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Risk of QTc Interval Prolongation Associated With Circulating Anti-Ro/SSA Antibodies Among US Veterans: An Observational Cohort Study.
Lazzerini, PE, Cevenini, G, Qu, YS, Fabris, F, El-Sherif, N, Acampa, M, Cartocci, A, Laghi-Pasini, F, Capecchi, PL, Boutjdir, M, et al
Journal of the American Heart Association. 2021;(4):e018735
Abstract
Background Anti-Sjögren's syndrome-related antigen A-antibodies (anti-Ro/SSA-antibodies) are responsible for a novel form of acquired long-QT syndrome, owing to autoimmune-mediated inhibition of cardiac human ether-a-go-go-related gene-potassium channels. However, current evidence derives only from basic mechanistic studies and relatively small sample-size clinical investigations. Hence, the aim of our study is to estimate the risk of QTc prolongation associated with the presence of anti-Ro/SSA-antibodies in a large population of unselected subjects. Methods and Results This is a retrospective observational cohort study using the Veterans Affairs Informatics and Computing Infrastructure. Participants were veterans who were tested for anti-Ro/SSA status and had an ECG. Descriptive statistics and univariate and multivariate logistic regression analyses were performed to identify risk factors for heart rate-corrected QT interval (QTc) prolongation. The study population consisted of 7339 subjects (61.4±12.2 years), 612 of whom were anti-Ro/SSA-positive (8.3%). Subjects who were anti-Ro/SSA-positive showed an increased prevalence of QTc prolongation, in the presence of other concomitant risk factors (crude odds ratios [OR], 1.67 [1.26-2.21] for QTc >470/480 ms; 2.32 [1.54-3.49] for QTc >490 ms; 2.77 [1.66-4.60] for QTc >500 ms), independent of a connective tissue disease history. Adjustments for age, sex, electrolytes, cardiovascular risk factors/diseases, and medications gradually attenuated QTc prolongation estimates, particularly when QT-prolonging drugs were added to the model. Nevertheless, stepwise-fully adjusted OR for the higher cutoffs remained significantly increased in anti-Ro/SSA-positive subjects, particularly for QTc >500 ms (2.27 [1.34-3.87]). Conclusions Anti-Ro/SSA-antibody positivity was independently associated with an increased risk of marked QTc prolongation in a large cohort of US veterans. Our data suggest that within the general population individuals who are anti-Ro/SSA-positive may represent a subgroup of patients particularly predisposed to ventricular arrhythmias/sudden cardiac death.
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Multicenter Analysis of Dosing Protocols for Sotalol Initiation.
Biswas, M, Levy, A, Weber, R, Tarakji, K, Chung, M, Noseworthy, PA, Newton-Cheh, C, Rosenberg, MA
Journal of cardiovascular pharmacology and therapeutics. 2020;(3):212-218
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Abstract
Sotalol, a Vaughan-Williams Class III antiarrhythmic medication, is used to manage atrial arrhythmias. Due to its QT-prolonging effect and subsequent increased risk of torsade de pointes, many centers admit patients during the initial dosing period. Despite its widespread use, little information is available regarding dosing protocols during this period. In this multicenter investigation, dosing protocols in patients initiating sotalol therapy were examined to identify predictors of successful sotalol initiation. Over a 4-year period, patients admitted to 5 hospitals in the United States for inpatient telemetry monitoring during initiation for nonresearch purposes were enrolled. A 3-day course of 5 of 6 doses of sotalol was considered successful completion of the loading protocol. Of the 213 enrolled patients, over 90% were successfully discharged on sotalol. Significant bradycardia, ineffectiveness, and excessive QT prolongation were reasons for failed completion. Absence of a dose adjustment was a strong predictor of successful initiation (odds ratio: 6.6, 95% confidence interval: 1.3-32.7, P = .02). Hypertension, use of a calcium channel blocker, use of a separate β-blocker, and presence of a pacemaker were predictors of dose adjustments. Marginal structural models (ie, inverse probability weighting based on probability of a dose adjustment) verified that these factors also predicted successful initiation via preventing any dose adjustment and suggests that considering these factors may result in a higher likelihood of successful initiation in future investigations. In conclusion, we found that the majority of patients admitted for sotalol initiation are successfully discharged on the medication. The study findings suggest that factors predicting need for dose adjustment can be used to identify patients who could undergo outpatient initiation. Prospective studies are needed to verify this approach.
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Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients.
Nielsen, R, Møller, N, Gormsen, LC, Tolbod, LP, Hansson, NH, Sorensen, J, Harms, HJ, Frøkiær, J, Eiskjaer, H, Jespersen, NR, et al
Circulation. 2019;(18):2129-2141
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Abstract
BACKGROUND Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors' aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. METHODS Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography. RESULTS 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM ( P<0.001). CO rose by 2.0±0.2 L/min ( P<0.001) because of an increase in stroke volume of 20±2 mL ( P<0.001) and heart rate of 7±2 beats per minute (bpm) ( P<0.001). Left ventricular ejection fraction increased 8±1% ( P<0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM ( P<0.001). 3-OHB increased MVO2 without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers. CONCLUSIONS 3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.
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A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation.
Camm, AJ, Dorian, P, Hohnloser, SH, Kowey, PR, Tyl, B, Ni, Y, Vandzhura, V, Maison-Blanche, P, de Melis, M, Sanders, P
European heart journal. Cardiovascular pharmacotherapy. 2019;(1):21-28
Abstract
AIMS: Antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current IKur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects. METHODS AND RESULTS A randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1% and 70% after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective IKur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients. The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3% to 10.3% at baseline in the four treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up. CONCLUSIONS DIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective IKur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.
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Blood pressure, heart rate, and mortality in chronic obstructive pulmonary disease: the SUMMIT trial.
Byrd, JB, Newby, DE, Anderson, JA, Calverley, PMA, Celli, BR, Cowans, NJ, Crim, C, Martinez, FJ, Vestbo, J, Yates, J, et al
European heart journal. 2018;(33):3128-3134
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AIMS: To characterize the relationship between blood pressure (BP) or heart rate and mortality and morbidity in chronic obstructive pulmonary disease (COPD). METHODS AND RESULTS We performed post hoc analysis of baseline BP or heart rate and all-cause mortality and cardiovascular events in the SUMMIT trial. SUMMIT was a randomized double-blind outcome trial of 16 485 participants (65 ± 8 years, 75% male, and 47% active smokers) enrolled at 1368 sites in 43 countries. Participants with moderate COPD with or at risk for cardiovascular disease (CVD) were randomized to placebo, long-acting beta agonist, inhaled corticosteroid, or their combination. All-cause mortality increased in relation to high systolic [≥140 mmHg; hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45] or diastolic (≥90 mmHg; HR 1.35, 95% CI 1.14-1.59) BP and low systolic (<120 mmHg; HR 1.36, 95% CI 1.13-1.63) or diastolic (<80 mmHg; HR 1.15, 95% CI 1.00-1.32) BP. Higher heart rates (≥80 per minute; HR 1.39, 95% CI 1.21-1.60) and pulse pressures (≥80 mmHg; HR 1.39, 95% CI 1.07-1.80) were more linearly related to increases in all-cause mortality. The risks of cardiovascular events followed similar patterns to all-cause mortality. Similar findings were observed in subgroups of patients without established CVD. CONCLUSION A 'U-shaped' relationship between BP and all-cause mortality and cardiovascular events exists in patients with COPD and heightened cardiovascular risk. A linear relationship exists between heart rate and all-cause mortality and cardiovascular events in this population. These findings extend the prognostic importance of BP to this growing group of patients and raise concerns that both high and low BP may pose health risks.
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High-intensity interval training and cardiac autonomic control in individuals with metabolic syndrome: A randomised trial.
Ramos, JS, Dalleck, LC, Borrani, F, Beetham, KS, Mielke, GI, Dias, KA, Wallen, MP, Keating, SE, Fassett, RG, Coombes, JS
International journal of cardiology. 2017;:245-252
Abstract
BACKGROUND Insulin resistance has been postulated to play a central role in the co-appearance of various cardiovascular disease risk factors constituting the metabolic syndrome (MetS). There is evidence that altered cardiac autonomic function (CAF) may precede the onset of insulin resistance. Exercise training has been shown to improve CAF in different populations, yet little is known regarding the exercise dose response for CAF. The aim of this study was to investigate the impact of different volumes of high-intensity interval training (HIIT) and traditional moderate-intensity continuous training (MICT) on CAF in participants with MetS. METHODS Individuals with MetS (n=56) were randomised into the following 16-week training interventions: i) MICT (n=16, 30min at 60-70%HRpeak, 5×/week); ii) 4HIIT (n=19, 4×4min bouts at 85-95%HRpeak, interspersed with 3min of active recovery at 50-70%HRpeak, 3×/week); or iii) 1HIIT (n=21, 1×4min bout at 85-95%HRpeak, 3×/week). R-R interval recorded for 5min in a supine position at pre- and post-intervention was used to derive linear (SDNN, RMSSD, pNN50, LF, HF, LF/HF) and non-linear (SD1, SD2, Alpha1, Alpha2, SampEn) heart rate variability (HRV) indices as measures of CAF. Group×time interaction effects were examined (ANCOVA) and Eta squared (η2) interaction effect sizes calculated. RESULTS While there were no significant between-group differences in CAF indices, there were small-to-medium group×time interaction effects on SDNN [F(2,52)=0.70, p=0.50, η2=0.02], RMSSD [F(2,52)=1.35, p=0.27, η2=0.03], HF power [F(2,52)=1.27, p=0.29, η2=0.03], SD1 [F(2,52)=0.47, p=0.63, η2=0.01], and SD2 [F(2,52)=0.41, p=0.67, η2=0.01]. The following represent the relative percentage increases across these variables for 4HIIT, MICT, and 1HIIT respectively (SDNN, +30%, +17%, 9%; RMSSD, +30%, +22%, -2%; HF power, +69%, +18%, +7%; SD1, +30%, +22%,-2%; SD2, +22%, +14%, 4%). CONCLUSIONS There were no significant between-group differences for the effects of exercise dose on CAF indices, however; high-volume HIIT demonstrated the greatest magnitude of effect for improving CAF in individuals with MetS.
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Resting Heart Rate and Long-term Outcomes Among the African American Population: Insights From the Jackson Heart Study.
Parikh, KS, Greiner, MA, Suzuki, T, DeVore, AD, Blackshear, C, Maher, JF, Curtis, LH, Hernandez, AF, O'Brien, EC, Mentz, RJ
JAMA cardiology. 2017;(2):172-180
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IMPORTANCE Increased resting heart rate is associated with worse outcomes in studies of mostly white populations, but its significance is not well established in African Americans persons whose cardiac comorbidities and structural abnormalities differ. OBJECTIVE To study the prognostic utility of heart rate in a community-based African American cohort in the Jackson Heart Study. DESIGN, SETTING, AND PARTICIPANTS A total of 5261 participants in the Jackson Heart Study, a prospective, community-based study in Jackson, Mississippi, were evaluated. Baseline heart rate was assessed by quintiles and as a continuous variable. All participants with baseline heart rate documented by a 12-lead electrocardiogram without pacing or atrial fibrillation noted on their baseline Jackson Heart Study examination were included in the study. Follow-up began September 26, 2000, and was completed December 31, 2011. Data analysis was performed from July to October 2015. MAIN OUTCOMES AND MEASURES Unadjusted and adjusted associations between heart rate and all-cause mortality and heart failure hospitalization using Cox proportional hazards regression models. RESULTS Of the 5261 individuals included in the analysis, 1921 (36.5%) were men; median (25th-75th percentile) age was 55.7 (45.4-64.8) years. Median (25th-75th percentile) baseline heart rate was 63 beats per minute (bpm) (57-71 bpm). The highest heart rate quintile (73-118 bpm) had higher rates of diabetes (398 [37.4%]; P < .001) and hypertension (735 [69.1%]; P < .001), higher body mass index (median [IQR], 32.4 [28.1-38.3]; P < .001), less physical activity (0 hours per week, 561 [52.8%]; P < .001), and lower β-blocker use (73 [6.9%]; P < .001) compared with lower quintiles. Caffeine intake (from 80.7 to 85.5 mg/d; P = .57) and left ventricular ejection fraction (from 62% to 62.3%; P = .01) were similar between groups. As a continuous variable, elevated heart rate was associated with increased mortality and heart failure hospitalizations, with adjusted hazard ratios for every 5-bpm increase of 1.14 (95% CI, 1.10-1.19) and 1.10 (95% CI, 1.05-1.16), respectively. Similar patterns were observed in comparisons between the highest and lowest quintiles. CONCLUSIONS AND RELEVANCE Higher baseline heart rate was associated with increased mortality and heart failure hospitalizations among African American participants in the Jackson Heart Study. These findings are similar to those seen in white populations, but further study is needed to understand whether African American individuals benefit from interventions targeting heart rate reduction.
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Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High-Fidelity Cardiovascular Phenotyping.
Heusser, K, Tank, J, Brinkmann, J, Schroeder, C, May, M, Großhennig, A, Wenzel, D, Diedrich, A, Sweep, FC, Mehling, H, et al
Journal of the American Heart Association. 2016;(1)
Abstract
BACKGROUND Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization-activated cyclic nucleotide-gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. METHODS AND RESULTS We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading. CONCLUSIONS HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.
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Complex Influence of Gonadotropins and Sex Steroid Hormones on QT Interval Duration.
Abehsira, G, Bachelot, A, Badilini, F, Koehl, L, Lebot, M, Favet, C, Touraine, P, Funck-Brentano, C, Salem, JE
The Journal of clinical endocrinology and metabolism. 2016;(7):2776-84
Abstract
CONTEXT QT interval duration is longer in women than in men. Sex steroid hormones have inconsistently been suggested to explain this difference. The implication of gonadotropins has never been studied. OBJECTIVE We report here the combined influence of sex steroid hormones and gonadotropins on QT interval duration in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of T and progesterone overexpression. DESIGN AND PATIENTS Eighty-four CAH patients (58 women) and 84 healthy subjects matched and paired for sex and age were prospectively included. Circulating concentrations of 17-OH-progesterone, progesterone, T, estradiol, FSH, and LH were measured concomitantly to the recording of a digitized electrocardiogram. RESULTS QTcFridericia (QTcF) was shorter in women with CAH than in control women (404 ± 2 vs 413 ± 2.1 milliseconds; P ≤ .001). 17-OH-progesterone, progesterone, the progesterone/estradiol ratio, and total T were higher in women with CAH than in female controls (P < .05), whereas FSH was lower (P ≤ .05). According to multivariable analysis in all women, the progesterone/estradiol ratio (β = -0.33) and FSH levels (β = 0.34) were related to QTcF (r = 0.5; P < .0001), with no influence of CAH or healthy status. QTcF was not different between CAH (404.7 ± 3.7 milliseconds) or healthy men (396 ± 2.8 milliseconds). For men, QTcF (r = 0.48; P < .01) was negatively related to free T (β = -0.29) and positively to FSH levels (β = 0.34). CONCLUSION Cardiac repolarization is influenced by complex interactions between sex steroid hormones and gonadotropins, depending on gender. Our results indicate that the progesterone/estradiol ratio in women, T in men, and FSH in both genders are major determinants of ventricular repolarization with opposite effects on QTc interval.
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Current Antiarrhythmic Therapy for Nonvalvular Atrial Fibrillation in Spain. Data From the FANTASIIA Registry.
Roldán Rabadán, I, Anguita Sánchez, M, Marín, F, Quesada, MA, Camacho Siles, J, Peinado, R, Bertomeu, V, Cequier Fillat, Á, Badimón, L, Muñiz, J, et al
Revista espanola de cardiologia (English ed.). 2016;(1):54-60
Abstract
INTRODUCTION AND OBJECTIVES Recently, there have been many developments in the management of nonvalvular atrial fibrillation, antiarrhythmic and anticoagulant therapy, and nonpharmacological treatment, but these developments are not applied immediately in clinical practice. The aim of this study was to identify the overall management and antiarrhythmic therapy used in the current general population of patients with nonvalvular atrial fibrillation in Spain. METHODS A prospective, observational study of 1318 consecutive anticoagulated patients with nonvalvular atrial fibrillation, recruited between June 2013 and March 2014. We analyzed the patients' general characteristics, management, and antiarrhythmic therapy. RESULTS Mean age was 73.8 ± 9.4 years; 42.5% were women. Atrial fibrillation was paroxysmal in 28% of the patients, permanent in 50%, persistent in 17.6%, long-standing persistent in 4.5%, and new-onset in 66 patients (5%). A rhythm control strategy was chosen in 39.4% of the patients and rate control in 60.6%. Beta-blockers were prescribed in 60.2% of the patients, digoxin in 19.5%, and calcium channel antagonists in 10.7%. The antiarrhythmic agents used were amiodarone (12.6%), flecainide (8.9%), propafenone (0.4%), sotalol (0.5%), and dronedarone (2.3%). Cardioversion had been performed previously in 41.9% of the patients, ablation in 3.4%, and atrial appendage closure in 0.2%. CONCLUSIONS Currently, patients with nonvalvular atrial fibrillation in Spain are managed mainly with rate control, and beta-blockers in particular. They receive few antiarrhythmic agents and only a very small number of these patients undergo nonpharmacological treatments.