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Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects.
Midei, MG, Darpo, B, Ayers, G, Brown, R, Couderc, JP, Daly, W, Ferber, G, Sager, PT, Camm, AJ
Journal of clinical pharmacology. 2021;(12):1606-1617
Abstract
Perhexiline has been used to treat hypertrophic cardiomyopathy. In addition to its effect on carnitine-palmitoyltransferase-1, it has mixed ion channel effects through inhibition of several cardiac ion currents. Effects on cardiac ion channels expressed in mammalian cells were assayed using a manual patch-clamp technique, action potential duration (APD) was measured in ventricular trabeculae of human donor hearts, and electrocardiogram effects were evaluated in healthy subjects in a thorough QT (TQT) study. Perhexiline blocked several cardiac ion currents at concentrations within the therapeutic range (150-600 ng/mL) with IC50 for hCav1.2 ∼ hERG < late hNav1.5. A significant APD shortening was observed in perhexiline-treated cardiomyocytes. The TQT study was conducted with a pilot part in 9 subjects to evaluate a dosing schedule that would achieve therapeutic and supratherapeutic perhexiline plasma concentrations on days 4 and 6, respectively. Guided by the results from the pilot, 104 subjects were enrolled in a parallel-designed part with a nested crossover comparison for the positive control. Perhexiline caused QTc prolongation, with the largest effect on ΔΔQTcF, 14.7 milliseconds at therapeutic concentrations and 25.6 milliseconds at supratherapeutic concentrations and a positive and statistically significant slope of the concentration-ΔΔQTcF relationship (0.018 milliseconds per ng/mL; 90%CI, 0.0119-0.0237 milliseconds per ng/mL). In contrast, the JTpeak interval was shortened with a negative concentration-JTpeak relationship, a pattern consistent with multichannel block. Further studies are needed to evaluate whether this results in a low proarrhythmic risk.
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The Heart in Diabetic Ketoacidosis: A Narrative Review Focusing on the Acute Cardiac Effects and Electrocardiographic Abnormalities.
Carrizales-Sepúlveda, EF, Vera-Pineda, R, Jiménez-Castillo, RA, Violante-Cumpa, JR, Flores-Ramírez, R, Ordaz-Farías, A
The American journal of the medical sciences. 2021;(6):690-701
Abstract
Diabetic ketoacidosis (DKA) is a serious complication of diabetes mellitus. Hyperglycemia, acidosis, and electrolyte imbalances can directly affect the heart by inducing toxicity, impairing myocardial blood flow, autonomic dysfunction, and altering activation and conduction of electrical impulses throughout the heart, increasing the risk of arrhythmias and ischemia. The electrocardiogram is useful in monitoring patients during and after an episode of DKA, as it allows the detection of arrhythmias and guides metabolic correction. Unfortunately, reports on electrocardiographic abnormalities in patients with DKA are lacking. We found two electrocardiographic patterns that are frequently reported in the literature: a pseudo-myocardial infarction and a Brugada Phenocopy. Both are associated with DKA metabolic anomalies and they resolve after treatment. Because of their clinical relevance and the challenge they represent for clinicians, we analyzed the clinical characteristics of these patients and the mechanisms involved in these electrocardiographic findings.
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Cost-effectiveness of screening of coronary artery disease in patients with type 2 DIABetes at a very high cardiovascular risk (SCADIAB study) rational and design.
Mohammedi, K, Préaubert, N, Cariou, T, Rigalleau, V, Foussard, N, Piazza, L, Bairras-Martin, C, Couffinhal, T, Bezin, J, Benard, A
Cardiovascular diabetology. 2021;(1):63
Abstract
BACKGROUND Screening for coronary artery disease (CAD) remains broadly performed in patients with type 2 diabetes (T2DM), although the lack of evidence. We conduct a real-world evidence (RWE) study to assess the risk of major clinical outcomes and economic impact of routine CAD screening in T2DM individuals at a very high cardiovascular risk. METHODS SCADIAB is a comparative nationwide cohort study using data from the French National Health Data System. The main inclusion criteria are: age ≥ 40 years, DT2 diagnosed for ≥ 7 years, with ≥ 2 additional cardiovascular risk factors plus a history of microvascular or macrovascular disease, except CAD. We estimated ≥ 90,000 eligible participants for our study. Data will be extracted from 01/01/2008 to 31/12/2019. Eligible participants will be identified during a first 7-year selection period (2008-2015). Each participant will be assigned either in experimental (CAD screening procedure during the selection period) or control group (no CAD screening) on 01/01/2015, and followed for 5 years. The primary endpoint is the incremental cost per life year saved over 5 years in CAD screening group versus no CAD screening. The main secondary endpoints are: total 5-year direct costs of each strategy; incidence of major cardiovascular (acute coronary syndrome, hospitalization for heart failure, coronary revascularization or all-cause death), cerebrovascular (hospitalization for transient ischemic attack, stroke, or carotid revascularization) and lower-limb events (peripheral artery disease, ischemic diabetic foot, lower-limb revascularization or amputation); and the budget impact for the French Insurance system to promote the cost-effective strategy. Analyses will be adjusted for a high-dimension propensity score taking into account known and unknown confounders. SCADIAB has been funded by the French Ministry of Health and the protocol has been approved by the French ethic authorities. Data management and analyses will start in the second half of 2021. DISCUSSION SCADIAB is a large and contemporary RWE study that will assess the economic and clinical impacts of routine CAD screening in T2DM people at a very high cardiovascular risk. It will also evaluate the clinical practice regarding CAD screening and help to make future recommendations and optimize the use of health care resources. Trial registration ClinicalTrials.gov Identifier: NCT04534530 ( https://clinicaltrials.gov/ct2/show/NCT04534530 ).
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Role of acetylcholine spasm provocation test as a pathophysiological assessment in nonobstructive coronary artery disease.
Suzuki, S, Kaikita, K, Yamamoto, E, Jinnouchi, H, Tsujita, K
Cardiovascular intervention and therapeutics. 2021;(1):39-51
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Abstract
Coronary angiography (CAG) sometimes shows nonobstructive coronary arteries in patients with suspected angina or acute coronary syndrome (ACS). The high prevalence of nonobstructive coronary artery disease (CAD) in those patients has recently been reported not only in Japan but also in Western countries, and is clinically attracting attention. Coronary spasm is considered to be one of the leading causes of both suspected stable angina and ACS with nonobstructive coronary arteries. Coronary spasm could also be associated with left ventricular dysfunction leading to heart failure, which could be improved following the administration of calcium channel blockers. Because we rarely capture spontaneous attacks of coronary spasm with electrocardiograms or Holter recordings, an invasive diagnostic modality, acetylcholine (ACh) provocation test, can be useful in detecting coronary spasm during CAG. Furthermore, we can use the ACh-provocation test to identify high-risk patients with coronary spasm complicated with organic coronary stenosis, and then treat with intensive care. Nonobstructive CAD includes not only epicardial coronary spasm but also microvascular spasm or dysfunction that can be associated with recurrent anginal attacks and poor quality of life. ACh-provocation test could also be helpful for the assessment of microvascular spasm or dysfunction. We hope that cardiologists will increasingly perform ACh-provocation test to assess the pathophysiology of nonobstructive CAD.
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High prevalence of fragmented QRS on electrocardiography in Japanese patients with diabetes irrespective of metabolic syndrome.
Yagi, K, Nagata, Y, Yamagami, T, Chujo, D, Kamigishi, M, Yokoyama-Nakagawa, M, Shikata, M, Enkaku, A, Takikawa-Nishida, A, Honoki, H, et al
Journal of diabetes investigation. 2021;(9):1680-1688
Abstract
AIMS/INTRODUCTION Fragmented QRS (fQRS) on electrocardiography is a marker of myocardial fibrosis and myocardial scar formation. This study aimed to clarify the relationship of fQRS with diabetes mellitus and metabolic syndrome (MetS) in Japanese patients. MATERIALS AND METHODS Approximately 702 individuals who had a routine health checkup at the Hokuriku Health Service Association (Toyama, Japan) in October 2014 were enrolled and categorized into one of the following four groups based on MetS and diabetes mellitus status: with diabetes mellitus (+) MetS+ (164 participants); diabetes mellitus+ without MetS (Mets-; 103 participants); diabetes mellitus- MetS+ (133 participants); and diabetes mellitus- MetS- (302 participants). fQRS was assessed using the results of electrocardiography. RESULTS The prevalence of fQRS was statistically higher in patients with diabetes mellitus+ MetS+ (37%) and diabetes mellitus+ MetS- (35%), than those with diabetes mellitus- MetS+ (14%) or diabetes mellitus- MetS- (10%; P < 0.0001). Significant differences were observed between the fQRS(+) and fQRS(-) groups for age, sex, waist circumference, heart rate, hypertension, hemoglobin A1c, total cholesterol, MetS and diabetes mellitus. The area under the receiver operating characteristic curve for traditional risk factors and diabetes mellitus was 0.72 (P = 0.0007, 95% confidence interval 0.67-0.76), and for traditional risk factors and MetS it was 0.67 (P = 0.28, 95% confidence interval 0.62-0.72). Patients with diabetes mellitus had more than threefold higher likelihood of showing fQRS (odds ratio 3.41; 95% confidence interval 2.25-5.22; P < 0.0001) compared with the reference group without diabetes mellitus, after adjusting for age, sex, dyslipidemia, hypertension and waist circumference. CONCLUSIONS fQRS was observed more frequently in diabetes mellitus patients than in MetS and control individuals. Diabetes mellitus was the most significant determinant for fQRS among MetS and other traditional metabolic risk factors.
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Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.
Darpo, B, Benson, C, Brown, R, Dota, C, Ferber, G, Ferry, J, Jarugula, V, Keirns, J, Ortemann-Renon, C, Pham, T, et al
Journal of clinical pharmacology. 2020;(1):125-139
Abstract
The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.
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First Clinical Study with AP30663 - a KCa 2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation.
Gal, P, Klaassen, ES, Bergmann, KR, Saghari, M, Burggraaf, J, Kemme, MJB, Sylvest, C, Sørensen, U, Bentzen, BH, Grunnet, M, et al
Clinical and translational science. 2020;(6):1336-1344
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Abstract
Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca2+ activated K+ (KCa 2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (Cmax ) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel KCa 2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.
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Changes in global electrical heterogeneity associated with dofetilide, quinidine, ranolazine, and verapamil.
Stabenau, HF, Shen, C, Tereshchenko, LG, Waks, JW
Heart rhythm. 2020;(3):460-467
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Abstract
BACKGROUND Electrocardiographic (ECG) markers of antiarrhythmic drug (AAD) activity could be used to optimize efficacy and minimize toxicity. Vectorcardiographic global electrical heterogeneity (GEH) is associated with ventricular arrhythmias and sudden death, but it is unclear how GEH measurements change in response to AADs. OBJECTIVE The purpose of this study was to characterize acute effects of AADs on GEH measurements. METHODS We analyzed double-blind placebo-controlled trial data from healthy volunteers given 1 dose of placebo, dofetilide, quinidine, ranolazine, or verapamil on subsequent visits. Serial ECGs and plasma drug concentrations were collected. Vectorcardiographic GEH parameters (spatial ventricular gradient [SVG], spatial QRST angle, sum absolute QRST integral, and SVG-QRS peak angle) were measured. Placebo-corrected change from baseline was regressed on drug concentration stratified by sex using linear mixed effects models. RESULTS Among 22 persons (11 (50%) male median age 27 ± 5 years), 5232 ECGs were analyzed. Dofetilide and quinidine were associated with significant changes in more GEH parameters (5) compared with verapamil (2) and ranolazine (1). The most notable change occurred in SVG azimuth, with largest changes (degrees per unit normalized drug concentration) in dofetilide (6.1; 95% confidence interval [CI] 4.2-8.0) and quinidine (9.4; 95% CI 6.7-12.0), and smaller effects in verapamil (4.4; 95% CI 2.9-5.9) and ranolazine (5.4; 95% CI 3.5-7.3). AAD-induced GEH changes significantly differed in men and women. CONCLUSION AADs change GEH measurements. These changes, which differ by sex, are likely driven by alterations in ion channel function and dispersion of depolarization or repolarization. GEH measurement may allow early assessment of favorable or adverse AAD effects.
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Nano-copper enhanced flexible device for simultaneous measurement of human respiratory and electro-cardiac activities.
Wang, L, Zhang, F, Lu, K, Abdulaziz, M, Li, C, Zhang, C, Chen, J, Li, Y
Journal of nanobiotechnology. 2020;(1):82
Abstract
BACKGROUND Dysfunction of human respiratory and electro-cardiac activities could affect the ability of the heart to pump blood and the lungs to inhale oxygen. Thus, a device could simultaneously measure electro-cardiac signal and respiratory pressure could provide vital signs for predicting early warning of cardio-pulmonary function-related chronic diseases such as cardiovascular disease, and respiratory system disease. RESULTS In this study, a flexible device integrated with piezo-resistive sensing element and voltage-sensing element was developed to simultaneously measure human respiration and electro-cardiac signal (including respiratory pressure, respiration frequency, and respiration rhythm; electro-cardio frequency, electro-cardio amplitude, and electro-cardio rhythm). When applied to the measurement of respiratory pressure, the piezo-resistive performance of the device was enhanced by nano-copper modification, which detection limitation of pressure can reduce to 100 Pa and the sensitivity of pressure can achieve to 0.053 ± 0.00079 kPa-1. In addition, the signal-to-noise ratio during bio-electrical measurement was increased to 10.7 ± 1.4, five times better than that of the non-modified device. CONCLUSION This paper presents a flexible device for the simultaneous detection of human respiration and cardiac electrical activity. To avoid interference between the two signals, the layout of the electrode and the strain sensor was optimized by FEA simulation analysis. To improve the piezo-resistive sensitivity and bio-electric capturing capability of the device, a feather-shaped nano-copper was modified onto the surface of carbon fiber. The operation simplicity, compact size, and portability of the device open up new possibilities for multi-parameter monitoring.
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Chronic Hyperkalemia in Cardiorenal Patients: Risk Factors, Diagnosis, and New Treatment Options.
Di Lullo, L, Ronco, C, Granata, A, Paoletti, E, Barbera, V, Cozzolino, M, Ravera, M, Fusaro, M, Bellasi, A
Cardiorenal medicine. 2019;(1):8-21
Abstract
Chronic hyperkalemia (HK) is a serious medical condition that often manifests in patients with chronic kidney disease (CKD) and heart failure (HF) leading to poor outcomes and necessitating careful management by cardionephrologists. CKD, HF, diabetes, and renin-angiotensin-aldosterone system inhibitors use is known to induce HK. Current therapeutic options are not optimal, as pointed out by a large number of CKD and HF patients with HK. The following review will focus on the main risk factors for developing HK and also aims to provide a guide for a correct diagnosis and present new approaches to therapy.