QT Interval Research Articles

Ventricular stimulation in patients with myotonic dystrophy type 1 may not predict future ventricular arrhythmias

Myotonic dystrophy type 1 (DM1) is associated with progressive conduction disease. Furthermore, DM1 patients are at risk ventricular arrhythmias (VAs), although prediction remains difficult. The 2022 Heart Rhythm Expert Consensus Statement gives a IIb recommendation to the use of electrophysiology study (EPS) to risk-stratify patients for VAs. The utility of EPS in predicting the development of VAs, however, has not been explored in this patient population. The study sought to examine the natural history of DM1 patients with positive and negative ventricular stimulation (v-stim) during EPS. Patients with a history of DM1 undergoing EPS with associated v-stim from 2008 to present were retrospectively identified. From 2008 to 2022, 26 consecutive DM1 patients presented for EPS with v-stim. Four v-stim protocols were positive for sustained or hemodynamically significant ventricular tachycardia (VT), one of which was induced with 600 doubles, the others with triple extrastimuli. A total of 22 of 26 subjects received a device implant, with 18 receiving permanent pacemakers and 4 implantable cardioverter-defibrillators. All 4 of the patients with positive v-stims underwent ICD implantation. After a mean of 5.7 years of follow-up, 7 patients had sustained VT, 6 of whom had negative v-stims. Of the 4 patients with positive v-stims, only 1 developed sustained VT in follow-up. Other than baseline QT interval at time of EPS, no baseline characteristics were significantly different between patients with and without subsequent VT. In this single center, v-stim in DM1 patients did not predict clinical VAs, as a vast majority of DM1 patients who developed VAs had negative v-stims.

Substance abuse and cardiovascular risk: energy drinks

The consumption of energy drinks (ED) has become a growing public health issue, since potentially ED-related serious adverse cardiovascular events, including arrhythmias, myocardial infarction, cardiomyopathies, and sudden cardiac death, have been reported in recent years. The substances contained in ED include caffeine, taurine, sugars, B group vitamins and phyto-derivatives, which, especially if taken in large quantities and in a short amount of time, could cause serious side effects through various mechanisms of action, such as increased blood pressure and QT interval prolongation. Although there are still many open questions on ED that require further specific investigations, there is an urgent need for information and educational plans to the population, as well as for regulatory actions, particularly regarding transparency of substances and possible adverse effects.

Cardiovascular effects of long-duration space flight.

Early studies exploring the physiological effects of space travel have indicated the body's capacity for reversible adaptation. However, the impact of long-duration spaceflight, exceeding 6 months, presents more intricate challenges. Extended exposure to microgravity and radiation profoundly affects the CV system. Notable phenomena include fluid shifts toward the head and modified arterial pressure. These changes disrupt blood pressure regulation and elevate cardiac output. Additionally, the loss of venous compression leads to a reduction in central venous pressure. The displacement of fluid from the vascular system to the interstitium, driven by baroreceptor stimulation, results in a 10%-15% decline in plasma volume. Intriguingly, despite potential increases in cardiac workload, cardiac muscle atrophy and perplexing variations in hematocrit levels have been observed. The mechanism underlying atrophy appears to involve a shift in protein synthesis from the endoplasmic reticulum to the mitochondria via mortalin-mediated mechanisms. Instances of arrhythmias have been recurrently documented, although generally nonlethal, in both Russian and American space missions. Long-duration spaceflight has been associated with the prolongation of the QT interval, particularly in extended missions. Exposure of the heart to the proton and heavy ion radiation pervasive in deep space contributes to coronary artery degeneration, augmented aortic stiffness, and carotid intima thickening through collagen-mediated processes. Moreover, it accelerates the onset of atherosclerosis and triggers proinflammatory responses. Upon reentry, astronauts frequently experience orthostatic intolerance and altered sympathetic responses, which bear potential hazards in scenarios requiring rapid mobilization or evacuation. Consequently, careful monitoring of these cardiac risks is imperative for forthcoming missions. While early studies illuminate the adaptability of the body to space travel's challenges, the intricacies of long-duration missions and their effects on the CV system necessitate continued investigation and vigilance to ensure astronaut health and mission success.

Novel variants in TECRL leading to catecholaminergic polymorphic ventricular tachycardia.

Pathogenic and likely pathogenic variants in the TECRL gene are known to be associated with recessive catecholaminergic polymorphic ventricular tachycardia 3, which can include prolonged QT intervals (MIM#614021). We report a case of cardiac arrest in a previously healthy adolescent male in the community. The patient was found to have a novel maternally inherited likely pathogenic variant in TECRL (c.915T>G [p.Tyr305Ter]) and an additional 19-kb duplication encompassing multiple exons of TECRL (chr4:65165944-65185287, dup [4q13.1]) not identified in the mother. Genetic results were revealed via rapid whole-genome sequencing, which allowed appropriate treatment and prognostication.

Citalopram & escitalopram: Mechanisms of cardiotoxicity, toxicology predisposition and risks of use in geriatric & hemodialysis populations.

The selective serotonin reuptake inhibitors (SSRIs) citalopram and escitalopram are extensively prescribed for various psychopathies. Despite their reputation for safety compared to older antidepressants, concerns have arisen regarding their cardiotoxic potential, notably in prolonging the QTc interval. In this comprehensive review, we investigate the intricate mechanisms of cardiotoxicity induction by citalopram/escitalopram, with a special focus on their interactions with ion channels like Kv11.1, Nav1.5, and Cav1.2 which may contribute to QTc-prolongation, increasing the risk of life-threatening arrhythmias such as Torsades de Pointes (TdP). Moreover, we explore the predisposing factors to their associated cardiotoxicity along with an investigation of the QRS/QTc ratio as a potential biomarker for identifying patients at risk of ventricular arrhythmias, taking into consideration the impact of genetic variations and drug interactions, especially those involving the liver CYP2C19 metabolism. Our review extends to the geriatric population's use of citalopram and escitalopram, emphasizing the significance of assessing a patient's medical history and cumulative drug use to evaluate their susceptibility to cardiac adverse events. Finally, we scrutinize the compound relationship between QTc-prolongation, proton pump inhibitors (PPIs) and serum-to-dialysate potassium gradients in influencing the proarrhythmic potential of citalopram/escitalopram in hemodialysis patients.

Cardioprotective effect of chelidonic acid against doxorubicin-induced cardiac toxicity in rats

Introduction and objectivesThe current study evaluates the effect of chelidonic acid on doxorubicin-induced cardiac toxicity. Chelidonic acid (CA) is a natural pyran-skeleton heterocyclic compound found in rhizomes of the perennial plant, celandine (Chelidonium majus). MethodsWistar rats were given an intraperitoneal injection of doxorubicin (1.25 mg/kg, cumulative dose of 20 mg/kg) four times per week for a duration of four weeks to induce cardiotoxicity. CA treatment (10, 20, and 40 mg/kg orally for four weeks) was started together with doxorubicin. ResultsCA treatment reduced myocardial damage and improved cardiac dysfunction in doxorubicin-treated rats. It improved blood pressure, restored ST wave height and normalized the QTc interval compared to the rats treated only with doxorubicin. Administration of CA for four weeks reduced left ventricular end-diastolic pressure. Moreover, CA treatment decreased the level of cardiac markers such as creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and cardiac troponin-T. Masson's trichrome, hematoxylin, and eosin staining of heart tissue revealed that CA attenuated the deleterious effects of doxorubicin and prevented further damage and fibrosis in rats. ConclusionThe study findings confirm that CA treatment can protect the myocardium against doxorubicin-induced cardiotoxicity.

A Narrative Review of Bedaquiline and Delamanid: New Arsenals Against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis.

The treatment of multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) is a formidable challenge. Treatment of MDR- and XDR-TB using bedaquiline (BDQ) and delamanid (DLM), two newly introduced medications, is steadily increasing. This narrative review aimed to present a concise overview of the existing information regarding BDQ and DLM, and elucidate their antimicrobial characteristics, resistance mechanisms, synergism with other drugs, and side effects. To collect the required information about the antimicrobial properties, a search for scientific evidence from the Scopus, PubMed, and Embase databases was performed, and all recently published articles up to May 2024 were considered. BDQ had potent antimicrobial effects on various types of nontuberculous mycobacteria (NTM), including rapid-growing and slow-growing species, and MDR/XDR Mycobacterium tuberculosis. The mechanisms of BDQ resistance in M. tuberculosis primarily involve mutations in three genes: atpE, mmpR (Rv0678) and pepQ. BDQ may have synergistic effects when combined with DLM, pyrazinamide, and pretomanid/linezolid. BDQ has a low incidence of side effects. The use of BDQ may prolong the QTc interval. Similarly, DLM showed potent antimicrobial effects on NTM and MDR/XDR M. tuberculosis. The main resistance mechanisms to DLM are induced by mutations in fbiA, fbiB, fbiC, fgd1, and ddn genes. The DLM had synergistic effects with BDQ and moxifloxacin. The DLM also has few side effects in some patients including QTc prolongation. BDQ and DLM are suitable antibiotics with few side effects for the treatment of MDR/XDR-TB. These antibiotics have synergistic effects when combined with other antituberculosis drugs.

Serum Magnesium Levels and QTc Interval Prolongation As Prognostic Markers in Acute Myocardial Infarction: A Randomized Controlled Study.

Introduction Acute myocardial infarction (AMI) is frequently preceded by arrhythmias, which continue to be a prominent cause of abrupt fatality in AMI. Abnormal magnesium levels have been linked to the emergence of arrhythmia because it enhances myocardial metabolism and cardiac output and prevents calcium buildup and myocardial cell death by lowering arrhythmias. The objectives of this study were to evaluate serum magnesium levels and QTc interval as prognostic indicators in AMI patients during the initial 48 hours of hospital stay and to correlate these parameters with the Global Registry of Acute Coronary Events (GRACE) scoring. We studied AMI patients by dividing them into two groups: those with abnormal and those with normal serum magnesium levels. Methods After obtaining ethical approvals, patients were subjected to detailed history, which included sociodemographic details, drug history, clinical examination, and investigations such as creatine kinase myocardial band (CK-MB), CK-total, troponin-T, ECG (QTc interval), two-dimensional echocardiogram (2D-ECHO), serum creatinine and magnesium levels, heart rate, and blood pressure. We also calculated the GRACE score for all patients. Results We found that patients in the age group of 51-60 years were more prone to developing arrhythmias, and while AMI was more prevalent in males, the occurrence of arrhythmias was slightly higher in females with AMI. Anterior wall motion abnormality (AWMA) was the most predominant abnormality, and 12.3% of AWMA patients had arrhythmias. QTc interval was significantly longer in patients who developed arrhythmias. Interestingly, among patients with QTc prolongation, 35% patients had abnormal magnesium levels, while 65% had normal magnesium levels. In our study, of the 25 patients with hypermagnesemia, nine (36%) developed arrhythmias, while of the 75 patients with hypomagnesemia, 15 (20%) patients developed arrhythmias. Interestingly, we found that there was a positive correlation between GRACE score and serum magnesium as well as QTc interval prolongation. Lastly, among the six deaths reported, three (50%) patients had arrhythmias. Conclusion Overall, we conclude that serum magnesium levels play a pivotal role as a prognostic tool for arrhythmias and are a useful investigation during the initial 48 hours of admission in AMI patients.

Risk of corrected QT interval prolongation in patients receiving antipsychotics.

Antipsychotic (AP) use has been associated to QT interval prolongation on the surface electrocardiogram (ECG). Our study aimed to determine the incidence of corrected QT (QTc) interval prolongation among patients admitted to a psychiatric hospitalization unit requiring AP treatment and to assess the relationship between administered dose and QTc interval changes. We enrolled 179 patients admitted to the Hospital Psiquiátrico Departamental Universitario del Valle in Cali, Colombia. ECGs were conducted upon admission, and again at 3 and 7 days postadmission. The QT interval was measured, and QTc interval correction was performed using Bazzet's formula. QTc interval prolongation at time points B or C was observed in 9.5% of patients. Clozapine was the most common AP associated with QTc interval prolongation (20.59%), followed by olanzapine (15.38%). The relative risk of QT interval prolongation with clozapine compared to haloperidol was 4.17 (95% confidence interval, 1.14-15.17, P = 0.02). AP use upon hospital admission was linked to early (within 3 days) QTc interval prolongation. Clozapine and olanzapine were associated with a greater increase in QTc interval compared to haloperidol, indicating a need for rigorous electrocardiographic monitoring with their use.

Long QT Syndrome With Drugs Used in the Management of Arrhythmias: A Systematic Review.

Long QT syndrome (LQTS) is a severe cardiac disorder characterized by an abnormally prolonged QTc interval on an electrocardiogram (ECG), which can result in life-threatening irregular heart rhythms. The use of certain medications, particularly anti-arrhythmic drugs such as quinidine, sotalol, and amiodarone, can lead to acquired LQTS by prolonging the QT interval through the inhibition of specific ion channels responsible for heart repolarization, which may present symptoms like fainting, seizures, and sudden cardiac arrest. This systematic review, conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, focused on analyzing the association between Long QT syndrome and drugs utilized for managing arrhythmias, involving a thorough examination of six selected studies from an initial pool of 68 articles. It was found that antiarrhythmic drugs such as amiodarone, sotalol, dofetilide, procainamide, quinidine, and flecainide have the potential to cause QT prolongation as a side effect, which is often influenced by factors including dosage, coexisting medical conditions, electrolyte imbalances, and other risk factors. Prolonged QT interval significantly elevates the risk of a life-threatening arrhythmia called torsade de pointes. The management of this side effect typically involves reducing the medication dosage or discontinuing it altogether and, in some cases, employing selective beta blockers. However, further research is essential to improve the understanding and implementation of strategies to prevent and manage QT prolongation caused by antiarrhythmic drugs. Additional clinical studies are warranted to enhance knowledge and provide comprehensive guidelines to healthcare practitioners regarding the appropriate use of these medications. Close monitoring of the QT interval is recommended for patients receiving anti-arrhythmic therapy, and consideration should be given to patient-specific risk factors for LQTS, including age, sex, and electrolyte imbalances.

Early identification of severe immune checkpoint inhibitor associated myocarditis: From an electrocardiographic perspective.

Immune checkpoint inhibitor (ICI)-associated myocarditis, particularly severe ICI-associated myocarditis, has a high mortality rate. However, the predictive value of electrocardiogram (ECG) remains unclear. The present study aimed to evaluate the predictive value of clinical and electrocardiographic parameters for severe myocarditis. Clinical and electrocardiographic data of 73 cancer patients with ICI-associated myocarditis were retrospectively collected. The severity of ICI-associated myocarditis was graded using the NCCN guidelines for managing immunotherapy-related toxicities. Myocarditis grades 1-2 and grades 3-4 were classified as mild and severe myocarditis, respectively. Logistic regression analysis was performed to analyze the predictive value of each parameter in predicting severe myocarditis. Among the 73 patients with myocarditis, 20 (27.4%) patients had severe myocarditis. Compared with mild myocarditis group, sinus tachycardia (p = 0.001), QRS duration ≥110 ms (p = 0.001), prolonged QTc interval (p < 0.001), and bundle branch block (p = 0.007) at the time of myocarditis were more common in the severe myocarditis group. Logistic regression analysis revealed that sinus tachycardia (p = 0.028) and QTc interval prolongation (p = 0.007) were predictors of severe myocarditis. Whereas the predictive value of other electrocardiographic parameters was weak. Concurrent targeted therapy didn't increase the risk of severe myocarditis. A high NT-proBNP level was associated with severe myocarditis. ECG at the onset of myocarditis manifested as sinus tachycardia and prolonged QTc interval predicted a high risk of severe myocarditis. Early detection of ECG abnormalities may faciliate early detection of severe ICI-associated myocarditis.

Clinical presentation and genetic characterization of early-onset atrial fibrillation in patients affected by long QT syndrome: A single-center experience.

Early-onset atrial fibrillation (AF) has already been observed in approximately 2% of patients with genetically proven long QT syndrome (LQTS). This frequency is higher than population-based estimates of early-onset AF. However, the concomitant expression of AF in LQTS is likely underestimated. The purpose of this study was to examine the clinical presentation, genetic background, and outcomes of a cohort of patients with LQTS and early-onset AF referred to a single tertiary center. Twenty-seven patients diagnosed with congenital LQTS were included in the study based on the documentation of early-onset (age ≤50 years) clinical or subclinical AF episodes in all available medical records, including standard electrocardiograms, wearable monitor or cardiac implantable electronic devices. Seventeen patients experienced clinical AF during the follow-up period. Subclinical AF was detected in 10 patients through insertable or wearable cardiac monitors. In our series, the mean heart rate during AF episodes was found to be relatively low despite the patients' young age and the low or minimal effective doses of beta-blockers used for QTc interval control. All patients exhibiting LQTS and early-onset AF were genotype positive, carrying mutations in the KCNQ1 (66%), KCNH2, KCNE1, and SCN5A genes. Notably, most of these patients carried the same p.(R231C) mutation in the KCNQ1 gene (59%) and were from the same families, suggesting concurrent expression of familial AF and LQTS. LQTS patients are prone to developing clinical and subclinical AF, even at a younger age. The occurrence of early-onset AF in the LQTS population could be more frequent than previously assumed. AF should be considered as a potential dysrhythmia related to LQTS. Our study emphasizes the importance of carefully researching clinical and/or subclinical episodes of AF through strict heart rhythm monitoring in the LQTS population.

Prevalence of contraindicated combinations amid behavioral and mental health medications filled in a pediatric population

BackgroundBehavioral or mental health disorders are common in children, adolescents, and young adults. Medication use is increasingly common, with few data describing drug-drug combinations in ambulatory settings. The objectives of this study were to describe the pharmaco-epidemiology of behavioral and mental health (BMH) medications among children, adolescents, and young adults in New York Medicaid and assess the prevalence of contraindicated drug pairs within this population.MethodsThis observational cross-sectional study evaluated New York State Medicaid managed care and fee-for-service enrollees under 21 years of age dispensed BMH medications in 2014. Main outcomes included number of members with prescriptions filled; number filling > 1 medication prescription concurrently for ≥ 30 days (polypharmacy), and number and nature of potentially contraindicated drug pairs.ResultsOf 2,430,434 children, adolescents, and young adults, 422,486 (17.4%) had a visit associated with a BMH diagnosis and 141,363 (5.8%) received one or more BMH medications. With 84 distinct medications evaluated, polypharmacy was common, experienced by 53,388 individuals (37.8% of those with a prescription filled), generating 11,115 distinct drug combinations. 392 individuals filled prescriptions for a contraindicated pair of ≥ 2 BMH medications for 30 days or longer. With ≥ 1 day overlap, 651 were exposed to contraindicated medications. The most common contraindicated pairs increased potential risk for prolonged QT interval and serotonin syndrome (n = 378 and n = 250 patients, respectively). Most combinations involved ziprasidone (3247.1 per 10,000 ziprasidone prescriptions filled).ConclusionsWith nearly 6% of members dispensed a BMH medication, contraindicated drug pairs were uncommon. However, any of those combinations represent a potential risk. Clinicians should attend to the balance of potential risks and benefits before contraindicated pairs are dispensed. The methodology described could serve as a basis for monitoring such rare instances and might reduce harm.

Feasibility and accuracy of mobile QT interval monitoring strategies in bedaquiline-enhanced prophylactic leprosy treatment.

Some anti-mycobacterial drugs are known to cause QT interval prolongation, potentially leading to life-threatening ventricular arrhythmia. However, the highest leprosy and tuberculosis burden occurs in settings where electrocardiographic monitoring is challenging. The feasibility and accuracy of alternative strategies, such as the use of automated measurements or a mobile electrocardiogram (mECG) device, have not been evaluated in this context. As part of the phase II randomized controlled BE-PEOPLE trial evaluating the safety of bedaquiline-enhanced post-exposure prophylaxis (bedaquiline and rifampicin, BE-PEP, versus rifampicin, SDR-PEP) for leprosy, all participants had corrected QT intervals (QTc) measured at baseline and on the day after receiving post-exposure prophylaxis. The accuracy of mECG measurements as well as automated 12L-ECG measurements was evaluated. In total, 635 mECGs from 323 participants were recorded, of which 616 (97%) were of sufficient quality for QTc measurement. Mean manually read QTc on 12L-ECG and mECG were 394 ± 19 and 385 ± 18 ms, respectively (p < 0.001), with a strong correlation (r = 0.793). The mean absolute QTc difference between both modalities was 11 ± 10 ms. Mean manual and automated 12L-ECG QTc were 394 ± 19 and 409 ± 19 ms, respectively (n = 636; p < 0.001), corresponding to moderate agreement (r = 0.655). The use of a mECG device for QT interval monitoring was feasible and yielded a median absolute QTc error of 8 ms. Automated QTc measurements were less accurate, yielding longer QTc intervals.

Preliminary study on the role and mechanism of IL-6 receptor antagonists in improving post-infarction ventricular arrhythmia

Objective: To investigate the effect of tocilizumab (TCZ) on ventricular arrhythmias (VAs) after myocardial infarction (MI) in Sprague-Dawley rats and explore its potential mechanism. Methods: The random number table method was used to divide 32 adult male Sprague-Dawley rats into 4 groups: Sham group, TCZ group, MI group and MI+TCZ group, with 8 rats in each group. The MI model was established by ligation of the left anterior descending branch of the coronary artery in the MI and MI+TCZ groups, and only sutured without ligation in the Sham and TCZ groups. TCZ was injected into the left superior cervical ganglion (SCG) of rats in the TCZ and MI+TCZ groups after successful modeling or sham operation, and the same amount of normal saline was injected in the Sham and MI groups. 24 h after successful modeling, ECG of rats in each group was recorded, heart rate variability (HRV, including low frequency power (LF), high frequency power (HF), LF/HF ratio), QT interval, QTc interval were calculated, and left ventricular effective refractory period (ERP) and VA inducibility were measured. Myocardial infarct size and tissue changes were observed with triphenyl tetrazolium chloride staining and HE staining. Real-time PCR analysis was used to detect the messager RNA (mRNA) expression of interleukin-6 (IL-6) and signal transducer and activator of transcription (STAT) 3 in SCG and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in myocardial infarction periphery. The expression of c-fos in SCG was detected by immunofluorescence staining. Results: Compared with Sham group and MI+TCZ group, rats in MI group had higher LF and LF/HF ratio, longer QT interval and QTc interval, more VAs induced, lower HF and shorter ERP (P all<0.05). Triphenyl tetrazolium chloride staining and HE staining showed that rats in the Sham and TCZ groups had normal myocardial tissue structure, those in the MI group had severe myocardial injury, and those in the MI+TCZ group had less myocardial injury than those in the MI group. Real-ime PCR analysis showed that compared with Sham group and MI+TCZ group, mRNA expression levels of IL-6 and STAT3 in SCG of rats in MI group were higher, and mRNA expression level of myocardial Kcnd2 was lower (P all<0.05). Immunofluorescence staining showed that the content of c-fos in SCG of rats in MI group was higher than that of Sham group and MI+TCZ group (P all<0.05). Conclusions: TCZ may reduce neural activity of the SCG after MI by inhibiting the IL-6/STAT3 signaling pathway, thereby alleviating myocardial injury and inhibiting VAs.

Cardiac diastolic dysfunction by cigarette smoking is associated with mitochondrial integrity in the heart.

Cigarette smoking behaviors are harmful and cause one out of ten deaths due to cardiovascular disease. As population sizes grow and number of cigarette smokers increases, it is vital that we understand the mechanisms leading to heart failure in cigarette smokers. We have reported that metabolic regulation of a histone deacetylase, SIRT1, modulates cardiovascular and mitochondrial function under stress. Given this conclusion, we hypothesized that chronic cigarette smoking led to cardiovascular dysfunction via a reduction SIRT1. Mice were randomly organized into smoking or nonsmoking groups, and the smoking group received cigarette smoke exposure for 16 weeks. Following 16-week exposure, diastolic function of the heart was impaired in the smoking group as compared to sham, indicated by a significant increase in E/e'. The electrical function of the heart was also impaired in the smoking group compared to the sham group, indicated by increased PR interval and decreased QTc interval. This diastolic dysfunction was not accompanied by increased fibrosis in mouse hearts, although samples from human chronic smokers indicated increased fibrosis compared to their nonsmoker counterparts. As well as diastolic dysfunction, mitochondria from the 16-week smoking group showed significantly impaired function, evidenced by significant decreases in all parameters measured by the mitochondrial stress test. We further found biochemical evidence of a significantly decreased level of SIRT1 in left ventricles of both mouse and human smoking groups compared to nonsmoking counterparts. Data from this study indicate that decreased SIRT1 levels by cigarette smoking are associated with diastolic dysfunction caused by compromised mitochondrial integrity.

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study

Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

Electrocardiogram (ECG) changes in working people with and without history of COVID-19

Introduction: During the COVID-19 pandemic, the greatest focus was on the respiratory system, but recently awareness has increased about the cardiovascular manifestations of the COVID-19 disease and the adverse effect of cardiovascular involvement on its prognosis. Since so far no comprehensive study has investigated electrocardiogram changes in patients with COVID-19 in Iran, the purpose of this study is to assess electrocardiogram changes in adults aged 20-70 with and without a history of COVID-19. Materials and Methods: The current study was a cohort study conducted on two groups of working people with a history of COVID-19 and controls without a history of COVID-19. The case and control subjects were selected randomly from the participants of the Yazd Health study and the Shahdieh cohort study. ECG was taken from both groups before and after Covid-19 and then QTc interval and ST segment measurements were recorded and interpreted. Results: In the present study, 77 patients including 45 patients with COVID-19 (58.4%) and 32 non-COVID-19 patients (41.6%) were selected. Heart rate/min before and after COVID-19 was 69.08±10.89 and 73.5±14.05, respectively (P&lt;0.01). There was a non-significant difference before and after COVID-19 in terms of QTi, and QTc (P&gt;0.05). Conclusion: According to the results of the present study, COVID-19 disease is associated with a change in heart rate in the two studies' participants, but no effect was observed on the parameters of QTi, and QTC. Therefore, it seems that echocardiography is not necessary in patients with COVID-19.

Artificial Intelligence-Enabled Electrocardiography Predicts Future Pacemaker Implantation and Adverse Cardiovascular Events.

Medical advances prolonging life have led to more permanent pacemaker implants. When pacemaker implantation (PMI) is commonly caused by sick sinus syndrome or conduction disorders, predicting PMI is challenging, as patients often experience related symptoms. This study was designed to create a deep learning model (DLM) for predicting future PMI from ECG data and assess its ability to predict future cardiovascular events. In this study, a DLM was trained on a dataset of 158,471 ECGs from 42,903 academic medical center patients, with additional validation involving 25,640 medical center patients and 26,538 community hospital patients. Primary analysis focused on predicting PMI within 90 days, while all-cause mortality, cardiovascular disease (CVD) mortality, and the development of various cardiovascular conditions were addressed with secondary analysis. The study's raw ECG DLM achieved area under the curve (AUC) values of 0.870, 0.878, and 0.883 for PMI prediction within 30, 60, and 90 days, respectively, along with sensitivities exceeding 82.0% and specificities over 81.9% in the internal validation. Significant ECG features included the PR interval, corrected QT interval, heart rate, QRS duration, P-wave axis, T-wave axis, and QRS complex axis. The AI-predicted PMI group had higher risks of PMI after 90 days (hazard ratio [HR]: 7.49, 95% CI: 5.40-10.39), all-cause mortality (HR: 1.91, 95% CI: 1.74-2.10), CVD mortality (HR: 3.53, 95% CI: 2.73-4.57), and new-onset adverse cardiovascular events. External validation confirmed the model's accuracy. Through ECG analyses, our AI DLM can alert clinicians and patients to the possibility of future PMI and related mortality and cardiovascular risks, aiding in timely patient intervention.

Chart Review and Practical Recommendations for the Use of Methadone as an Alternative to Opioid Rotation in the Management of Cancer-Related Pain

Abstract Introduction Palliative care, with a focus on enhancing the quality of life for individuals facing life-limiting illnesses, relies on effective pain management as a fundamental component. Opioids, particularly methadone, play a crucial role in addressing moderate to severe pain in palliative care due to their unique pharmacological properties. Methadone, a long-acting opioid agonist and N-methyl-D-aspartate receptor antagonist, is valuable for treating both nociceptive and neuropathic pain. However, the transition to methadone from other opioids requires careful consideration. Objectives This study examines the use of methadone as an alternative to morphine or fentanyl for managing refractory cancer pain in a tertiary care hospital in India. Methods We conducted a retrospective analysis of anonymized medical records of cancer patients initiated on oral methadone for pain management at a tertiary cancer center's palliative medicine outpatient clinic from February 2020 to June 2021. Data included demographic characteristics, pain descriptions, concurrent analgesic use, reasons for transitioning to methadone, rotation methods, methadone dosages, clinical outcomes, adverse effects, and treatment discontinuations. Patients were routinely followed up, with pain scores, morphine equivalent daily doses, and methadone requirements recorded at each visit. Results Forty-four patients received methadone, either as a coanalgesic (41/44) or primary opioid (3/44). Refractory cancer pain, with a neuropathic component, was the predominant indication for methadone use. Following the methadone initiation, all patients experienced significant pain relief. Median daily methadone dose increased from 5 to 7.5 mg after 1 week. Adverse effects were minimal, with one patient experiencing QTc interval prolongation. Patient-specific factors often necessitated deviations from equianalgesic conversion tables in determining methadone dosages. Conclusion Methadone offers a viable option for refractory cancer pain when conventional treatments fall short. Physicians should prioritize personalized titration and thorough assessment during opioid rotation, rather than relying solely on conversion tables. Further research is needed to explore alternative approaches for opioid rotation and to expand our understanding of methadone's optimal use in cancer pain management.