Prolonged Corrected QT Research Articles

HIV and body mass index are associated with prolonged corrected QT interval among people with drug-resistant tuberculosis on bedaquiline-containing regimen in Uganda

ObjectivesPeople with drug-resistant tuberculosis (DR-TB) on bedaquiline-containing regimens are at risk for a prolonged corrected QT (QTc) interval but this problem is understudied in low-resource countries. We determined the magnitude and risk factors for QTc interval prolongation among people with DR-TB on bedaquiline-containing regimens at three referral hospitals in Uganda. MethodsUsing retrospectively collected data, we designed a matched case-control study, with cases as participants with prolonged QTc interval and controls as those with normal QTc interval in 1:1. QTc interval prolongation was defined as an increase in QTc interval by 60 milliseconds in electrocardiogram from the baseline or ≥500 milliseconds during follow-up for men and women. Factors associated with cases compared with controls were identified using a multivariable conditional regression analysis at a 5% significance level, reported using odds ratio (OR) and the 95% confidence interval (CI). ResultsOf 153 participants, 39 (25.5%) had a prolonged QTc interval. We matched 30 participants with prolonged QTc interval (cases) with 30 participants with normal QTc interval (controls). Cases and controls were similar in several sociodemographic and clinical characteristics but different regarding the baseline body mass index (BMI), baseline weight, and HIV infection. Increasing BMI (adjusted OR 1.29, 95% CI 1.02-1.63) and HIV infection (adjusted OR 0.27, 95% CI 0.08-0.96) were associated with the cases compared with the controls. ConclusionsWe found a relatively high prevalence of QTc interval prolongation among people with DR-TB on a bedaquiline-containing regimen compared with the prevalence in healthy individuals, with a higher likelihood in those with increasing BMI and a lower likelihood in those with HIV. We recommend routine anthropometric measurements to identify individuals with DR-TB at a high risk for QTc interval prolongation. In addition, tuberculosis/HIV treatment guidelines for people with DR-TB on bedaquiline-containing regimens should include risk assessment for prolonged QTc intervals.

Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC. Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS). Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n= 60), PSA50 was 32% (n= 19), including 50% (n= 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations. BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status.

Prevalence, Outcomes, and Predictors of Prolonged Corrected QT Interval in Hydroxychloroquine-Naïve Hospitalized COVID-19 Patients.

The studies regarding prevalence, outcomes, and predictors of prolonged corrected QT (QTc) among COVID-19 patients not on QTc-prolonging medication are not available in the literature. In this retrospective cohort study, the QTc of 295 hospital-admitted COVID-19 patients was analyzed and its association with in-hospital mortality was determined. The QTc was prolonged in 14.6% (43/295) of the study population. Prolonged QTc was seen in patients with older age (P = 0.018), coronary artery disease (P = 0.001), congestive heart failure (P = 0.042), elevated N-terminal-pro-B-type natriuretic peptide (NT-ProBNP) (P < 0.0001), and on remdesivir (P = 0.046). No episode of torsades de pointes arrhythmia or any arrhythmic death was observed among patients with prolonged QTc. The mortality was significantly high in patients with prolonged QTc (P = 0.003). The multivariate logistic regression analysis showed coronary artery disease (odds ratio (OR): 4.153, 95% CI 1.37-14.86;P = 0.013), and NT-ProBNP (ng/L) (OR: 1.000, 95% CI 1.000-1.000;P = 0.007) as predictors of prolonged QTc. The prolonged QTc was associated with the worst in-hospital survival (p by log-rank 0.001). A significant independent association was observed between prolonged QTc and in-hospital mortality in multivariate cox-regression analysis (adjusted hazard ratio: 3.861; (95% CI 1.719-6.523), P < 0.0001). QTc was found to be a marker of underlying comorbidities among COVID-19 patients. Prolonged QTc in hospitalized COVID-19 patients was independently associated with in-hospital mortality.

Investigating corrected QT prolongation with hydroxychloroquine use among patients with cutaneous sarcoidosis: A multicenter retrospective study

Investigating corrected QT prolongation with hydroxychloroquine use among patients with cutaneous sarcoidosis: A multicenter retrospective study

#886 Prevalence and prognostic relevance of electrocardiographic abnormalities among patients with ANCA-associated vasculitis

Abstract Background and Aims Cardiovascular disease (CVD) is one of the leading causes of death in patients with ANCA-associated vasculitis (AAV). However, in current clinical guidelines, limited evidence is available to support the recommendation of AAV-specific screening for cardiovascular comorbidities. This study reported the prevalence of electrocardiogram (ECG) abnormalities and investigated associations between ECG abnormalities and fatal CVD in a validated cohort of patients with AAV compared to matched controls. Method Based on a retrospective matched cohort design, patients with granulomatosis with polyangiitis [ICD-10: DM31.3] or microscopic polyangiitis [ICD-10: DM3.17] and accessible ECGs were identified in nationwide Danish health care registers from 2000 to 2021. Patients with AAV were matched 1:3 on age, sex, and calendar year of ECG measurement with controls without AAV. Index date was defined as the date of ECG measurement. ECGs were hierarchically categorized as either no, minor, or major ECG abnormalities according to contemporary literature. The associations between ECG abnormalities and fatal CVD were assessed in multiple Cox regression models adjusted for age, sex, and comorbidities. Counterfactual G-estimation of hazard ratios (HRs) standardized to age and sex was performed to estimate the 5-year absolute risk (AR) of fatal CVD according to ECG-abnormalities. Results A total of 1431 patients with AAV were matched to 4293 controls. The median age of patients with AAV and matched controls was 69 (IQR 58-77) years, and 52.3% were males. Median study follow-up time was 4.8 (IQR, 2.7-7.8) years. AAV was associated with increased prevalence of left ventricular hypertrophy (17.5% vs. 12.5%, p &amp;lt; 0.001), ST-T deviations (10.1% vs. 7.1%, p &amp;lt; 0.001), atrial fibrillation (9.6% vs. 7.5%, p = 0.017) and corrected QT prolongation (5.9% vs. 3.6%, p &amp;lt; 0.001) compared to controls. When examining associations of fatal CVD across no, minor or major ECG abnormalities, only the patients with AAV and major ECG abnormalities had a higher risk of fatal CVD [HR 1.99 (95% CI, 1.49-2.65)], compared to matched controls. This corresponded to a significantly higher standardized 5-year AR of fatal CVD compared to controls: 19.14% (95% CI, 16-22%) vs. 9.41% (95% CI, 8-11%). Conclusion AAV was associated with a higher prevalence of major ECG abnormalities such as left ventricular hypertrophy, atrial fibrillation, and ST-T deviations compared to matched controls. Moreover, the patients with AAV demonstrating major ECG abnormalities had a particularly elevated risk of fatal CVD. This indicates that AAV patients with major ECG abnormalities are a distinct high-risk group within AAV patients prone to cardiovascular-related mortality.

Extracellular Kir2.1C122Y Mutant Upsets Kir2.1-PIP2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.

Deep Learning–Augmented ECG Analysis for Screening and Genotype Prediction of Congenital Long QT Syndrome

Congenital long QT syndrome (LQTS) is associated with syncope, ventricular arrhythmias, and sudden death. Half of patients with LQTS have a normal or borderline-normal QT interval despite LQTS often being detected by QT prolongation on resting electrocardiography (ECG). To develop a deep learning-based neural network for identification of LQTS and differentiation of genotypes (LQTS1 and LQTS2) using 12-lead ECG. This diagnostic accuracy study used ECGs from patients with suspected inherited arrhythmia enrolled in the Hearts in Rhythm Organization Registry (HiRO) from August 2012 to December 2021. The internal dataset was derived at 2 sites and an external validation dataset at 4 sites within the HiRO Registry; an additional cross-sectional validation dataset was from the Montreal Heart Institute. The cohort with LQTS included probands and relatives with pathogenic or likely pathogenic variants in KCNQ1 or KCNH2 genes with normal or prolonged corrected QT (QTc) intervals. Convolutional neural network (CNN) discrimination between LQTS1, LQTS2, and negative genetic test results. The main outcomes were area under the curve (AUC), F1 scores, and sensitivity for detecting LQTS and differentiating genotypes using a CNN method compared with QTc-based detection. A total of 4521 ECGs from 990 patients (mean [SD] age, 42 [18] years; 589 [59.5%] female) were analyzed. External validation within the national registry (101 patients) demonstrated the CNN's high diagnostic capacity for LQTS detection (AUC, 0.93; 95% CI, 0.89-0.96) and genotype differentiation (AUC, 0.91; 95% CI, 0.86-0.96). This surpassed expert-measured QTc intervals in detecting LQTS (F1 score, 0.84 [95% CI, 0.78-0.90] vs 0.22 [95% CI, 0.13-0.31]; sensitivity, 0.90 [95% CI, 0.86-0.94] vs 0.36 [95% CI, 0.23-0.47]), including in patients with normal or borderline QTc intervals (F1 score, 0.70 [95% CI, 0.40-1.00]; sensitivity, 0.78 [95% CI, 0.53-0.95]). In further validation in a cross-sectional cohort (406 patients) of high-risk patients and genotype-negative controls, the CNN detected LQTS with an AUC of 0.81 (95% CI, 0.80-0.85), which was better than QTc interval-based detection (AUC, 0.74; 95% CI, 0.69-0.78). The deep learning model improved detection of congenital LQTS from resting ECGs and allowed for differentiation between the 2 most common genetic subtypes. Broader validation over an unselected general population may support application of this model to patients with suspected LQTS.

Electrocardiographic abnormalities in patients with sickle cell disease: A systematic review and meta-analysis.

Previous studies have documented that electrocardiography (ECG) can reveal a range of abnormalities, offering valuable insights into the cardiac evaluation of patients with sickle cell disease (SCD). The objective of this study is to assess the patterns of ECG abnormalities observed in these patients with SCD, and to determine their prevalence. We systematically reviewed the literature using online databases of PubMed, Scopus, Web of Science, Embase, and Google Scholar to identify original studies that reported findings of standard ECG assessments in patients with SCD. Statistical analyses were performed using the random effects model. Additional analyses including sensitivity analysis and subgroup analysis were also conducted. Analysis of data from 59 studies involving 897,920 individuals with SCD revealed that 75% of these patients had abnormal ECG findings (67%-81%), which were predominantly nonspecific ST-T changes, left ventricular hypertrophy, T-wave changes, prolonged corrected QT (QTc) interval, and ischemic changes. Besides, it was shown that these patients had significantly higher odds of having any ECG abnormalities (OR of 17.50, 4.68-65.49), right atrial enlargement (6.09, 1.48-25.09), left ventricular hypertrophy (3.45, 1.73-6.89), right ventricular hypertrophy (7.18, 2.28-22.57), biventricular hypertrophy (10.11, 1.99-51.38), prolonged QTc interval (5.54, 2.44-12.59), ST depression (3.34, 1.87-5.97), and T-wave changes (5.41, 1.43-20.56). Moreover, the mean of QTc interval was significantly higher among those with SCD (23.51milliseconds, 16.08-30.94). Our meta-analysis showed a higher prevalence of abnormal ECG findings among individuals with SCD. A significant proportion of these patients had various ECG abnormalities, suggesting a potential need for regular ECG assessments for patients with SCD.

Prevalence of prolonged QTc interval among HIV infected patients on highly active antiretroviral therapy (HAART) and its relationship with CD4 cells count and viral load at a tertiary hospital in North Eastern Nigeria.

Patients living with HIV infection remain at increased risk of cardiovascular diseases and sudden cardiac death. Various prevalence of electrocardiographic (ECG) abnormalities among HIV-infected patients were reported: Attamah et al reported the prevalence of electrocardiographic abnormalities among HIV-infected patients as 34.5%, while Orunta et al reported a prevalence of 42.9%, and Njoku et al reported a prevalence of 93.0%. Human immunodeficiency virus-infected patients are at increased risk of developing prolonged QT interval. Sani et al reported the prevalence of prolonged corrected QT interval among HIV-infected patients as 45.0%. Innocent et al reported a prevalence of48.0%, while Ajala et al reported a prevalence of 18%. Prolonged QTc interval increases the risk of premature ventricular contraction which can degenerate into ventricular tachycardia and or ventricular that can result in sudden cardiac death. The study was a cross-sectional conducted among HIV-infected patients receiving HAART at the Federal Medical Centre Nguru, Yobe State, North Eastern Nigeria. One hundred and seven (107) subjects were recruited into the study comprising thirty-three (37.0%) males and 70(65.4%) females. The mean CD4 cell count, and viral load of the studied patients were 612.64±34.75 cells/μL and4646.30±58.68 copies/mL respectively. Twenty (18.7%) patients had prolonged QTc interval, this gave us the prevalence of prolonged QTc in this study as 18.7%. The commonest cardiac rhythm was sinus rhythm (69.2%), followed by sinus tachycardia (26.2%) and atrial fibrillation 5(4.7%). Other electrocardiographic findings include First-degree atrioventricular block was seen in seven (6.5%) patients, Premature ventricular contractions were found in16.8%, RBBB was observed in 2.8%, 3.7% of patients had LBBB and 4.7% had left posterior hemiblock. The distribution of QTc interval according to CD4 cells count and viral revealed a statistically significant difference across the groups. All the patients with prolonged QTc interval had lower CD4 cells count and higher viral load suggesting that HIV disease severity is associated with prolonged QTc interval. In conclusion, the study revealed that the prevalence of prolonged QTc interval among HIV infected patients on highly active antiretroviral therapy was found to be 18.7%, and that HIV disease severity increases the risk of developing prolonged QTc interval.

The Heart of Rett Syndrome: A Quantitative Analysis of Cardiac Repolarization.

Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, MECP2 patients had prolonged QTc compared to CDKL5 and FOXG1 patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients. Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.

A Scoping Review of Varying Mobile Electrocardiographic Devices.

The electrocardiogram (ECG) can now be measured using mobile devices. Mobile ECG devices, which are defined as devices capable of recording and transmitting non-standard ECGs, offer numerous advantages such as cost-effectiveness and being user-friendly. Mobile ECG can also extend recording lengths (e.g., 2days, 14days), which is necessary to capture important intermittent events (e.g., cardiac arrhythmias) and evaluate prognostic risk markers (e.g., prolonged corrected QT (QTc) interval). Some mobile ECG devices can even connect to broadband networks allowing patients to remotely transmit their ECG to a clinician. This article systematically examines different mobile ECG devices used in prior studies and provides a detailed assessment of five diverse yet commonly used mobile ECG devices: AliveCor KardiaMobile; AliveCor KardiaMobile 6L; iRhythm ZioPatch; Apple Smartwatch ECG; and CardioSecur System. These mobile ECG devices are diverse in the number of leads measured and the duration of monitoring. Similar to their diversity, there has been a wide range of clinical applications of mobile ECG devices. Despite significant progress, questions regarding data quality, and clinican and patient acceptance and compliance persist.

Relationship between corrected QT prolongation and new-onset atrial fibrillation in the general Japanese population

Abstract Background The QT interval, an electrocardiogram (ECG) parameter, can be corrected for heart rate, giving the QTc. The QTc is an indicator of ventricular repolarisation and is widely used as a predictor of ventricular arrhythmia. Recent studies have reported a relationship between prolonged QTc and atrial fibrillation (AF) development. Purpose We investigated whether a relationship between QTc prolongation and new-onset AF could be identified in the general Japanese population. Methods This retrospective study evaluated the annual health check-up data of 103,304 adults (50,438 males; age, 54±15 years) that did not have AF at baseline, from April 2005 to October 2018. Most participants underwent annual health examinations as recommended by the Japanese health welfare policy. The QTc times were calculated with the Bazett formula (QTc=QT/√RR), using the mean QT and RR intervals. Participants were grouped according to QTc time: long-QTc group (males, &amp;gt;440 ms; females, &amp;gt;460 ms) and normal-QTc group. AF was diagnosed using a 12-lead surface ECG. Logistic regression analyses were performed to determine the strength of the association between prolonged QTc and new-onset AF. Multivariate analyses were adjusted for clinical variables (age, sex, obesity, hypertension, dyslipidaemia, diabetes, estimated glomerular filtration rate, and habitual drinking). Results The median follow-up time for the total study population was 6 years. During follow-up, 341 (0.3%) new cases of AF were recorded. Univariate analysis revealed a significant increase in new-onset AF in the long-QTc group (odds ratio [OR], 2.80; 95% confidence interval [CI], 1.85–4.25; p&amp;lt;0.001). After adjusting for clinical variables, multivariate analysis revealed that a long QTc was significantly associated with new-onset AF (OR, 1.71; 95% CI, 1.12–2.61; p=0.013). In the multivariate analysis, age (OR, 1.06; 95% CI, 1.05–1.07; p&amp;lt;0.001), sex (OR, 2.55; 95% CI, 1.95–3.33; p&amp;lt;0.001), obesity (OR, 1.46; 95% CI, 1.16–1.84; p=0.001), and habitual drinking (OR, 1.90; 95% CI, 1.50–2.41; p&amp;lt;0.001) were also significant predictors of new-onset AF. Conclusions Prolonged QTc is associated with an increased risk of new-onset AF in the general Japanese population. The mechanism of this causal relationship requires further investigation.

Hypokalemia as a risk factor for prolonged QT interval and arrhythmia in inherited salt-losing tubulopathy

Purpose: To analyze electrocardiograms (ECGs) of patients with a salt-losing tubulopathy (SLT) and to determine the frequency and risk factors for long QT and arrhythmia.Methods: A total of 203 patients aged &lt;19 years with SLT, specifically Bartter syndrome and Gitelman syndrome, who had a 12-lead ECG were included in this retrospective study. We analyzed the presence of an arrhythmia or prolonged corrected QT (QTc) on ECGs obtained for these patients. Demographic and laboratory data were compared between patients with abnormal and normal ECG findings.Results: Out of the 203 SLT patients, 38 (18.7%) underwent electrocardiography and 10 (40.0%) of 25 patients with inherited SLT had abnormal ECG findings, including prolonged QTc and arrhythmias. The abnormal ECG group had significantly lower serum potassium levels than the normal group (median [interquartile range]: 2.50 mmol/L [2.20–2.83] vs. 2.90 mmol/L [2.70–3.30], &lt;i&gt;p&lt;/i&gt;=0.036), whereas other serum chemistry values did not show significant differences. The cutoff level for a significant difference in QTc interval was serum potassium level &lt;2.50 mmol/L. One cardiac event occurred in a 13-year-old boy, who developed paroxysmal supraventricular tachycardia and underwent cardiac ablation. No sudden cardiac deaths occurred in this cohort.Conclusions: The incidence of ECG abnormalities in patients with inherited SLT was 40.0%, whereas the ECG screening rate was relatively low (18.7%). Therefore, we recommend ECG screening in patients with inherited SLT, especially in those with serum potassium level &lt;2.50 mmol/L.

The Impact of Chronic Disease on the Corrected QT (QTc) Value in Women in a British Columbia First Nations Population

BackgroundIndigenous women have higher rates of chronic disease than Indigenous men and non-Indigenous women. Long QT syndrome (LQTS) can be inherited or acquired; the latter may occur with chronic disease. A prolonged corrected QT value (QTc) is an independent risk factor for ventricular arrhythmias and sudden death, but few studies have quantified the impact of chronic disease on the QTc. We assessed the association between chronic disease and QTc prolongation in a population of First Nations women previously ascertained to study a high rate of inherited LQTS due to a unique genetic (founder) variant in their community. MethodsThis substudy focusing on women expands on the original research where patients with clinical features of LQTS and their relatives were assessed for genetic variants discovered to affect the QTc. Medical records were retrospectively reviewed and chronic diseases documented. Using multivariate linear regression, adjusting for the effect of genetic variants, age, and QTc-prolonging medications, we evaluated the association between chronic disease and the QTc. ResultsIn total, 275 women were included. After adjustments, a prolonged QTc was associated with coronary artery disease (26.5 ms, 95% confidence interval [CI] 9.0-44.1 ms; P = 0.003), conduction system disease (26.8 ms, 95% CI 2.2-51.4 ms; P = 0.033), rheumatoid arthritis (28.9 ms, 95% CI 12.7-45.1 ms; P = 0.001), and type 2 diabetes mellitus (17.9 ms, 95% CI 3.6-32.3 ms; P = 0.015). ConclusionsThis quantification of the association between chronic disease and QTc prolongation in an Indigenous cohort provides insight into the nongenetic determinants of QTc prolongation. Corroboration in other populations will provide evidence for generalisability of these results.

Impact of Cerium Oxide Nanoparticles on Metabolic, Apoptotic, Autophagic and Antioxidant Changes in Doxorubicin-Induced Cardiomyopathy: Possible Underlying Mechanisms.

In the current study, the effects of cerium oxide nanoparticles (nanocerium; NC) on doxorubicin (DOX)-induced cardiomyopathy and its possible underlying mechanisms were addressed. 32 adult male rats were allocated into 4 groups; i) control group, ii) NC group; rats received NC (0.2 mg/kg, i.p., daily), iii) DOX group; rats received DOX 4 mg/kg (2 injections with a 14-day interval), and iv) DOX+NC group as DOX but rats received NC. At the end of the experiment, ECG and ECHO recordings and assessments of the levels of cardiac enzymes (CK-MB, LDH), and myocardial oxidative stress (MDA, catalase, and GSH), the expression of LC3 and beclin1 (markers of autophagy), caspase3 (marker of apoptosis) by immunohistochemistry, the expression of acetyl-CoA carboxylase alpha (ACCA) by PCR, and 5'adenosine monophosphate-activated protein kinase (AMPK) levels in the heart tissues were performed. The DOX group displayed a prolonged corrected QT interval, an increase in cardiac enzymes (CK-MB and LDH), myocardial oxidative stress (high MDA with low catalase and GSH), expression of ACCA, caspase-3, beclin1, and LC3 in myocardial tissues, with reduction in myocardial AMPK levels, and myocardial contractility (low ejection fraction, and fractional shortening). On the other hand, administration of NC with DOX resulted in significant improvement of all studied parameters. NC offers a cardioprotective effect against DOX-induced cardiomyopathy. This effect might be due to its antioxidant and antiapoptotic effects as well as to the modulation of autophagy and metabolic dysfunctions induced by DOX in the heart tissues.

Tako-Tsubo syndrome in patients with COVID-19: a single-center retrospective case series.

Growing evidence shows that COVID-19 is associated with an increase in Tako-Tsubo syndrome (TTS) incidence. We collected data from patients hospitalized in our multidisciplinary COVID-19 department who had a diagnosis of TTS during the second and third waves of the pandemic in Italy. We reported four cases of TTS associated with COVID-19. Except for COVID-19, no patient had any classical TTS triggers. The mean age was 72 years (67-81) and all patients had COVID-19-related interstitial pneumonia confirmed by computed tomography. Typical apical ballooning and transitory reduction in left ventricle (LV) systolic function with a complete recovery before discharge were observed in all patients. The mean LV ejection fraction at TTS onset was 42% (40-48%). The electrocardiogram showed ST-segment elevation in two cases, while an evolution with negative T waves and corrected QT prolongation was observed in all patients. Three patients underwent coronary angiography. Two patients had Alzheimer's disease. The time interval from hospital admission to TTS onset was 4 (2-6) days, and the time interval from COVID-19 symptom onset to TTS diagnosis was 10 (8-12) days. COVID-19 may be a trigger for TTS, though TTS pathophysiology in COVID-19 patients remains unclear, likely due to its multifactorial nature.

Sex and Gene Influence Arrhythmia Susceptibility in Murine Models of Calmodulinopathy.

Pathogenic variants in genes encoding CaM (calmodulin) are associated with a life-threatening ventricular arrhythmia syndrome (calmodulinopathy). The in vivo consequences of CaM variants have not been studied extensively and there is incomplete understanding of the genotype-phenotype relationship for recurrent variants. We investigated effects of different factors on calmodulinopathy phenotypes using 2 mouse models with a recurrent pathogenic variant (N98S) in Calm1 or Calm2. Genetically engineered mice with heterozygous N98S pathogenic variants in Calm1 or Calm2 were generated. Differences between the sexes and affected genes were assessed using multiple physiological assays at the cellular and whole animal levels. Statistical significance among groups was evaluated using 1-way ANOVA or the Kruskal-Wallis test when data were not normally distributed. Calm1N98S/+ (Calm1S/+) or Calm2N98S/+ (Calm2S/+) mice exhibited sinus bradycardia and were more susceptible to arrhythmias after exposure to epinephrine and caffeine. Male Calm1S/+ mice had the most severe arrhythmia phenotype with evidence of early embryonic lethality, greater susceptibility for arrhythmic events, frequent premature beats, corrected QT prolongation, and more heart rate variability after epinephrine and caffeine than females with the same genotype. Calm2 S/+ mice exhibited a less severe phenotype, with female Calm2 S/+ mice having the least severe arrhythmia susceptibility. Flecainide was not effective in preventing arrhythmias in heterozygous CaM-N98S mice. Intracellular Ca2+ transients observed in isolated ventricular cardiomyocytes from male heterozygous CaM-N98S mice had lower peak amplitudes and slower sarcoplasmic reticulum Ca2+ release following in vitro exposure to epinephrine and caffeine, which were not observed in cardiomyocytes from heterozygous female CaM-N98S mice. We report heterogeneity in arrhythmia susceptibility and cardiomyocyte Ca2+ dynamics among male and female mice heterozygous for a recurrent pathogenic variant in Calm1 or Calm2, illustrating a complex calmodulinopathy phenotype in vivo. Further investigation of sex and genetic differences may help identify the molecular basis for this heterogeneity.

#4771 PROGNOSTIC RELEVANCE OF ELECTROCARDIOGRAPHIC ABNORMALITIES ACCORDING TO EGFR CATEGORIES

Abstract Background and Aims Electrocardiogram (ECG) abnormalities are associated with adverse cardiovascular outcomes in patients with chronic kidney disease (CKD), but their prognostic relevance according to estimated glomerular filtration rate (eGFR) categories remains unexplored. This study investigated the associations between no, minor, and major ECG abnormalities and fatal cardiovascular disease (CVD) according to different strata of renal function. Method This was a retrospective cohort study including 310.060 individuals aged ≥16 years from the Copenhagen General Practitioners' Laboratory that had an available digital ECG and creatinine measurement within 7 days from 2001–2015. eGFR was calculated using The Chronic Kidney Disease Epidemiology Collaboration equation, and data were cross-linked with Danish nation-wide healthcare registries to gain information on medication, comorbidity, and fatal CVD. ECG abnormalities were categorized as either no abnormalities, minor (first-degree atrioventricular block, incomplete bundle branch block or corrected QT prolongation) or major (left ventricular hypertrophy, atrial fibrillation/flutter, bundle branch block, Q waves, or ST-T deviations), as done previously [1]. Patients with both minor and major ECG abnormalities were assigned as major ECG abnormalities. ECG abnormalities and their association with fatal CVD were compared across strata of renal function [eGFR (ml/min/1.73m2) &amp;gt;90, 61–90, 46–60, 31–45, 16–30 and ≤15] based on multivariable Cox-regression analysis adjusted for age, sex, and comorbidities. Counterfactual G-estimation of Hazard Ratios (HRs) standardized to age and sex was performed to estimate 5-year absolute risk of fatal CVD. Results The median age was 55 [IQR, 41-69] years and 46% were male. Median study follow-up time was 10.3 [IQR, 6.7-14.4] years. A total of 47,249 (17.9%) of the included patients had an eGFR &amp;lt;60. The rate of fatal CVD according to ECG abnormalities and their adjusted HRs is shown in Fig. 1, while 5-year standardized risk of fatal CVD is depicted in Fig. 2. Generally, having minor or major ECG abnormalities, conferred a worse prognosis across all eGFR strata, with the highest 5-year absolute risk of fatal CVD being observed among patients with major ECG abnormalities and an eGFR between 31–45 [19% (95% CI, 18–20%)], eGFR 16–30 [25% (95% CI, 24–26%)] or an eGFR ≤15 [27.5% (95% CI, 24–31%)], Fig. 1–2. Conclusion In a population-based setting, having minor or major ECG abnormalities were associated with an increased risk of fatal CVD across all strata of renal function. Patients with an eGFR ≤45 and major ECG abnormalities represent a high-risk population, that might benefit from careful monitoring and cardiovascular risk management.

Remote Monitoring of the QT Interval During Polychemotherapy

Aim To evaluate the incidence of prolonged corrected QT interval (QTc) by remote single-channel electrocardiogram (ECG) monitoring in primary oncological patients with elective polychemotherapy (PCT).Material and methods This study included 49 oncological patients with elective PCT. A single-channel portable CardioQVARK electrocardiograph was used to record single-channel, one-lead ECG between the first and second courses of PCT.Results Analysis of QTc interval detected a prolonged QTc interval &gt;500 msec in 8.2 % of cases, prolonged QTc &gt;480 msec in 18.3 % f cases, and prolonged QTc interval &gt;60 msec compared to baseline in 12.2 % of cases.Conclusion Remote recording of single-channel ECG using a portable electrocardiograph is an effective method for recording and detecting various forms of heart rhythm disorders.

Gefitinib Increases the Incidence of QT Prolongation in Patients with Non-Small Cell Lung Cancer.

Gefitinib (GEF) may increase the risk of corrected QT prolongation (QTc). We aimed to evaluate whether gefitinib increases the risk of corrected QT interval (QTc) prolongation and analyze the associated risk factors.A total of 122 cases of advanced EGFR-mutated non-small cell lung cancer (NSCLC) who received gefitinib therapy from January 2015 to December 2020 were evaluated. The results of at least two resting 12-lead electrocardiogram before and after gefitinib treatment were obtained. The Bazett and Fridericia formulas were used to calculate the QTc interval, and the changes of QTc interval values before and after treatment were evaluated. The correlation between gefitinib and QTc interval prolongation and related risk factors were analyzed.After gefitinib-targeted therapy, 23 patients (18.9%) had a prolonged QTc interval, which increased from a mean of 446 ± 25 ms at baseline to 478 ± 18 ms (P < 0.001). Three of the patients met criteria for Grade 3 QTc prolongation in the common term V5.0 for clinical adverse events. Univariate analysis showed that age (ORR, 1.054; 95% confidence interval [CI], 1.003-1.107; P = 0.038), history of hypertension (ORR, 3.409; 95% CI, 1.334-8.713; P = 0.01), CCB medication history (ORR, 0.259; 95% CI, 0.094-0.712; P = 0.009), history of lung cancer surgery (ORR, 0.231; 95% CI, 0.064-0.829; P = 0.025), and baseline QT interval (ORR, 0.978; 95% CI, 0.964-0.993; P = 0.004) were important predictors of QTc interval prolongation in patients treated with gefitinib. The results of multivariate analysis showed that the history of lung cancer surgery and the baseline QT interval were important factors affecting QTc interval prolongation in patients treated with gefitinib.Gefitinib increases the risk of QTc prolongation in NSCLC patients, which may be more pronounced in patients with advanced age, hypertension, CCB therapy, lung cancer surgery, and a long QT interval at baseline.