Elevated Interleukin-6 Levels Are Associated With an Increased Risk of QTc Interval Prolongation in a Large Cohort of US Veterans.

BACKGROUND: Although accumulating data indicate that IL-6 (interleukin-6) can promote heart rate-corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac electrophysiology, current evidence comes from basic investigations and small clinical studies only. Therefore, IL-6 is still largely ignored in the clinical management of long-QT syndrome and related arrhythmias. The aim of this study was to estimate the risk of QTc prolongation associated with elevated IL-6 levels in a large population of unselected subjects. METHODS AND RESULTS: An observational study using the Veterans Affairs Informatics and Computing Infrastructure was performed. Participants were US veterans who had an ECG and were tested for IL-6. Descriptive statistics and univariate and multivariate regression analyses were performed to study the relationship between IL-6 and QTc prolongation risk. Study population comprised 1085 individuals, 306 showing normal (<5 pg/mL), 376 moderately high (5-25 pg/mL), and 403 high (>25 pg/mL) IL-6 levels. Subjects with elevated IL-6 showed a concentration-dependent increase in the prevalence of QTc prolongation, and those presenting with QTc prolongation exhibited higher circulating IL-6 levels. Stepwise multivariate regression analyses demonstrated that increased IL-6 level was significantly associated with a risk of QTc prolongation up to 2 times the odds of the reference category of QTc (e.g. QTc >470 ms men/480 ms women ms: odds ratio, 2.28 [95% CI, 1.12-4.50] for IL-6 >25 pg/mL) regardless of the underlying cause. Specifically, the mean QTc increase observed in the presence of elevated IL-6 was quantitatively comparable (IL-6 >25 pg/mL:+6.7 ms) to that of major recognized QT-prolonging risk factors, such as hypokalemia and history of myocardial infarction. CONCLUSIONS: Our data provide evidence that a high circulating IL-6 level is a robust risk factor for QTc prolongation in a large cohort of US veterans, supporting a potentially important arrhythmogenic role for this cytokine in the general population.

Prevalence and Risk Factors of QTc Prolongation in Prostate Cancer Patients Undergoing Brachytherapy.

QTc prolongation is linked to Torsade de Pointes, sudden cardiac death, and overall cardiovascular mortality. 754 prostate cancer patients undergoing brachytherapy were analyzed, prolonged QTc was defined as ≥450ms. A prolonged QTc was more frequent (10.1 vs. 5.1%, p = 0.040) in patients with high-risk cancer than in low to intermediate risk patients. The absolute QTc-time was correlated with age (r = 0.125), neutrophil count (r = 0.130) and negatively correlated with the testosterone level (r=-0.205). Treating physicians should be aware of this and monitor the QTc during ADT to possibly decrease cardiac morbidity/mortality in these patients who are more likely to require ADT.

De novo electrocardiographic abnormalities in persons living with HIV.

Persons living with HIV (PLWH) may have increased incidence of cardiovascular events and longer QTc intervals than uninfected persons. We aimed to investigate the incidence and risk factors of de novo major electrocardiogram (ECG) abnormalities and QTc prolongation in well-treated PLWH. We included virologically suppressed PLWH without major ECG abnormalities, who attended the 2-year follow-up in the Copenhagen comorbidity in HIV infection (COCOMO) study. ECGs were categorized according to Minnesota Code Manual. We defined de novo major ECG abnormalities as new major Minnesota Code Manual abnormalities. Prolonged QTc was defined as QTc > 460 ms in females and QTc > 450 ms in males. Of 667 PLWH without major ECG abnormalities at baseline, 34 (5%) developed de novo major ECG abnormalities after a median of 2.3 years. After adjustment, age (RR: 1.57 [1.08-2.28] per decade older), being underweight (RR: 5.79 [1.70-19.71]), current smoking (RR: 2.34 [1.06-5.16]), diabetes (RR: 3.89 [1.72-8.80]) and protease inhibitor use (RR: 2.45 [1.27-4.74) were associated with higher risk of getting de novo major ECG abnormalities. Of PLWH without prolonged QTc at baseline, only 11 (1.6%) participants developed de novo prolonged QTc. Five percent of well-treated PLWH acquired de novo major ECG abnormalities and protease inhibitor use was associated with more than twice the risk of de novo major ECG abnormalities. De novo prolonged QTc was rare and did not seem to constitute a problem in well-treated PLWH.

Polymorphic Ventricular Tachycardia with QT Interval Prolongation Due to a Brain Tumor.

We herein report the case of a 20-year-old man with a history of epilepsy who presented with frequent transient loss of consciousness (T-LOC) and polymorphic ventricular tachycardia (VT) with QT interval prolongation. Blood investigations revealed panhypopituitarism. Following a biopsy, he was diagnosed with brain germinoma. During the biopsy, he had an episode of polymorphous VT with QT prolongation. There was no recurrence of T-LOC following chemotherapy and hormone replacement therapy. This case indicates the importance of checking the QT interval in patients with T-LOC, including those with seizures and brain tumors, to ensure appropriate treatment.

QTc interval in survivors of out of hospital cardiac arrest.

BACKGROUND: QTc interval (QTc) prolongation is seen on the post-arrest electrocardiogram (ECG) of many out of hospital cardiac arrest (OHCA) survivors. It remains unclear whether this is a transient phenomenon or a manifestation of an underlying arrhythmic substrate. This observational study assessed the trend of QTc in an unselected group of patients presenting with OHCA. We sought to identify any relationship between QTc, gender and aetiology of arrest. We observed whether targeted temperature management (TTM) is associated with malignant arrhythmia. METHOD: We analysed 60 patients presenting with OHCA to the Bristol Heart Institute during a 20-month period. We measured QTc on admission and assessed for persistence, development and resolution of prolongation at up to 5 time points post-OHCA. Aetiology of arrest was divided into coronary, non-coronary or primary arrhythmic to investigate for patterns in QTc behaviour. RESULTS: 81.7% (49/60) of arrests were attributed to an acute coronary event. 55% (33/60) had QTc prolongation on admission, of which 79% resolved. There were no significant differences in QTc behaviour by aetiology. One patient presenting with a normal QTc, developed prolongation during admission and received a genetic diagnosis of Long QT Syndrome. TTM was employed in 57/60, with no increased incidence of malignant arrhythmia. CONCLUSIONS: Prolonged QTc on admission does not imply a primary arrhythmic aetiology and resolves in the majority pre-discharge. However, an initial normal QTc post-OHCA does not preclude a diagnosis of Long QT syndrome, highlighting the importance of thorough investigations in these patients. TTM appears safe from a cardiac perspective.

Malignant prolongation of the QTc interval due to severe vitamin D deficiency: an unusual presentation.

Long QT syndrome with Torsades de Pointes (TdP) is a life-threatening polymorphic ventricular arrhythmia. The corrected QT (QTc) prolongation >500 milliseconds (ms) has been associated with TdP. Hypocalcaemia due to severe vitamin D deficiency is an uncommon cause of acquired long QT. We hereby present a case of a 40-year-old woman with sensorineural deafness and having symptoms of palpitations and presyncope. She had a QTc interval of 556 ms (reference range, QTc 451-470 ms in adult healthy woman) on 24-hour Holter analysis. Genetic analysis for congenital long QT syndrome was negative. She was diagnosed with severe hypocalcaemia secondary to severe vitamin D deficiency. After treatment with intravenous calcium gluconate, followed by oral vitamin D and calcium supplementation, the QTc became normalised and no further episode of palpitations or presyncope occurred. The causes of vitamin D deficiency was due to inadequate exposure to sunlight and a strict vegan diet.

System biological investigations of hydroxychloroquine and azithromycin targets and their implications in QT interval prolongation.

COVID-2019 pandemic is affecting people worldwide in the absence of an effective treatment strategy. Several suggestive therapeutic options through drug repurposing are recommended, but a complete consensus is not reached. A combination of Hydroxychloroquine (HCQ) and Azithromycin (AZM) has been widely tried and discussed but its administration has also led to potential adversities in patients. Studies are suggesting that most prominent adverse event with HCQ and AZM combination is QT interval prolongation. We studied interaction of HCQ with AZM and subsequent effect of this drug combination on QT interval prolongation. We performed system biological investigation of HCQ and AZM targets and screened important targets and pathways possibly involved in QT interval prolongation. The best core hub protein drug targets involved in QT interval prolongation were identified as HSP90AA1 exclusively associated with HCQ, while AKT1 exclusively associated with AZM on the basis of node degree value. It was found that PI3K/Akt, VEGF, ERBB2 pathways must be given consideration for understanding the role of HCQ and AZM in QT interval prolongation. Conclusion: Computational methods have certain limitations based on source database coverage and prediction algorithms and therefore this data needs experimental correlation to draw final conclusion, but current findings screen targets for QT interval prolongation associated with HCQ and AZM. These proteins and pathways may provide ways to reduce this major risk associated with this combination.

Palliative and Supportive Care Prescribing Considerations Around QT Prolongation Risk in the Context of COVID-19 (Coronavirus Disease 2019) Management.

COVID-19 brings with it unprecedented challenges in clinical management. An important component of care is the provision of safe and effective symptom control. Given the emerging literature reporting on the risk of QT prolongation and arrhythmias associated with COVID-19 disease and experimental therapies, we highlight some considerations for the prescribing of palliative care medications in this context. Based on the experience gained from palliative care referrals at our institution prior to and during the COVID-19 pandemic, and in collaboration with our clinical pharmacology colleagues, we outline some general prescribing principles which may assist with weighing the risks and benefits of prescribing symptomatic medications in and beyond the current pandemic.

A Case of Severe QTc Prolongation During Targeted Temperature Management - What Can We Learn?

BACKGROUND QTc prolongation during targeted temperature management (TTM) post cardiac arrest is a known effect of hypothermia, but its significance is unclear. Several studies suggest that temporary prolongation during TTM is not prognostic and does not potentiate fatal arrhythmias; however, there are limited cases of patients presenting with QTc intervals >700 milliseconds. CASE REPORT We describe a case in which a 57-year-old woman with diabetes, hypertension, and atrial fibrillation presented with concern for stroke. The hospital course was complicated by cardiac arrest requiring TTM, which was stopped early due to significant QTc prolongation of 746 milliseconds. CONCLUSIONS TTM is beneficial post resuscitation for good neurological outcomes, but it also has known adverse cardiac effects such as QTc prolongation. The significance of QTc prolongation during TTM is unclear as several studies have shown no increased incidence of malignant arrhythmias. One case report in the literature describes the incidence of torsades de pointes due to QTc prolongation during TTM. Further study and guidelines regarding electrocardiogram monitoring are needed to determine the importance of QTc prolongation during TTM.

Regadenoson administration and QT interval prolongation during pharmacological radionuclide myocardial perfusion imaging.

The objective of our study is to assess change in QTc interval with Regadenoson administration during myocardial perfusion imaging (MPI). We conducted a retrospective, observational analysis of 1497 consecutive patients who underwent pharmacological radionuclide MPI. On multivariate logistic regression analyses, there was no statistical significance of QTc prolongation when adjusted for ischemia/fixed perfusion defect on MPI and QT prolonging medications being taken prior to stress testing. However, a positive stress ECG after Regadenoson injection had a statistical significance (p value 0.0004). Regadenoson is a safe drug for use in MPI with little, if any, side effects of major clinical significance.

QTc prolongation after haloperidol administration in critically ill patients post cardiovascular surgery: A cohort study and review of the literature.

OBJECTIVE: From case reports, haloperidol administration has been associated with QTc prolongation, torsades de pointes, and sudden cardiac death. In a vulnerable population of critically ill patients after cardiac surgery, however, it is unclear whether haloperidol administration affects the QTc interval. Thus, the aim of this study is to explore the effect of haloperidol in low doses on this interval. METHOD: This retrospective cohort study was performed on a cardio-surgical intensive care unit (ICU), screened 2,216 patients and eventually included 68 patients with delirium managed with oral and intravenous haloperidol. In this retrospective analysis, electrocardiograms were taken prior and within 24 h after haloperidol administration. The effect of haloperidol on QTc was determined with a Person correlation, and inter-group differences were measured with new long QT comparisons. RESULTS: In total, 68 patients were included, the median age was 71 (64-79) years and predominantly male (77%). Haloperidol administration followed ICU admission by three days and the cumulative dose was 4 (2-9) mg. As a result, haloperidol administration did not affect the QTc (r = 0.144, p = 0.23). In total, 31% (21/68 patients) had a long QT before and 27.9% (19/68 patients) after haloperidol administration. Only 12% (8/68 patients) developed a newly onset long QT. These patients were not different in the route of administration, cumulative haloperidol doses, comorbidities, laboratory findings, or medications. SIGNIFICANCE OF RESULTS: These results indicated that low-dose intravenous haloperidol was safe and not clinically relevant for the development of a newly onset long QT syndrome or adverse outcomes and support recent findings inside and outside the ICU setting.

A distinct molecular mechanism by which phenytoin rescues a novel long QT 3 variant.

BACKGROUND: Genetic variants in SCN5A can result in channelopathies such as the long QT syndrome type 3 (LQT3), but the therapeutic response to Na+ channel blockers can vary. We previously reported a case of an infant with malignant LQT3 and a missense Q1475P SCN5A variant, who was effectively treated with phenytoin, but only partially with mexiletine. Here, we functionally characterized this variant and investigated possible mechanisms for the differential drug actions. METHODS: Wild-type or mutant Nav1.5 cDNAs were examined in transfected HEK293 cells with patch clamping and biochemical assays. We used computational modeling to provide insights into altered channel kinetics and to predict effects on the action potential. RESULTS: The Q1475P variant in Nav1.5 reduced the current density and channel surface expression, characteristic of a trafficking defect. The variant also led to positive shifts in the voltage dependence of steady-state activation and inactivation, faster inactivation and recovery from inactivation, and increased the "late" Na+ current. Simulations of Nav1.5 gating with a 9-state Markov model suggested that transitions from inactivated to closed states were accelerated in Q1475P channels, leading to accumulation of channels in non-inactivated closed states. Simulations with a human ventricular myocyte model predicted action potential prolongation with Q1475P, compared with wild type, channels. Patch clamp data showed that mexiletine and phenytoin similarly rescued some of the gating defects. Chronic incubation with mexiletine, but not phenytoin, rescued the Nav1.5-Q1475P trafficking defect, thus increasing mutant channel expression. CONCLUSIONS: The gain-of-function effects of Nav1.5-Q1475P predominate to cause a malignant long QT phenotype. Phenytoin partially corrects the gating defect without restoring surface expression of the mutant channel, whereas mexiletine restores surface expression of the mutant channel, which may explain the lack of efficacy of mexiletine when compared to phenytoin. Our data makes a case for experimental studies before embarking on a one-for-all therapy of arrhythmias.

QT Prolongation After Minor Head Trauma in a Pediatric Patient.

We report a case of QTc prolongation associated with mild concussion in a pediatric patient. An 11-year-old male presented to the emergency department after sustaining a head injury during football practice. He complained of headache and blurry vision. Physical examination was within normal apart from an irregular heart rhythm. Electrocardiogram (ECG) showed normal sinus rhythm with QTc (Bazett formula) 460 ms. The patient was diagnosed with concussion and referred for cardiology follow-up of the QTc. ECG the next day showed QTc 462 ms (heart rate 105 bpm) supine and 494 ms after suddenly standing up (heart rate 120 bpm). Family history was negative for sudden cardiac events. Exercise stress testing 1 week later showed a baseline QTc 462 ms and 488 ms at 4 min into recovery. Holter monitoring showed evidence of increased parasympathetic activity manifested by marked sinus arrhythmia. Repeated ECG, exercise stress testing, and Holter monitoring 3 months later showed normalized QTc values. His concussion symptoms were resolved at the time of repeat testing. Mild head trauma/concussion could be associated with prolonged QTc and abnormal cardiac repolarization. While these changes seem to be self-limiting, they remain a possible substrate for malignant arrhythmias. Recognition of these changes would lead to appropriate reassurance and/or precautions in the acute setting, especially in at-risk populations such as long QT syndrome patients.

Ibogaine Consumption With Seizure-Like Episodes, QTc-Prolongation, and Captured Cardiac Dysrhythmias.

BACKGROUND: Ibogaine is a psychoactive indole alkaloid that has been investigated for use as a treatment for opioid addiction. While not commercially available in the United States, it is available via Internet suppliers. Ibogaine use has been associated with significant cardiac and neurologic effects, such as QT-segment prolongation, cardiac dysrhythmias, hallucinations, seizures, and central nervous system depression. We present a case of verified ibogaine exposure with associated QTc prolongation and torsade de pointes with qualitative analysis of the ingested substance, and examine the history, social context, availability, and perceptions of ibogaine's effects and safety. CASE REPORT: A 34-year-old white woman with medical history significant for heroin and cocaine use disorder presented with reported seizures 1 day after ingestion of 2 g ibogaine powder purchased from an Internet supplier. Shortly after ingestion, she experienced hallucinations and was reported by family to have four to five seizure-like episodes, at one point becoming apneic. In the emergency department, she was noted to have QTc prolongation and several episodes of torsade de pointes. Qualitative analysis confirmed the presence of ibogaine in the empty foil packages containing the ingested substance. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As increasing numbers of opioid-dependent patients attempt to curtail their substance use disorders, we anticipate a rise in ibogaine exposures, necessitating awareness by front-line clinicians in recognizing and treating a drug exposure that can rapidly become life-threatening.

Clinical characterization of men with long QT syndrome and torsades de pointes associated with hypogonadism: A review and pharmacovigilance study.

BACKGROUND: Long QT syndrome (LQTS) can cause the potentially fatal ventricular tachycardia torsades de pointes (TdP). QT interval corrected for heart rate (QTc) is shorter in men than in women, with testosterone contributing to shorten QTc. We recently described male hypogonadism as a reversible risk factor for acquired LQTS and TdP, but the clinical characteristics of such patients have not been characterized. AIMS: To describe the clinical characteristics of men with acquired LQTS or TdP associated with hypogonadism caused by endocrine conditions or androgen deprivation therapy (ADT), and to evaluate the relationship between testosterone concentrations and electrocardiographic changes. METHODS: We searched MEDLINE (to 04 January 2019) and the French pharmacovigilance database (to 09 August 2018) to identify male cases of acquired LQTS and TdP associated with endocrine hypogonadism or ADT; their narratives were gathered from reporting collaborators. RESULTS: We identified seven cases of TdP (one fatal) with endocrine hypogonadism, abnormally long QTc and morphologically abnormal T-wave notches. After reversion of low testosterone concentrations in the surviving patients (N=6), QTc shortened, T-wave morphology normalized and there was no TdP recurrence. Among these cases, none had mutation in the LQTS genes, three men required testosterone and three had reversible hypogonadism after resolution of a concurrent acute severe illness. We found an additional 27 reports of men with LQTS (N=6), TdP (N=9; 2/9 fatal) or sudden death (N=12; 10/12 fatal) suspected to be induced or favoured by ADT (24/27 for prostate cancer). Generally, after ADT withdrawal, QTc shortened and no TdP recurred. CONCLUSION: We propose seeking for hypogonadism caused by endocrine conditions or ADT in men presenting with TdP. Caution is warranted when ADT is used in situations at risk of TdP. Testosterone may be useful to treat or prevent TdP.

Effect of itraconazole, food, and ethnic origin on the pharmacokinetics of ivosidenib in healthy subjects.

PURPOSE: To assess the effect of ethnicity, food, and itraconazole (strong CYP3A4 inhibitor) on the pharmacokinetics of ivosidenib after single oral doses in healthy subjects. METHODS: Three phase 1 open-label studies were performed. Study 1: Japanese and Caucasian subjects received single doses of 250, 500, or 1000 mg ivosidenib (NCT03071770). Part 1 of study 2 (a two-period crossover study): subjects received 500 mg ivosidenib after either an overnight fast or a high-fat meal. Subjects received 1000 mg ivosidenib after an overnight fast in the single period of part 2 (NCT02579707). Study 3: in period 1, subjects received 250 mg ivosidenib; then, in period 2, subjects received oral itraconazole (200 mg once daily) on days 1-18, plus 250 mg ivosidenib on day 5 (NCT02831972). RESULTS: Ivosidenib was well tolerated in all three studies. Study 1: pharmacokinetic profiles were generally comparable, although AUC and Cmax were slightly lower in Japanese subjects than in Caucasian subjects, by ~ 30 and 17%, respectively. Study 2: AUC increased by ~ 25% and Cmax by ~ 98%, when ivosidenib was administered with a high-fat meal compared with a fasted state. Study 3: co-administration of itraconazole increased ivosidenib AUC by 169% (90% CI 145-195) but had no effect on ivosidenib Cmax. CONCLUSIONS: No ivosidenib dose adjustment is deemed necessary for Japanese subjects. High-fat meals should be avoided when ivosidenib is taken with food. When co-administered with strong CYP3A4 inhibitors, monitoring for QT interval prolongation (a previously defined adverse event of interest) is recommended and an ivosidenib dose interruption or reduction may be considered. CLINICALTRIALS.GOV : NCT03071770, NCT02579707, and NCT02831972.

Prolonged QTc in HIV-Infected Patients: A Need for Routine ECG Screening.

BACKGROUND: With HIV-infected patients living longer, there is an increased burden of comorbidities related to aging, HIV itself, and polypharmacy. Cardiac morbidity is of particular importance. METHODS: This 2-group comparison study (156 HIV-positive and 105 HIV-negative patients) investigated the prevalence of abnormalities in and factors associated with an electrocardiogram (ECG) measure, corrected QT interval (QTc), where prolongation can lead to arrhythmia and sudden death. Medications prescribed (antiretroviral therapy, psychiatric medications, methadone, and antibiotics) at the time of ECG were noted. Patient characteristics, medications, QTc, and ECG characteristics were compared between the 2 groups. RESULTS: Prolongation (29% versus 19%) and extreme prolongation (6% versus 1%) in QTc were more frequent in those with HIV. Antiretroviral therapy was associated with lower odds of prolonged QTc (odds ratio [OR] = 0.35; P = .04), while methadone with higher odds (OR = 4.6; P = .01) in HIV-positive patients. With methadone and medication groups adjusted, HIV status was still associated with 17-millisecond longer QTc ( P = .04). CONCLUSION: This study provides evidence that patients with HIV may have clinically relevant longer QTc interval on ECG. Baseline and routine ECG monitoring may be warranted among patients living with HIV in clinical practice based on cumulative evidence.