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Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers.
Amore, BM, Cramer, CT, MacDougall, DE, Sasiela, WJ, Emery, MG
Clinical and translational science. 2021;(6):2487-2496
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Abstract
Bempedoic acid is an inhibitor of adenosine triphosphate-citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether-a-go-go-related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgus monkeys. A randomized, double-blind, parallel-design clinical study assessed the effects of steady-state bempedoic acid at a supratherapeutic dose (240 mg/day, 33.3% higher the180 mg/day therapeutic dose), placebo, and moxifloxacin (400 mg) in healthy subjects. In vitro binding potency for bempedoic acid to the hERG potassium channel was weak, with half-maximal inhibition (IC50 ) estimated at greater than 1000 μM (>1670-fold the bempedoic acid 180 mg/day steady-state unbound maximum concentration). In monkeys, individual rate-corrected QT intervals showed no time- or dose-dependent changes up to 100 mg/kg of bempedoic acid. In human subjects, the upper 90% confidence interval (CI) for the difference in QTc interval, corrected using Fridericia's formula (QTcF), between bempedoic acid and placebo was less than 5 msec at all time points. Concentration-QTcF analysis showed that maximum bempedoic acid concentration at steady-state was attained at a median 2.1 h postdose, and the predicted mean change (90% CI) in QTcF at the observed mean bempedoic acid concentration 2 h postdose was -0.5 (-5.0, 4.0) msec. The lower bound of the moxifloxacin 90% CI exceeded 5 msec at prespecified time points, establishing study sensitivity. Steady-state bempedoic acid at a supratherapeutic dose of 240 mg was generally well-tolerated and not associated with QTc prolongation in healthy subjects.
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QTc prolongation after ADHD medication.
Snircova, E, Marcincakova Husarova, V, Ondrejka, I, Hrtanek, I, Farsky, I, Nosalova, G
Neuro endocrinology letters. 2018;(8):549-554
Abstract
OBJECTIVE Multicenter studies have shown that cardiovascular risks of ADHD medication are extremely low. However, QTc length has been shown to be increased in smaller samples of patients or case reports after stimulant and atomoxetine medication. Based on recent studies of genetic polymorphisms associated with drug-induced QTc prolongation and polymorphisms linkage to regional populations, we hypothesized that the drug-induced QTc prolongation could be a factor of particular polymorphisms linked to specific regional populations undistinguished in multicenter studies. METHODS We included 69 patients from a region of central Slovakia, 36 patients were taking atomoxetine and 33 patients methylphenidate. QTc, heart rate, potassium levels and BMI were examined before and after 8 weeks of treatment. Therapeutic effect was measured by ADHD-RS-IV. RESULTS We found QTc prolongation after 8 weeks of treatment both with atomoxetine and methylphenidate that was neither followed by the significant changes in BMI and potassium levels nor the significant increase of heart rate. CONCLUSION This is the first study revealing QTc prolongation in the group of ADHD children from the same region after 8-week treatment with atomoxetine and methylphenidate, indicating the potential discrete abnormalities in cardiac functioning associated with polymorphisms in genes of dopaminergic and noradrenergic system.
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Effects of Long-Acting Loop Diuretics in Heart Failure With Reduced Ejection Fraction Patients With Cardiac Resynchronization Therapy.
Asami, M, Aoki, J, Tanimoto, S, Horiuchi, Y, Watanabe, M, Furui, K, Yasuhara, K, Sato, T, Tanabe, K, Hara, K
International heart journal. 2017;(2):211-219
Abstract
There have been no reports evaluating the impact of long-acting loop diuretics (LLD) on the outcome of heart failure (HF) and arrhythmia treatment in HF with reduced ejection fraction (HFrEF) patients implanted with a cardiac resynchronization therapy (CRT) device.This was a prospective, single-blind, randomized crossover study. We allocated 21 consecutive CRT implanted patients into 2 groups. The furosemide group received furosemide as a first treatment and azosemide as a second treatment. The azosemide group received this treatment in the reverse order. The first treatment was given to each group for 6 months and the second treatment continued for an additional 6 months. We combined the data of each medication regimen in each group and analyzed it at baseline, 6 months, and 1 year. The primary endpoints were the variation of fluid index and thoracic impedance measured by CRT at 6 months.The baseline characteristics were similar for both groups. The difference in the primary endpoints was not statistically significant between the 2 medication arms (fluid index: -29.6 ± 64.4 versus 16.2 ± 48.2; P = 0.22, thoracic impedance: -0.49 ± 17.8 versus 2.45 ± 12.5; P = 0.56). Likewise, the clinical outcome of HF and the CRT derived parameters in both arms were comparable.HFrEF patients taking LLD after CRT implantation might be comparable to those taking short-acting loop diuretics in the treatment of HF and HF-associated arrhythmias.
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A worldwide experience of the management of battery failures and chronic device retrieval of the Nanostim leadless pacemaker.
Lakkireddy, D, Knops, R, Atwater, B, Neuzil, P, Ip, J, Gonzalez, E, Friedman, P, Defaye, P, Exner, D, Aonuma, K, et al
Heart rhythm. 2017;(12):1756-1763
Abstract
BACKGROUND The Nanostim leadless pacemaker (LP) met the primary endpoints in an investigational device exemption trial, and was shown to be fully retrievable percutaneously. In October 2016, St Jude Medical issued a worldwide alert of a battery malfunction that caused lost pacing output and LP communication. OBJECTIVE To report the battery failure mechanism and incidence and the worldwide patient management, including device retrieval experiences. METHODS The affected LP battery is a custom lithium-carbon monofluoride cell. These were returned after failure and underwent analysis assessing electronics and battery performance. Data were collected in ongoing clinical studies when LPs were abandoned or retrieved. RESULTS Of 1423 LPs implanted worldwide, there were 34 battery failures, occurring at 2.9 ± 0.4 years with no instances of associated patient injury. Analysis of returned batteries revealed an increase in battery resistance caused by insufficient electrolyte availability at the cathode/anode interface. A total of 66 of 73 retrieval attempts were successful (90.4%; implant duration range: 0.2-4.0 years). The LP docking button was inaccessible in 6 patients, and the docking button detached from the LP during retrieval in 1 patient. There was 1 case of arteriovenous fistula and another case of the LP docking button migrating into the pulmonary artery. There were also 115 non-LP retrieval patients after the advisory who received an additional pacemaker, with no adverse device-to-device interactions reported. CONCLUSION As with standard pacers, LPs can have critical battery failures. Chronic retrieval of LPs is safe and efficacious.
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Heart palpitation relief with Melissa officinalis leaf extract: double blind, randomized, placebo controlled trial of efficacy and safety.
Alijaniha, F, Naseri, M, Afsharypuor, S, Fallahi, F, Noorbala, A, Mosaddegh, M, Faghihzadeh, S, Sadrai, S
Journal of ethnopharmacology. 2015;:378-84
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In Traditional Iranian Medicine (TIM), Melissa officinalis L. is commonly regarded as an effective therapy for heart palpitations. OBJECTIVE Heart palpitation is a common complaint that is often benign and associated with a marked distress that makes the condition difficult to treat. Herbal medicines provide an alternative to conventional drugs for treating various kinds of diseases. This study was done as a double blind randomized placebo-controlled clinical trial to evaluate the efficacy and safety of the dried extract of M. officinalis on adults suffering from benign palpitations. MATERIALS AND METHODS Eligible volunteers were randomly assigned as outpatients to a 14 day treatment with 500 mg twice a day of lyophilized aqueous extract of M. officinalis leaves (or placebo). Participants in the tests, physicians and researchers were blind to group assignments. Both primary and secondary outcomes were patient-reported. Primary outcomes were obtained from two measures: mean frequency of palpitation episodes per week, derived from patients׳ diaries, and mean intensity of palpitation estimated through Visual Analogue Scale (VAS) in a self-report questionnaire. Psychiatric symptoms (somatization, anxiety and insomnia, social dysfunction and severe depression) were evaluated as secondary outcomes by General Health Questionnaire-28 (GHQ-28), before and after intervention. RESULTS Fifty-five volunteers out of 71 recruited study subjects completed the trial. Results showed that 14-day of treatment with lyophilized aqueous extract of M. officinalis leaves reduced frequency of palpitation episodes and significantly reduced the number of anxious patients in comparison to the placebo (P=0.0001, P=0.004 resp.). Also, M. officinalis extract showed no indication of any serious side effects. CONCLUSION Lyophilized aqueous extract of M. officinalis leaves may be a proper and safe herbal drug for the treatment of benign palpitations.
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n-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical cardioversion of chronic persistent atrial fibrillation: a randomized, double-blind, multicentre study.
Bianconi, L, Calò, L, Mennuni, M, Santini, L, Morosetti, P, Azzolini, P, Barbato, G, Biscione, F, Romano, P, Santini, M
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2011;(2):174-81
Abstract
AIMS: Persistent atrial fibrillation (AF) often recurs after direct current electrical cardioversion (ECV). As several experimental and clinical studies suggest that n-3 polyunsaturated fatty acids (PUFAs) may have antiarrhythmic properties even at the atrial level, we aimed to evaluate whether oral supplementation with PUFAs, in addition to conventional antiarrhythmic drugs, could reduce the recurrence rate of the arrhythmia after ECV of persistent AF. METHODS AND RESULTS Two hundred and four patients (mean age 69.3 years, 33% females) with persistent AF were randomly assigned to receive 3 g/day of PUFAs until ECV and 2 g/day thereafter (104 patients) or placebo (100 patients) for 6 months, beginning at least 1 week before ECV. Selection of conventional antiarrhythmic prophylaxis was left to local medical advice. The cardiac rhythm was assessed by both trans-telephonic monitoring and clinical visits. Primary end-point was the recurrence rate of AF. Sinus rhythm was restored, either spontaneously or after ECV, in 187 patients (91.7%); 95 patients (91.4%) on PUFAs and 92 patients (92.0%) on placebo (P=not significant). AF relapsed in 56 (58.9%) of the PUFAs patients and in 47 (51.1%) of the placebo patients (P=0.28). The mean time to AF recurrence was 83±8 days in the PUFAs group and 106±9 days in the placebo group (P=0.29). CONCLUSION Our results do not support the hypothesis that, in patients undergoing ECV of chronic persistent AF, supplementation with PUFAs in addition to the usual antiarrhythmic treatment reduces recurrent AF.
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[Levosimendan and dobutamine have a similar profile for potential risk for cardiac arrhythmias during 24-hour infusion in patients with acute decompensated heart failure].
Tek, M, Cavuşoğlu, Y, Demirüstü, C, Birdane, A, Ünalır, A, Görenek, B, Göktekin, Ö, Ata, N
Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir. 2010;(5):334-40
Abstract
OBJECTIVES Unlike traditional inotropic agents, levosimendan is thought to have a lower potential to induce arrhythmias because it does not increase intracellular calcium levels and myocardial oxygen consumption. We compared the potential effect of levosimendan and dobutamine to induce cardiac arrhythmias in patients with decompensated heart failure. STUDY DESIGN Fifty patients with acute decompensated heart failure (NYHA class III-IV, ejection fraction <35%) who were in need of inotropic support were randomized to dobutamine (n=25; mean age 69±10 years) or levosimendan (n=25; mean age 67.5±11.5 years) and underwent 24-hour Holter monitoring before and during inotropic infusion. Holter recordings were analyzed with respect to heart rate (HR), ventricular premature contraction (VPC), couplets of VPC, supraventricular premature contraction (SVPC), paroxysmal atrial fibrillation (PAF), and nonsustained ventricular tachycardia (NSVT). RESULTS Before infusions, the two groups were similar with respect to HR, VPC, couplets of VPC, SVPC, and PAF episodes, but the number of NSVT episodes was significantly higher in the levosimendan group. Heart rate and the number of VPCs increased significantly during infusions of levosimendan (p=0.036 and p<0.001, respectively) and dobutamine (for both p<0.001). Increase in couplets of VPC was significant only with dobutamine (p=0.012). The episodes of NSVT and PAF increased with levosimendan, without reaching significance. Levosimendan and dobutamine groups were similar in terms of percentage changes in arrhythmias (55±224% vs. 11±16% for VPC; 2±2.7% vs. 12±9% for couplets of VPC; 3.4±5.8% vs. 16±39% for SVPC, 0.4±2.8% vs. -2±0% for NSVT) and percentage change in total arrhythmias (41±190% vs. 18±35.4%), and the mean HR, VPC, couplets of VPC, SVPC, and episodes of NSVT and PAF (p>0.05). CONCLUSION Our findings suggest that levosimendan and dobutamine have a similar profile for potential risk for cardiac arrhythmias.
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Randomized control trial investigating the influence of coffee on heart rate variability in patients with ST-segment elevation myocardial infarction.
Richardson, T, Baker, J, Thomas, PW, Meckes, C, Rozkovec, A, Kerr, D
QJM : monthly journal of the Association of Physicians. 2009;(8):555-61
Abstract
BACKGROUND Cardiac autonomic dysfunction post ST-segment elevation myocardial infarction (STEMI) has been linked to an excess risk of premature cardiovascular morbidity and mortality above those with normal autonomic function post-STEMI. AIM: The aim of this study was to evaluate the effect of acute ingestion of coffee on autonomic function and cardiovascular outcomes in patients with acute STEMI. DESIGN Randomized control trial. METHODS We randomized 103 patients with acute STEMI, admitted to our Coronary Care Unit, to receive regular coffee (caffeinated) or de-caffeinated coffee using a randomized controlled double-blinded design. Heart rate variability was assessed 5 days post-STEMI to assess the effect of caffeine on autonomic function. RESULTS In the group randomized to regular coffee, parasympathetic activity increased by up to 96% (P = 0.04) after 5 days. There was no detrimental effect of regular coffee on cardiac rhythm post-STEMI. CONCLUSION Coffee ingestion is associated with an increase in parasympathetic autonomic function immediately post-STEMI. Coffee was found to be safe and not associated with any adverse cardiovascular outcomes in the short term.
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Spironolactone has antiarrhythmic activity in ischaemic cardiac patients without cardiac failure.
Shah, NC, Pringle, SD, Donnan, PT, Struthers, AD
Journal of hypertension. 2007;(11):2345-51
Abstract
OBJECTIVES To examine whether endogenous aldosterone can cause either arrhythmias (and some of their underlying mechanisms) or endothelial dysfunction in patients with coronary artery disease (CAD) but without heart failure. BACKGROUND Aldosterone blockade has been shown to reduce the incidence of sudden death in patients with heart failure. This could be caused by a reduction in arrhythmias or in coronary events. Whether either effect also occurs in other cardiac patients without heart failure is currently unknown. METHOD We performed a randomized, placebo-controlled, double-blind crossover study on 98 patients with CAD but without heart failure on standard therapy, comparing 12.5-50 mg/day spironolactone (3 months) with placebo. Endothelial function was assessed by bilateral forearm venous occlusion plethysmography. Ventricular extrasystoles, procollagen III N-terminal peptide (PIIINP) and QT interval length were used to represent arrhythmias and their determinants. RESULTS Spironolactone produced a highly significant 75% reduction in ventricular extrasystoles (median 192, range 48-744) on placebo compared with spironolactone (median 48, range 19.2-288, P < 0.003). Spironolactone also decreased the QT interval from a mean of 440 +/- 28 to a mean of 425 +/- 25 (P < 0.001) and a collagen marker (PIIINP) from a mean of 3.6 +/- 0.9 to a mean of 3.0 +/- 0.8 (P < 0.001), but did not significantly change endothelial dysfunction or heart rate variability. CONCLUSION These results suggest that despite conventional therapy, endogenous aldosterone can be an arrhythmogenic influence in patients with CAD, but without heart failure. The possible mechanisms are that aldosterone promotes myocardial fibrosis and lengthens the QTc interval as well as decreasing potassium in CAD patients without heart failure.
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Randomised trial on the influence of continuous magnesium infusion on arrhythmias following cardiopulmonary bypass surgery for congenital heart disease.
Dittrich, S, Germanakis, J, Dähnert, I, Stiller, B, Dittrich, H, Vogel, M, Lange, PE
Intensive care medicine. 2003;(7):1141-4
Abstract
OBJECTIVES To check the hypothesis that continuous magnesium infusion protects the heart from arrhythmias following cardiopulmonary bypass surgery for congenital heart disease. DESIGN A prospective randomised placebo-controlled study, with patients stratified in three weight groups. PATIENTS AND PARTICIPANTS The study group ( n=65) postoperatively received a magnesium infusion (1 mmol/kg), the control group ( n=66) received placebo. In both groups serum and ionised magnesium values were followed, and all postoperative arrhythmias were documented for 24 h. MEASUREMENTS AND RESULTS Serum and ionised magnesium in the blood was elevated after the end of bypass (0.54+/-0.15 mmol l(-1) pre-operatively, 0.88+/-0.24 mmol l(-1) postoperatively), where a cardioplegia solution containing magnesium was used. Magnesium values remained at this elevated level in the magnesium therapy group, and decreased to normal pre-operative values within 24 h in controls ( P<0.001). The incidence of postoperative arrhythmias was lower in the study group: 8/65 in the study group and 17/66 in the control group, respectively (chi-squared test, P=0.05). Lower patient weight (32.7 kg versus 22.6 kg), longer cardiopulmonary bypass time (128.7 min versus 87.9 min) and deeper body temperature during extracorporeal circulation (29.2 degrees C versus 32.6 degrees C) were identified as risk factors for postoperative arrhythmias ( P<0.05). CONCLUSIONS Continuous magnesium infusion effectively reduces the rate of arrhythmias following cardiopulmonary bypass surgery for congenital heart disease and should, therefore, be routinely used.