed after a long-term genomic exposure. The results show a hormetic response of DEP, inducing a Ca2+ current inhibition of the rat aorta, which may be responsible for impaired cardiovascular electrical health. Thus, these findings contribute to a greater scientific knowledge about DEP's effects in the cardiovascular system, specifically its implications in the development of electrical disturbances like arrhythmias and its possible mechanisms.

Adverse Impact of Cannabis on Human Health.

Cannabis, the most commonly used recreational drug, is illicit in many areas of the world. With increasing decriminalization and legalization, cannabis use is increasing in the United States and other countries. The adverse effects of cannabis are unclear because its status as a Schedule 1 drug in the United States restricts research. Despite a paucity of data, cannabis is commonly perceived as a benign or even beneficial drug. However, recent studies show that cannabis has adverse cardiovascular and pulmonary effects and is linked with malignancy. Moreover, case reports have shown an association between cannabis use and neuropsychiatric disorders. With growing availability, cannabis misuse by minors has led to increasing incidences of overdose and toxicity. Though difficult to detect, cannabis intoxication may be linked to impaired driving and motor vehicle accidents. Overall, cannabis use is on the rise, and adverse effects are becoming apparent in clinical data sets.

An anchor-tether ‘hindered’ HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model

BackgroundNeuropathic pain impairs quality of life, is widely prevalent, and incurs significant costs. Current pharmacological therapies have poor/no efficacy and significant adverse effects; safe and effective alternatives are needed. Hyperpolarisation-activated cyclic nucleotide-regulated (HCN) channels are causally implicated in some forms of peripherally mediated neuropathic pain. Whilst 2,6-substituted phenols, such as 2,6-di-tert-butylphenol (26DTB-P), selectively inhibit HCN1 gating and are antihyperalgesic, the development of therapeutically tolerable, HCN-selective antihyperalgesics based on their inverse agonist activity requires that such drugs spare the cardiac isoforms and do not cross the blood–brain barrier. MethodsIn silico molecular dynamics simulation, in vitro electrophysiology, and in vivo rat spared nerve injury methods were used to test whether ‘hindered’ variants of 26DTB-P (wherein a hydrophilic ‘anchor’ is attached in the para-position of 26DTB-P via an acyl chain ‘tether’) had the desired properties. ResultsMolecular dynamics simulation showed that membrane penetration of hindered 26DTB-Ps is controlled by a tethered diol anchor without elimination of head group rotational freedom. In vitro and in vivo analysis showed that BP4L-18:1:1, a variant wherein a diol anchor is attached to 26DTB-P via an 18-carbon tether, is an HCN1 inverse agonist and an orally available antihyperalgesic. With a CNS multiparameter optimisation score of 2.25, a >100-fold lower drug load in the brain vs blood, and an absence of adverse cardiovascular or CNS effects, BP4L-18:1:1 was shown to be poorly CNS penetrant and cardiac sparing. ConclusionsThese findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.

Evaluation of intraoperative bleeding in shoulder arthroscopy with preoperative injection of epinephrine saline: a retrospective comparative study.

Several studies report the positive effects of epinephrine saline irrigation in shoulder arthroscopy3,4,15,18,22,23. Cardiovascular adverse effects have been described1,2,5,6,7,9,19. The Wide Awake Local Anesthesia No Tourniquet (WALANT) limits bleeding13,16,24,25. The aim of this study is to evaluate the effects of epinephrine saline infiltrations of the shoulder on arthroscopic visual comfort. We carried out a retrospective comparative study composed of 2 groups. We included all patients admitted to the department for a rotator cuff surgery. Our exclusion criteria were any other surgical indication and patient refusal. The protocol consisted in making 3 preoperative shoulder infiltrations of 20 ml of epinephrine saline at 0.005 mg/mL. Injections were performed in all patients in group 1 and no specific treatment was performed in group 2 (control group). Data collection was performed the same way in both groups. The main judgment criterion was the evaluation of the surgeon's overall visual comfort using the Visual Analogue Scale (VAS) at the end of the procedure. We also evaluated the intraoperative discomfort related to bleeding every 15 minutes by an objective scale (the Visual Numeric Rating Scale VNRS), as well as the cumulative bleeding time, operating time, the quantity of irrigation fluid used, the blood pressure at the times of the bleeding, the mean blood pressure during the surgery and the presence of thromboembolic and cardiovascular adverse events. We included 30 patients in group 1 and 30 patients in the control group. The mean VAS value at the end of the intervention is significantly higher in group 1 than in the control group: VAS = 10 in group 1 versus VAS = 5 in group 2 (p<0.0001) (higher is better). We also observed a significant decrease in VNRS between the two groups: VNRS = 0.25 in group 1 versus VNRS = 1,00 in group 2 (p<0.0001) (lower is better). Bleeding time was significantly lower in patients in group 1 (1min 39s) compared to patients in group 2 (9min 57s) (p<0.0001). No significant difference was demonstrated concerning the operating times, the quantity of irrigation fluid used and the blood pressure data of the two groups. No adverse effects were observed. The infiltration of low doses of adrenaline as performed in WALANT procedures seems effective in improving visualization in arthroscopy by reducing the bleeding. It can be a simple, efficient, and cost-effective technique with no iatrogenic risk to improve the surgeon's comfort in arthroscopic procedures.

RISCO DE MORTE SÚBITA CARDÍACA E EFEITOS ADVERSOS CARDIOVASCULARES ASSOCIADOS AO USO DE ANTIDEPRESSIVOS

Introduction: Treatment of depression / depressive disorder requires effective therapeutic agents, well tolerated and with a low rate of complications and adverse events. However, some antidepressants(AD)have been associated with an increased risk of sudden cardiac death (SCD) and general and cardiovascular adverse events, important in daily clinical practice. Objective: Raise possible adverse cardiovascular events and risk of SCD associated with AD use in adult patients. Additionally, investigate general adverse effects, action mechanisms and main risk drug interactions with AD and guidelines for monitoring / optimized clinical management of patients. Methodology: integrative review aiming, from scientific literature, to collect information regarding the objectives of this review in the main databases: PubMed; Lilacs; Google Scholar; Brazilian´s Health Ministry. Selection criteria were: meta-analysis articles, systematic review, review, guidelines, consensus and observational studies (cohort studies, case-control or cross-sectional studies) and randomized control studies, published between 2010 and April 2023. Results: 173 publications were selected allowing verify which patients had high risk for developing adverse cardiovascular events associated with the use of AD: elderly; preexisting cardiovascular risk factors; patients with comorbidities (mainly acute and/or chronic coronary artery disease, heart failure and renal failure); CYP450 poor/slow metabolizers; previous history of ventricular arrhythmias or syncope; carriers of channelopathies; family history of long QT syndrome, sudden death, diabetes mellitus and arterial hypertension; polypharmacy; AD use in high doses; electrolyte abnormalities (eg: hypokalemia, hypomagnesaemia, etc.). Studies demonstrated that selective serotonin reuptake inhibitors had a relative risk of SCD of 2.39 (95%CI 1.20-4.80) while tricyclic ADs risk ranging from 1.69 (95%CI 1.14-2.50) at 4.37 (95%CI 1.23-15.60). We summarized the risk information in tables and charts with recommendations from main studies and guidelines regarding the clinical management, monitoring and management of adverse events. Conclusion: Although the use of ADs has recognized general and cardiovascular adverse effects, their risks shouldn´t deprive patients of appropriate therapy for psychiatric disorders, including those with cardiovascular diseases. The available literature data allow adopting screening of patients who need the use of DA, monitoring treatment and adopting effective preventive measures to reduce the risk of possible complications.

COMPARISON OF KETAMINE-MIDAZOLAM AND KETAMINE-MIDAZOLAM-BUTORPHANOL PREMEDICATION PRIOR TO SEVOFLURANE ANESTHESIA IN WOODCHUCKS (MARMOTA MONAX).

Cardiovascular disease is a frequent cause of death in the critically endangered Vancouver Island marmots (Marmota vancouverensis). This warrants the use of anesthetic protocols with minimal cardiovascular adverse effects. In this study, 12 adult male woodchucks (Marmota monax) were used as models for Vancouver Island marmots. The objective was to compare the physiological effects of two premedication protocols during induction and maintenance of anesthesia with sevoflurane. The two premedications were ketamine 10 mg/kg and midazolam 0.5 mg/kg (KM) or ketamine 10 mg/kg, midazolam 0.5 mg/kg, and butorphanol 1.0 mg/kg (KMB), administered intramuscularly prior to mask induction. Each marmot underwent three anesthetic events and protocols were assigned using a blinded randomized crossover design. Heart rate, respiratory rate, oxygen saturation, and body temperature were recorded throughout, and blood gases were assessed following induction. Resistance to induction was scored and time to induction was recorded. Although mask induction with sevoflurane was successful in all events (mean induction time of 2.1 min), KMB premedication resulted in a faster induction (mean induction time reduced by 1.2 ± 0.3 min) and lower resistance scores. Both protocols resulted in significant cardiovascular and respiratory depression; however, animals that received KMB were more hypercapnic than KM by 8.8 ± 2.8 mm Hg (P = 0.03) (mean venous partial pressure of carbon dioxide [PvCO2] for all: 79.9 mm Hg). In conclusion, if shorter induction times are desired, KMB premedication is preferred. However, cardiorespiratory variables including blood pressure should be monitored, and endotracheal intubation is recommended to allow for ETCO2 monitoring and provision of intermittent positive pressure ventilation.