Prolongation Of Myocardial Repolarization Research Articles

Antipsychotic drugs and QT interval prolongation

Prolongation of myocardial repolarization, i.e. lengthening of the QTc interval on surface electrocardiogram (ECG), with increased risk of cardiac arrhythmias, has been recognized as a side effect of many drugs. Most first and second generation antipsychotic drugs can cause dose-related prolongation of QTc, although there are important differences in the potency of individual agents. ECGs in 46 patients suffering from schizophrenic disorder and treated with different antipsychotic drugs one week after the admission to the psychiatric hospital were analyzed in this prospective observational study. Hearth rate, QT interval and QTc interval were assessed. The average daily dose of prescribed antipsychotic drugs was calculated. Average QTc interval was 417 msec, only 3 out of 46 (6,5%) patients had QTc over 450 msec and only one patient (2,2%) had QTc over 500 msec. No differences in QTc interval between patients who were treated either with first or second generation antipsychotic drug or with combination of both were found. Female participants had significantly longer OTc interval than male participants (p < 0,05). Results raise the question of the clinical relevance of a single ECG for diagnostics of cardiac complications in schizophrenia patients and suggest the need to conduct ECG monitoring in patients with high risk for cardiac complications during antipsychotic treatment.

Is myocardial repolarization duration associated with repolarization heterogeneity?

Dispersion of repolarization is theorized as one mechanism by which myocardial repolarization prolongation causes lethal torsades de pointes, (TdP). Our primary purpose was to determine whether prolongation of myocardial repolarization as measured by the heart rate-corrected J-to-T peak interval (JTpkc), is associated with repolarization heterogeneity as measured by transmural dispersion, defined as the median duration from the peak to the end of the T wave (TpTe). A retrospective cohort study was performed at a single urban tertiary ED from July 2011-September 2012. Inclusion criteria included all consecutive ED patients with ECG based on QTc and QRS intervals. Automated measurements of all intervals were performed. The association of JTpkc with the dependent variable TpTe was assessed after adjustment for QRS and RR interval durations with a multiple linear regression model. A secondary analysis included a similar adjusted assessment of the association of JTpkc with QT dispersion, QTd. Finally, we constructed two multiple regression models to assess the association of clinical causative factors of TdP with TpTe and JTpkc. Eight hundred seventy-four cases were included: 186 with QTc <500ms, 118 with QTc ≥500 and QRS ≥120ms, and 570 with QTc ≥500 and QRS <120ms. The coefficient for association of JTpkc with TpTe was -0.10 (95%CI -0.15 to -0.05), and for JTpkc with QTd was 0.03 (95% CI -0.01 to 0.06). Clinical causative TdP factors were associated more with JTpkc than TpTe. Repolarization duration as measured by JTpkc is not positively associated with dispersion of repolarization as measured by TpTe or QTd. Dispersion of repolarization may not be a critical mechanistic link between QTc prolongation and TdP.

Severe proarrhythmic potential of risperidone compared to quetiapine in an experimental whole-heart model of proarrhythmia

In several case reports, proarrhythmic effects of antipsychotic drugs have been reported. The aim of the present study was to investigate if application of risperidone or quetiapine has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In 24 isolated rabbit hearts, risperidone (5 and 10μM, n=12) or quetiapine (5 and 10μM, n=12) was infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of risperidone as compared with baseline (5μM: +29ms, 10μM: +35ms, p<0.01) accompanied by an increase of action potential duration. Administration of risperidone also significantly increased spatial dispersion of repolarization (5μM: +16ms, 4μM: +19ms; p<0.05) as well as temporal dispersion of repolarization. Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EADs) in 8 of 12 hearts and polymorphic ventricular tachycardia resembling torsade de pointes in 6 of 12 hearts (10μM, 49 episodes). The results were compared with hearts treated with quetiapine (5 and 10μM). Quetiapine led to an increase in QT interval (5μM: +10ms; 10μM: +28ms; p<0.05) and a similar increase of APD90. However, treatment with quetiapine did not result in significant alterations of spatial and temporal dispersion of repolarization. No ventricular arrhythmias were observed in this group. In the present study, quetiapine demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, risperidone led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization.

Effects of hypothermia combined with dexmedetomidine on myocardial monophasic action potentials in isolated rabbit hearts

Objective To investigate the effects of hypothermia combined with dexmedetomidine on myocardial monophasic action potentials(MAPs)in isolated rabbit hearts. Methods Adult rabbits, weighing 2.0-2.5 kg, were heparinized and anesthetized with pentobarbital sodium 30 mg/kg.Their hearts were rapidly removed and retrogradely perfused in a Langendorff apparatus at 37 ℃.Eighteen hearts were randomly divided into 3 groups(n=6 each)using a random number table: control group(group C), hypothermia group(group H), and hypothermia+ dexmedetomidine group(group HD). The hearts were continuously perfused for 60 min with 37 ℃ K-H solution in group C, with 32 ℃ K-H solution in group H, or with 32 ℃ K-H solution containing dexmedetomidine 25 ng/ml in group HD.At the end of equilibration(T0)and at 15, 30 and 60 min of perfusion with K-H solution, HR and MAPs of left ventricular epicardium, mid-myocardium and endocardium were recorded.MAP duration at 50% repolarization(MAPD50)and at 90% repolarization(MAPD90), monophasic action potential amplitude(MAPA)and maximal velocity(Vmax)were calculated. Results Compared with group C, HR was significantly decreased, and MAPD50 and MAPD90 were prolonged at each time of perfusion with K-H solution in H and HD groups.There was no significant difference in HR, MAPD50 and MAPD90 between H group and HD group.There was no significant difference in MAPA and Vmax between the three groups. Conclusion Hypothermia combined with dexmedetomidine can lead to prolongation of myocardial repolarization, and dexmedetomidine exerts no effect on hypothermia-induced change in MAPs in isolated rabbit hearts. Key words: Hypothermia, induced; Dexmedetomidine; Action potentials; Intraoperative complications

A Dyshomeostasis of Electrolytes and Trace Elements in Acute Stressor States: Impact on the Heart

Acute stressor states are associated with a homeostatic activation of the hypothalamic-pituitary-adrenal axis. A hyperadrenergic state follows and leads to a dyshomeostasis of several intra- and extracellular cations, including K+, Mg2+, and Ca2+. Prolongation of myocardial repolarization and corrected QT interval (QTc) of the ECG are useful biomarkers of hypokalemia and/or hypomagnesemia and should be monitored to address the adequacy of cation replacement. A dyshomeostasis of several trace elements, including Zn2+ and Se2+, are also found in critically-ill patients to compromise metalloenzyme-based antioxidant defenses. Collectively, dyshomeostasis of these electrolytes and trace elements have deleterious consequences on the myocardium: atrial and ventricular arrhythmias; induction of oxidative stress with reduced antioxidant defenses; and adverse myocardial remodeling, including cardiomyocytes lost to necrosis and replaced by fibrous tissue. To minimize such consequences during hyperadrenergic states, systematic surveillance of electrolytes and trace elements, together with QTc, are warranted. Plasma K+ and Mg2+ should be maintained at ≥4.0 mEq/L and ≥2.0mg/dL, respectively (the 4 and 2 rule).

P03-16 Do antipsychotic drugs lengthen QT interval?

Objectives:Prolongation of myocardial repolarization, i.e. lengthening of the QTc interval on surface electrocardiogram, with increased risk of cardiac arrhythmias, has been recognized as a side effect of many drugs. Most conventional and atypical antipsychotic drugs can cause dose-related prolongation of QTc, although there are important differences in the potency of individual agents. Antipsychotic polipharmacy increases the risk for sever cardiac side effects.Subjects and methods:In this prospective clinical investigation, we analyzed ECGs in 46 patients suffering from schizophrenic disorder who were treated with different antipsychotic drugs one week after the admission to the psychiatric hospital. Hearth rate, QT interval and QTc interval were assessed. the average daily dose of prescribed antipsychotic drugs was calculated and transformed to chlorpromazine units.Results:Average QTc interval in patients undergoing our clinical investigation was 417 msec, only 3 out of 46 (6,5%) patients had QTc over 450 msec and only one patient (2,2%) had QTc over 500 msec.We found no differences in QTc interval between patients who were treated either with conventional or atypical antipsychotic or with combination of both, and no gender differences for QTc interval were found.Conclusions:Our results raise the question of the clinical relevance of a single ECG for diagnostics of cardiac complications in schizophrenia patients and suggest the need to conduct ECG monitoring in patients with high risk for cardiac complications during antipsychotic treatment.

Effect of Acute Unloading Via Head-Up Tilt on QTc Prolongation in Patients With Ischemic or Non-Ischemic Cardiomyopathy

Patients with advanced cardiomyopathy develop prolongations in ventricular myocyte action potential duration that are reflected by prolongations of QT intervals on surface electrocardiograms. Recent studies demonstrate that the placement of a left ventricular (LV) assist device, which induces profound cardiac decompression, acutely increases QT intervals within hours. The goal of this study was to use head-up tilt (HUT) to examine electrocardiographic responses to cardiac unloading in patients with cardiomyopathy. Surface electrocardiograms were analyzed during HUT in 21 patients with cardiomyopathy (ejection fraction <30%) and in 33 age-matched controls. Four to 6 different QT and RR intervals were measured at baseline (supine), at 5 and 25 minutes after HUT. The heart-rate-adjusted QT interval (QTc) was calculated using Bazett's formula. The mean QTc in control patients decreased at 5 minutes (426 +/- 31 vs 418 +/- 28 ms, p < 0.05, vs supine) and was unchanged at 25 minutes (426 +/- 31 vs 423 +/- 25 ms, p = NS, vs supine). However, in patients with cardiomyopathy, there was a significant increase in QTc during HUT (455 +/- 45 vs 473 +/- 42 and 479 +/- 42 ms, p < 0.001, vs supine). The change in heart rate during HUT did not differ between patients with cardiomyopathy and controls. In conclusion, HUT is associated with the immediate prolongation of myocardial repolarization in patients with cardiomyopathy. This response was not seen in age-matched controls. These results suggest that adaptations to chronic cardiac distention may include processes that help accelerate repolarization. Conversely, the prolongation of repolarization after unloading may modulate myocardial relaxation and arrhythmogenic risk.

Assessment of Cardiac Autonomic Nervous Activities by Means of ECG R‐R Interval Power Spectral Analysis and Cardiac Depolarization‐Repolarization Process

Background: Cardiac autonomic dysfunction is prevalent in diabetic patients and associated with prolongation of myocardial repolarization period. It was speculated that changes in autonomic nervous system activity, particularly the sympatho‐vagal balance contributes to the prolongation of myocardial repolarization.Methods: Ten patients with ischemic heart disease (IHD), thirty patients with diabetes mellitus, and ten control subjects (CONT) volunteered for this study. The patients with diabetes mellitus were further divided into three subgroups according to the severity of neuropathy: patients without any neuropathy (NO), with peripheral neuropathy (N1) and with autonomic neuropathy (N2). ECG activation time (AT), activation recovery interval (ARI), and recovery time (RT) was measured and ECG R‐R spectral analysis was performed.Result: There were significant decreases (P &lt; 0.01) in RTc in N1, N2, and IHD as compared with CONT and NO. In addition, HI of R‐R interval power spectrum were significantly decreased (P &lt; 0.01) in N1, N2, and IHD than those in CONT and NO.Conclusion: We have successfully developed and adapted a new computer system for simultaneous ECG RT measurements and ECG R‐R power spectral analysis, a putative index of autonomic dysfunction and risk for sudden cardiac death, to study patients with ischemic heart disease and with varying degrees of diabetic autonomic neuropathy. Those with little HI power, which reflects more severe diabetic neuropathy and a high risk of sudden cardiac death, had significantly longer RTc, which is consistent with sympatho‐vagal imbalance toward parasympathetic denervation.

Effect of erythromycin on myocardial repolarization in patients with community-acquired pneumonia.

Erythromycin has been associated with prolongation of myocardial repolarization and torsades de pointes (TdP). To determine the frequency, dose-response, and risk factors for erythromycin-associated prolongation of myocardial repolarization, we observed data of patients admitted to our hospital with pneumonia who were treated with erythromycin. In 35 women and 28 men enrolled in this study, the QTc increased from 434 +/- 4 milliseconds at baseline to 464 +/- 5 milliseconds after receiving a cumulative dose of 3.2 +/- 0.2 g of erythromycin. Neither age, sex, presence of preexistent congestive heart failure/coronary artery disease, electrolyte values, nor cumulative dose of erythromycin was associated with QTc prolongation. In 27 patients who received intravenous erythromycin for 3 days, the QTc increased from 427 +/- 5 milliseconds before to 461 +/- 8 milliseconds at 24 hours but did not increase further by day 3 (457 +/- 10 milliseconds). No patient in this cohort had TdP. Erythromycin therapy is associated with prolongation of myocardial repolarization that manifests after the first few doses in a majority of patients.