Ventricular Repolarization Duration Research Articles

Action potential morphology affects T-wave symmetry (simulation study)

BackgroundAssessing T-wave symmetry in addition to QT subintervals measurements can provide novel independent data about ventricular repolarization abnormalities linked with arrhythmogenesis. However, the causes of the changes of T-wave symmetry are not completely understood. In silico studies showed that the more symmetrical T-waves were associated with shorter action potential duration (APD) and larger dispersion of ventricular repolarization (DOR). The aim of present simulation was to study the association between T-wave symmetry and action potential (AP) shape. MethodsECGs were simulated using a cellular automata model shaped as a ventricular wall segment, and two biophysically-detailed models of ventricular AP – the rabbit and the human. The symmetry ratio (SR) was calculated as a T-wave onset-peak to peak-end area ratio. The individual and combined effects of APD, DOR and AP shape on SR were simulated. To study the effect of AP shape, different APs from triangulated to rectangular were simulated. ResultsThe simulations showed that AP shape along with APD and DOR contributes much to T-wave symmetry. APs with a flat phase 3 (triangulated) produced asymmetrical T-waves (SR ≥ 1.5) in all simulations, except the shortest APD range. APs with a rapid phase 3 (rectangular) were associated with more symmetrical T-waves (SR ≤ =1) both at the short and the long APDs. ConclusionSR marker in combination with the standard ECG parameters (QT interval, Tpeak-Tend interval) may be useful to identify the proarrhythmic triangulated AP shape.

Association between ventricular premature contraction burden and ventricular repolarization duration.

Premature ventricular contraction is generally known as benign in the absence of structural heart disease; however, premature ventricular contraction-induced left ventricular systolic dysfunction or ventricular arrhythmias are defined in some cases. Ventricular repolarization duration differs between myocardial cells, which causes myocardial electrical heterogeneity and is thought to be responsible for ventricular arrhythmias. In our study, we aimed to evaluate the association of ventricular repolarization parameters including Tp-Te interval, Tp-Te/QT ratio, and QRS-T angle with premature ventricular contraction frequency in patients with premature ventricular contraction burden. A total of 80 subjects who were admitted to our cardiology department and underwent 24-h electrocardiography Holter monitoring were included. Patients were divided into two groups: group 1 is defined as premature ventricular contraction burden that had frequent premature ventricular contraction ≥1% in 24-h Holter monitoring, and group 2 is defined as rare premature ventricular contraction <1% in 24-h Holter monitoring. Tp-Te interval and Tp-Te/QT ratio are statistically significantly prolonged in the premature ventricular contraction burden group than in the control group (85.3±13.9 vs. 65.7±11.9, p<0.001; 0.19±0.03 vs. 0.15±0.02, p<0.001, respectively). QRS-T angle was statistically significantly abnormal in the premature ventricular contraction burden group (p=0.024). Increased Tp-Te interval and widened QRS-T angle are associated with ventricular arrhythmias and might be used for the prediction of premature ventricular contraction burden in patients with premature ventricular contraction in electrocardiography in the absence of 24-h Holter monitoring.

Accelerated QT adaptation following atropine-induced heart rate increase in LQT1 patients versus healthy controls: A sign of disturbed hysteresis.

Hysteresis, a ubiquitous regulatory phenomenon, is a salient feature of the adaptation of ventricular repolarization duration to heart rate (HR) change. We therefore compared the QT interval adaptation to rapid HR increase in patients with the long QT syndrome type 1 (LQT1) versus healthy controls because LQT1 is caused by loss-of-function mutations affecting the repolarizing potassium channel current IKs , presumably an important player in QT hysteresis. The study was performed in an outpatient hospital setting. HR was increased in LQT1 patients and controls by administering an intravenous bolus of atropine (0.04 mg/kg body weight) for 30 s. RR and QT intervals were recorded by continuous Frank vectorcardiography. Atropine induced transient expected side effects but no adverse arrhythmias. There was no difference in HR response (RR intervals) to atropine between the groups. Although atropine-induced ΔQT was 48% greater in 18 LQT1 patients than in 28 controls (p < 0.001), QT adaptation was on average 25% faster in LQT1 patients (measured as the time constant τ for the mono-exponential function and the time for 90% of ΔQT; p < 0.01); however, there was some overlap between the groups, possibly a beta-blocker effect. The shorter QT adaptation time to atropine-induced HR increase in LQT1 patients on the group level corroborates the importance of IKs in QT adaptation hysteresis in humans and shows that LQT1 patients have a disturbed ultra-rapid cardiac memory. On the individual level, the QT adaptation time possibly reflects the effect-size of the loss-of-function mutation, but its clinical implications need to be shown.

Effects of β-blockers on ventricular repolarization documented by 24-hour electrocardiography in long QT syndrome type 2

Long QT syndrome (LQTS) is an inherited arrhythmia disorder characterized by ventricular repolarization abnormalities and a risk of sudden cardiac death. The electrophysiological components generating the high risk of arrhythmias in LQTS are prolonged repolarization, increased dispersion of repolarization, and early afterdepolarizations, which are clinically estimated as QT interval, T-wave peak to T-wave end (TPE) interval, and T2/T1-wave amplitude ratio, respectively. In experimental LQTS type 2 (LQT2) models, β-blockers decrease dispersion of repolarization and prevent early afterdepolarizations. In clinical studies in patients with LQT2 , β-blockers are more effective against exercise-induced than arousal-induced cardiac events. The aim of the study was to investigate the effects of β-blocker therapy on repolarization properties in LQT2. QT and TPE intervals and maximal T2/T1-wave amplitude ratios recorded by 24-hour electrocardiograms before and during β-blocker therapy were evaluated in 25 patients with LQT2. β-Blocker therapy decreased the maximal T2/T1-wave amplitude ratio from 2.9 ± 1.1 to 1.8 ± 0.7 (P < .001), but did not change the pause-induced T2/T1-wave amplitude ratio. Under medication, abrupt maximal TPE intervals were shorter at heart rates of ≥75 beats/min and maximal QT intervals were shorter at a heart rate of 100 beats/min. β-Blockers stabilize ventricular repolarization in LQT2 by reducing electrocardiographic early afterdepolarizations and by reducing abrupt prolongation of electrocardiographic dispersion of repolarization and ventricular repolarization duration at elevated heart rates. The effect of β-blockers on pause-induced electrocardiographic early afterdepolarizations is weak. The findings provide electrocardiographic explanation for the protective effects of β-blockers against exercise-induced cardiac events in LQT2.

Age and Gender Differences in Cardiovascular Autonomic Failure in the Transgenic PLP-syn Mouse, a Model of Multiple System Atrophy.

Multiple system atrophy (MSA) is a rare and progressive neurodegenerative disorder. Autonomic failure (AF) is one main clinical feature which has a significant impact on health-related quality of life. The neuropathological hallmark of MSA is the abnormal accumulation of α-synuclein in oligodendrocytes forming glial cytoplasmic inclusions. Only little is known about gender and age differences in AF in MSA. This study was carried out in 6 and 12 months old transgenic PLP-α-syn and WT male and female mice. Heart rate variability (HRV) was assessed both in time, frequential and non-linear domains. Baroreflex sensitivity (BRS) was estimated by the sequence method. Duration of ventricular depolarization and repolarization (QT/QTc intervals) were evaluated from the ECG signals. Three-way ANOVA (genotype x gender x age) with Sidak's method post-hoc was used to analyze data. BRS was significantly changed in PLP-α-syn mice and was age-dependent. QT and QTc intervals were not significantly modified in PLP-α-syn mice. An impaired HRV was observed at 12 months of age in PLP-α-syn female but not in male mice, indicative of cardiovascular AF.

Congenital Long QT Syndrome: A Review of Genetic and Pathophysiologic Etiologies, Phenotypic Subtypes, and Clinical Management.

Congenital Long QT Syndrome (CLQTS) is the most common inherited arrhythmia. The QT interval, which marks the duration of ventricular depolarization and repolarization in the myocardium, can be prolonged due to mutations in genes coding for the ion channel proteins that govern the cardiac action potential. The lengthening of the QT interval can lead to a wide range of clinical symptoms, including seizures, torsades de pointes, and fatal arrhythmias. There is a growing body of evidence that has revealed the genetic mutations responsible for the pathophysiology of CLQTS, and this has led to hypotheses regarding unique triggers and clinical features associated with specific gene mutations. Epidemiologic evidence has revealed a 1-year mortality rate of approximately 20% in untreated CLQTS patients, and a <1% of 1-year mortality rate in treated patients, underscoring the importance of timely diagnosis and effective clinical management. There are many phenotypic syndromes that constitute CLQTS, including but not limited to, Jervell and Lange-Nielsen syndrome, Romano and Ward syndrome, Andersen-Tawil syndrome, and Timothy syndrome. In this review, we aim to (1) summarize the genetic, epidemiologic, and pathophysiological basis of CLQTS and (2) outline the unique features of the phenotypic subtypes and their clinical management.

The Effect of Fasting on QT Interval

Introduction: QT interval reflects the total duration of ventricular depolarization and repolarization in the ECG. Experimental hypoglycaemia and spontaneous clinical episodes of hypoglycaemia lead to the lengthening of the heart rate corrected QT interval or QTc. This is associated with elevated risk of sudden death. Objective: To find out the effect of fasting blood glucose levels on QT interval and the Corrected QT interval (QTc). Materials and Methods: Fasting and post prandial blood glucose levels and ECG of healthy young adults were studied and QT interval, RR interval and QTc were determined. Results: The fasting QTc came out to be 0.408+-0.020 as compared to the post prandial value of 0.380+-0.019. The student’s t test showed a highly significant value (p

Sexual Dimorphisms, Anti-Hormonal Therapy and Cardiac Arrhythmias.

Significant variations from the normal QT interval range of 350 to 450 milliseconds (ms) in men and 360 to 460 ms in women increase the risk for ventricular arrhythmias. This difference in the QT interval between men and women has led to the understanding of the influence of sex hormones on the role of gender-specific channelopathies and development of ventricular arrhythmias. The QT interval, which represents the duration of ventricular repolarization of the heart, can be affected by androgen levels, resulting in a sex-specific predilection for acquired and inherited channelopathies such as acquired long QT syndrome in women and Brugada syndrome and early repolarization syndrome in men. Manipulation of the homeostasis of these sex hormones as either hormonal therapy for certain cancers, recreational therapy or family planning and in transgender treatment has also been shown to affect QT interval duration and increase the risk for ventricular arrhythmias. In this review, we highlight the effects of endogenous and exogenous sex hormones in the physiological and pathological states on QTc variation and predisposition to gender-specific pro-arrhythmias.

Evaluation of Cardiac Circadian Rhythm Deconditioning Induced by 5-to-60 Days of Head-Down Bed Rest.

Head-down tilt (HDT) bed rest elicits changes in cardiac circadian rhythms, generating possible adverse health outcomes such as increased arrhythmic risk. Our aim was to study the impact of HDT duration on the circadian rhythms of heart beat (RR) and ventricular repolarization (QTend) duration intervals from 24-h Holter ECG recordings acquired in 63 subjects during six different HDT bed rest campaigns of different duration (two 5-day, two 21-day, and two 60-day). Circadian rhythms of RR and QTend intervals series were evaluated by Cosinor analysis, resulting in a value of midline (MESOR), oscillation amplitude (OA) and acrophase (φ). In addition, the QTc (with Bazett correction) was computed, and day-time, night-time, maximum and minimum RR, QTend and QTc intervals were calculated. Statistical analysis was conducted, comparing: (1) the effects at 5 (HDT5), 21 (HDT21) and 58 (HDT58) days of HDT with baseline (PRE); (2) trends in recovery period at post-HDT epochs (R) in 5-day, 21-day, and 60-day HDT separately vs. PRE; (3) differences at R + 0 due to bed rest duration; (4) changes between the last HDT acquisition and the respective R + 0 in 5-day, 21-day, and 60-day HDT. During HDT, major changes were observed at HDT5, with increased RR and QTend intervals’ MESOR, mostly related to day-time lengthening and increased minima, while the QTc shortened. Afterward, a progressive trend toward baseline values was observed with HDT progression. Additionally, the φ anticipated, and the OA was reduced during HDT, decreasing system’s ability to react to incoming stimuli. Consequently, the restoration of the orthostatic position elicited the shortening of RR and QTend intervals together with QTc prolongation, notwithstanding the period spent in HDT. However, the magnitude of post-HDT changes, as well as the difference between the last HDT day and R + 0, showed a trend to increase with increasing HDT duration, and 5/7 days were not sufficient for recovering after 60-day HDT. Additionally, the φ postponed and the OA significantly increased at R + 0 compared to PRE after 5-day and 60-day HDT, possibly increasing the arrhythmic risk. These results provide evidence that continuous monitoring of astronauts’ circadian rhythms, and further investigations on possible measures for counteracting the observed modifications, will be key for future missions including long periods of weightlessness and gravity transitions, for preserving astronauts’ health and mission success.

Is mexiletine ready for prime time in patients with Type 2 Long QT Syndrome?

Abstract Background Mexiletine has been proven effective in shortening the duration of ventricular repolarization and reducing the arrhythmic events in type 3 Long QT Syndrome (LQT3). Initial reports indicate that mexiletine might also be effective in patients with type 2 Long QT Syndrome (LQT2, caused by loss-of-functions variants on KCNH2 gene, coding for HERG potassium channel), but this issue has not been investigated in detail. Purpose We quantified the electrocardiographic (ECG) effects of mexiletine in a cohort of LQT2 patients. Methods Twelve-lead ECGs were collected before and after the administration of mexiletine to evaluate the drug's effect on the heart rate-corrected QT interval (QTc). QTc intervals were classified as being (1) at “high-risk” if &amp;gt;500 ms or (2) “normal” if &amp;lt;460 ms, before and after the administration of the drug. KCNH2 variants were defined as (1) trafficking-deficient or (2) non-trafficking-deficient, based on functional studies. Results We tested the maximum tolerated dose of mexiletine in 20 patients (11 males, 55%), who were 17±16 years old at diagnosis, affected by genetically established LQT2. The mean age at the beginning of mexiletine administration was 23±15 years and the mean daily dose administered was 9±2 mg/kg/day. Before mexiletine, the mean QTc interval was 527±53 ms and 10/20 (50%) patients had high-risk QTc values (i.e. QTc &amp;gt;500 ms). After mexiletine, the mean QTc interval shortened to 484±47 ms in the overall population (p=0.001). In the majority of patients (18/20, 90%; Figure 1) QTc interval shortened, with a mean shortening of 42±28 ms, and a high-interindividual variability (range of shortening from 86 ms to 8 ms). Just 2 (10%) patients did not show any reduction of the QTc, despite receiving the highest adult dosages of mexiletine in our cohort (up to 10 mg/kg/day). As compared to baseline conditions, after mexiletine the proportion of patients with high risk QTc values (&amp;gt;500 ms) decreased non-significantly from 50% to 35% (p=0.52). Furthermore, in only 6/20 (30%) patients the QTc normalized (i.e. QTc &amp;lt;460 ms) after the initiation of treatment. The effect of mexiletine was not influenced by gender (p=0.89) or by the functional effect of the KCNH2 mutation (trafficking-deficient vs. non-trafficking-deficient variants, p=0.41). The effect of mexiletine in LQT2 patients was inferior to the one previously observed in a cohort of 34 LQT3 patients, who had similar QTc values at baseline and received similar dosages of mexiletine, but showed a significantly higher reduction of the average QTc interval (63±37 ms in LQT3 vs. 42±28 ms in LQT2, p=0.02). Conclusions Mexiletine induces a reduction of the QTc interval in most LQT2 patients, but many patients remain with high-risk QTc values after receiving the drug. The demonstration that an average QTc shortening of 42 ms is enough to reduce arrhythmic events is necessary, before the introduction of mexiletine in clinical practice for LQT2. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia)

Sex influences on ventricular repolarization duration in normal subjects and in type 1, 2 and 3 long QT syndrome patients: Different effect in acquired and congenital type 2 LQTS

AimTo evaluate the interaction between sex and rate corrected QT interval (QTc) duration in normal subjects after drug-induced QT prolongation and in LQTS patients. MethodsSemi-automated measurements were performed on 875 digital ECGs (200 normal subjects off drugs (100 females), 200 normal subjects on Moxifloxacin (100 females), 259 LQT1 patients (161 females), 183 LQT2 patients (100 females) and 33 LQT3 patients (15 females)). A sex specific coefficient was calculated in each group and was used to calculate group specific corrected QT intervals (QTci). ResultsThe mean sex difference (female minus male) in QTci interval duration was 17 ms 95%CI(12.7; 21.3) in normal subjects, 19 ms (14.5; 23.5) on Moxifloxacin, and 13 ms (4.8; 21.2) in LQT1 patients. The mean difference was 2 ms (−7.9; 11.9) in LQT2 and − 5 ms (−32.2; 22.2) in LQT3 patients (p = 0.0067 for the group and sex interaction).In the subgroup of patients above 15 years and without beta blocker treatment, the sex effect (female minus male) on QTci interval duration was 17 ms (4.1; 29.9) in LQT1 patients. QTc duration was not different between sex in LQT2 and in LQT3 patients (mean difference − 3 ms (−21.6; 15.6) and 12 ms (−28.4; 52.4), respectively) (p = 0.0191 for group and sex interaction). ConclusionsThe interaction between sex and QTc interval is preserved in type 1 LQTS and drug-induced QTc prolongation but blurred in type 2 LQTS. Further experimental studies are warranted to better understand the interaction of sexual hormones with malfunctioning KCNH2 encoded repolarizing potassium channel.

Thorough QTc Study of a Single Supratherapeutic Dose of Relebactam in Healthy Participants.

The effects of supratherapeutic doses of intravenous (IV) relebactam on duration of ventricular depolarization and subsequent repolarization were assessed in a thorough QT/corrected QT study. This was a single-dose, double-blind (relebactam only), randomized, placebo- and positive-controlled, 3-period, balanced crossover study in healthy participants. Participants received in randomized order, and separated by a washout (≥4 days), a single dose of IV relebactam 1150 mg, oral moxifloxacin 400 mg (open-label positive control), and IV placebo. Least squares mean and 2-sided 90% confidence interval for change from baseline in population-derived corrected QT intervals for relebactam, moxifloxacin, and placebo were estimated for 24 hours. The upper limit of the 90% confidence interval of all least squares mean population-derived corrected QT treatment differences from placebo was not >10 milliseconds at any time point for 24 hours. Corrected QT assay sensitivity was confirmed with moxifloxacin treatment. Analysis of electrocardiogram parameters resulted in no additional cardiac safety concerns. Overall, a supratherapeutic dose of relebactam yielded no cardiac safety events; the 1150-mg supratherapeutic dose (4.6-fold above the 250-mg therapeutic dose) was not associated with QT prolongation or other abnormal cardiodynamic parameters. This study lends additional support to relebactam's use as a β-lactamase inhibitor in antimicrobial therapy.

Acquired Long QT Syndrome: A Review of the Literature

The QT interval represents the duration of ventricular depolarization and repolarization. It is measured from the beginning of the QRS complex to the end of the T wave. Prolongation of the QT interval may be congenital or acquired. This increases the risk of polymorphic ventricular tachycardia (i.e torsades de pointes) and cardiac arrest. To increase the awareness of this life-threatening phenomenon I outline an illustrative case in which acquired prolongation of the QT interval due to electrolyte derangement and administration of ciprofloxacin resulted in cardiac arrest due to torsade de pointes. Management of a patient with a long QT syndrome includes Immediate cessation of drugs that prolong the QT interval; cardiac monitoring, serial 12 lead ECGs and transthoracic echocardiography; measurement of serum electrolytes; intravenous potassium replacement; intravenous magnesium replacement; beta-blockade. Causes of acquired prolongation of the QT interval are common in critically ill patients. It is important to recognize this and consider screening with 12 lead ECG to reduce the risk of life-threatening ventricular arrhythmias.

Adaptation of ventricular repolarization duration and dispersion during changes in heart rate induced by atrial stimulation.

BackgroundThe duration of ventricular repolarization (VR) and its spatial and temporal heterogeneity are central elements in arrhythmogenesis. We studied the adaptation of VR duration and dispersion and their relationship in healthy human subjects during atrial pacing.MethodsPatients 20‐50 years of age who were scheduled for ablation of supraventricular tachycardia without preexcitation but otherwise healthy were eligible. Vectorcardiography recordings with Frank leads were used for data collection. Incremental atrial pacing from a coronary sinus electrode was performed by decrements of 10ms/cycle from just above sinus rate, and then kept at a fixed heart rate (HR) just below the Wenckebach rate for ≥5min and then stopped. VR duration was measured as QT and VR dispersion as T area, T amplitude and ventricular gradient. The primary measure (T90 End) was the time to reach 90% change from baseline to the steady state value during and after pacing.ResultsA complete study protocol was accomplished in 9 individuals (6 women). VR duration displayed a monophasic adaptation during HR acceleration lasting on average 20s. The median (Q1‐Q3) T90 End for QT was 85s (51‐104), a delay by a factor >4. All dispersion measures displayed a tri‐phasic response pattern during HR acceleration and T90 End was 3‐5 times shorter than for VR duration.ConclusionsEven during close to “physiological” conditions, complex and differing response patterns in VR duration and dispersion measures followed changes in HR. Extended knowledge about these responses in disease conditions might assist in risk evaluation and finding therapeutic alternatives.

Heart Electrical Activity during Ventricular Repolarization in Subjects with Different Resistances to Hypoxia

The study of the electrical activity of the heart during ventricular repolarization period of healthy subjects with different resistances to oxygen deficiency to exposure of normobaric hypoxic hypoxia (12.3% O2) has been carried out using the simultaneous recording of the heart electrical unipolar potentials from a variety of leads on the body surface. It was revealed that in subjects with different resistances to a hypoxic stimulus the correlation of change in QT, J-TpeakII and Tpeak-TendII intervals under the influence of acute hypoxia was different: in subjects with a high resistance to hypoxia the decrease in the QT interval corresponded to the decrease in ventricular late repolarization duration, and in subjects with low resistance to hypoxia the decrease in the QT interval corresponded to the periods of early and late repolarization. The analysis of the cardioelectric field on the body surface of subjects with different resistances to a hypoxic stimulus revealed a statistically significant decrease in temporal characteristics of maximum cardioelectric potentials while amplitude characteristics remained practically unchanged independently of resistance to hypoxia.

Diagnostic accuracy of a novel predictive model for ischemic events based on small dense LDL-cholesterol concentration (SDLDL-C) and lipid characterization by NMR

Proper adaptation of ventricular repolarization (VR) to rapid heart rate (HR) increase is crucial for cardiac electro-mechanical function. The pattern and temporal aspects of this adaptation and its components (duration and dispersion) during normal conduction are, however, incompletely known in humans and were the topic of this study.The VR duration (QT & QTpeak) and dispersion (Tamplitude, Tarea & ventricular gradient; VG) responses were studied by continuous vectorcardiogram after a bolus injection of atropine 0.04 mg/kg b.w. in 31 healthy young adults (16 men). The primary measure (T90 End) was the time to reach 90% change from baseline to end value 300 s later.Mean (SD) of T90 End was 23 (9) s for a 41% RR decrease, 130 (35) s for a 16% QTend decrease and 110 (36) s for a 19% QTpeak decrease; the response was single-exponential for these measures. For 35–43% decreases of Tamplitude, Tarea & VG, mean (SD) of T90 End were 21 (10), 38 (20) and 40 (23) s and the response pattern was double-exponential with varying overshoot.VR duration and dispersion responses to a very rapid HR increase during normal conduction differed substantially. In contrast to the well-known single-exponential delay in VR duration adaptation the responses of VR dispersion measures were double-exponential and much more rapid. We describe a new and completely non-invasive phenotypic characterization of different components of VR adaptation.

QT interval – Its measurement and clinical significance

QT interval extends from the beginning of QRS complex to the end of T wave. Thus, it includes the duration of ventricular depolarization (QRS) and repolarization (J point to end of T wave). It corresponds to the duration of cellular action potential. “long-” and “short”-QT intervals are considered as risk markers for cardiac arrhythmias and sudden death. In the last decade, there have been significant advances in our understanding about measurement and significance of QT interval. We have made an attempt to review the literature to find the limitations and queries surrounding the present status of measurement of QT interval and its significance as a risk marker for cardiac arrhythmias and sudden death.

Carqueja (Baccharis trimera) essential oil chronic treatment induces ventricular repolarization disorder in healthy rats but not in type 2 diabetic rats

Background: Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease (CVD) development. The pharmacological treatment of T2DM can increase cardiovascular risk in diabetic patients. Carqueja (Baccharis trimera) is an antioxidant and hypoglycemic medicinal plant with promising action for T2DM non-pharmacological treatment. Objectives: The objective of this study is to investigate carqueja essential oil safety on the cardiovascular system of diabetic and non-diabetic rats. Materials and Methods: Four experimental groups were used to analyze the carqueja essential oil effects: control group (n = 5), carqueja-treated control group (n = 4), diabetic control group (n = 4), and carqueja-treated diabetic group (n = 5). T2DM was induced by hypercaloric diet followed by streptozotocin administration. Electrocardiogram parameters were used to analyze the alterations in the cardiovascular system. Results: Diabetic rats showed ventricular repolarization dysfunction with prolongation of QT and corrected QT intervals. The treatment increased ventricular repolarization duration in the control group. Conclusion: Carqueja essential oil treatment worsens ventricular repolarization in nondiabetic rats, increasing the arrhythmogenic risk.

Risk of sudden unexplained death after use of dihydroartemisinin–piperaquine for malaria: a systematic review and Bayesian meta-analysis

SummaryBackgroundDihydroartemisinin–piperaquine is an effective and well tolerated artemisinin-based combination therapy that has been assessed extensively for the prevention and treatment of malaria. Piperaquine, similar to several structurally related antimalarials currently used, can prolong cardiac ventricular repolarisation duration and the electrocardiographic QT interval, leading to concerns about its proarrhythmic potential. We aimed to assess the risk of potentially lethal iatrogenic ventricular arrhythmias in individuals receiving dihydroartemisinin–piperaquine.MethodsWe did a systematic review and Bayesian meta-analysis. We searched clinical bibliographic databases (last on May 24, 2017) for studies of dihydroartemisinin–piperaquine in human beings. Further unpublished studies were identified with the WHO Evidence Review Group on the Cardiotoxicity of Antimalarials. We searched for articles containing “dihydroartemisinin-piperaquine” as title, abstract, or subject heading keywords, with synonyms and variant spellings as additional search terms. We excluded animal studies, but did not apply limits on language or publication date. Eligible studies were prospective, randomised, controlled trials or cohort studies in which individuals received at least one 3-day treatment course of dihydroartemisinin–piperaquine for mass drug administration, preventive therapy, or case management of uncomplicated malaria, with follow-up over at least 3 days. At least two independent reviewers screened titles, abstracts, and full texts, agreed study eligibility, and extracted information about study and participant characteristics, adverse event surveillance methodology, dihydroartemisinin–piperaquine exposures, loss-to-follow up, and any deaths after dihydroartemisinin–piperaquine treatment into a standardised database. The risk of sudden unexplained death after dihydroartemisinin–piperaquine with 95% credible intervals (CI) generated by Bayesian meta-analysis was compared with the baseline rate of sudden cardiac death.FindingsOur search identified 94 eligible primary studies including data for 197 867 individuals who had received dihydroartemisinin–piperaquine: 154 505 in mass drug administration programmes; 15 188 in 14 studies of repeated courses in preventive therapies and case management of uncomplicated malaria; and 28 174 as single-course treatments of uncomplicated malaria in 76 case-management studies. There was one potentially drug-related sudden unexplained death: a healthy woman aged 16 in Mozambique who developed heart palpitations several hours after the second dose of dihydroartemisinin–piperaquine and collapsed and died on the way to hospital (no autopsy or ECG was done). The median pooled risk estimate of sudden unexplained death after dihydroartemisinin–piperaquine was 1 in 757 950 (95% CI 1 in 2 854 490 to 1 in 209 114). This risk estimate was not higher than the baseline rate of sudden cardiac death (0·7–11·9 per 100 000 person-years or 1 in 1 714 280 to 1 in 100 835 over a 30-day risk period). The risk of bias was low in most studies and unclear in a few.InterpretationDihydroartemisinin–piperaquine was associated with a low risk of sudden unexplained death that was not higher than the baseline rate of sudden cardiac death. Concerns about repolarisation-related cardiotoxicity need not limit its current use for the prevention and treatment of malaria.FundingWellcome Trust, UK Medical Research Council, WHO, Bill & Melinda Gates Foundation, and University of Oxford.

Validity of P-peak to R-peak interval compared to classical PR-interval to assess dynamic beat-to-beat AV conduction variability on surface electrocardiogram

Objective. Duration and dynamic changes of beat-by-beat PR intervals on surface electrocardiogram (ECG) requires accurate determination of QRS complex and P wave boundaries detection, which are influenced by signal-to-noise ratio and morphological variability. Atrioventricular duration (AVD), conventionally measured by PR-interval (ranging from P-onset to QRS-onset), requires adequate signal preprocessing and precise detection of fiducial points of ECG waves. This study aims at applying a method for dynamic beat-to-beat AVD variability measurement, based on the distance between P-wave and R-wave peaks (PR-peaks), and to validate the procedure in two different physical fitness status groups. Approach. The AVD interval was quantified by both conventional (PR-interval) and PR-peaks methods. Fiducial point detection was carried out in three different signal preprocessing conditions (low-pass filtering at 15 Hz, 25 Hz and 35 Hz). A comparative method was adopted to assess ventricular repolarization duration (VRD) measures (conventional QT-interval versus R-wave peak to T-wave interval) as reference of dynamic beat-by-beat variability. Eight male healthy sedentary and eight male elite runners, age, weight and height adjusted underwent 15 min resting ECG recording. Maximal VO2 consumption (VO2MAX) was also assessed defining physical fitness status. Main Results. For 15 Hz, 25 Hz and 35 Hz, the average correlation coefficient (r) values for PR-interval versus PR-peaks and QT-interval versus RT-interval were, respectively, 0.67, 0.59 and 0.50, and 0.76, 0.60 and 0.55. Additionally, for the same cutoff values, correlation coefficient between PSDs of intervals were, respectively, 0.87, 0.81 and 0.73; 0.99, 0.93 and 0.88. Bland Altman plots did not show inter methods differences across all cut-off frequencies. No-significant difference for AVD was observed for inter-group comparison, whereas, on the other hand, VRD was significantly larger in Athletes group. Significance. Assessment of PR-interval using either wave-onset or wave-peak approach as fiducial points provide accurate and precise results, and are appropriate to assess AVD physiological inter-beat interval variation.