Significant Prolongation Of QT Interval Research Articles

AMELIORATIVE EFFECT OF GALLIC ACID ON DOXORUBICIN INDUCED CARDIOTOXICITY IN ADULT WISTAR RATS

Doxorubicin is a potent antineoplastic anthracycline drug however, its use is greatly limited by its toxic side effects which occurs by formation of reactive oxygen species that disruption of cell function. This present study was conducted to assess the possible cardioprotective effect of gallic acid against doxorubicin‐ induced cardiotoxicity in rats.In this study, sixty (60) male Wistar rats were divided into six groups. Group A was the control. Group B rats was intoxicated with Doxorubicin (Dox) at 15 mg/kg body weight i.p. Group C pre‐treated with 60 mg/kg Gallic Acid (GA) orally for 7 days prior to administration of Dox 15 mg/kg, Group D pre‐treated with 120 mg/kg Gallic Acid (GA) orally for 7 days prior to administration of Dox 15 mg/kg, Group E received 60 mg/kg Gallic Acid (GA) orally alone for 7 days and Group F received 120 mg/kg Gallic Acid (GA) orally alone for 7 days. The parameters of study were cardiac antioxidant status, serum biomarker of cardiac damage and electrocardiography measurements.Exposure of rats to doxorubicin led to a significant (p < 0.05) decrease in cardiac glutathione peroxadise (GPx), glutathione‐S‐transferase (GST), reduced glutathione (GSH) content, superoxide dismutase (SOD) and catalase (CAT) activity. Similarly, a significant (p < 0.05) increase in protein thiol was recorded in doxorubicin treated rats while it was reduced in those pre‐treated with GA. Dox also caused elevation of Creatinine kinase‐muscle brain (CK‐MB) and Lactate Dehydrogenase (LDH). Histopathology of rats exposed to Dox showed focal areas of infiltration by inflammatory cells and degeneration of myofibres. Electrocardiography results showed a significant decrease in heart rate; increase in P wave duration, R‐amplitude, PR interval, QRS and QT‐segment prolongation.Pre‐treatment with GA significantly alleviated Dox associated ECG abnormalities, restored the antioxidant enzyme and decreased serum Creatinine kinase‐muscle brain CK‐MB and LDH. However, administration of GA alone in a set of groups led to a significant prolongation of QT interval which could predispose to the potentially fatal ventricular tachycardia, torsades de pointes. All these findings confirm the efficacy of GA against Dox induced cardiotoxicity but caution must be taken in its use.Support or Funding InformationNone

Life Threatening Severe QTc Prolongation in Patient with Systemic Lupus Erythematosus due to Hydroxychloroquine.

We present a case of a syncopal episode resulting from significant QT interval prolongation in a patient on hydroxychloroquine for the treatment of systemic lupus erythematosus and end stage renal disease. The patient had been treated with hydroxychloroquine for two years prior to presentation. After thorough workup for secondary causes of QT interval prolongation hydroxychloroquine was discontinued and the patient's QT interval shortened. The patient was treated with mexiletine to prevent sudden ventricular arrhythmias, which was unique compared to other documented cases in which lidocaine was used. The patient was noted to have mild prolongation of the QT interval on electrocardiogram prior to initiation of hydroxychloroquine therapy which was exacerbated by its use and may have been caused due to toxicity from underlying renal failure.

No Untoward Effect of Long-Term Ketoconazole Administration on Electrocardiographic QT Interval in Patients with Cushing's Disease.

Ketoconazole is listed among drugs that prolong QT interval and may increase the risk of torsade de pointes, a severe ventricular arrhythmia. This compound has recently been approved for treatment of Cushing's syndrome, a severe endocrine disorder. These patients harbour several risk factors for prolonged QT interval, for example hypokalaemia and left ventricular hypertrophy, but no study has evaluated whether administration of ketoconazole affects their QT interval. The aim of this study was to assess the QT interval in patients with Cushing's disease during long-term administration of ketoconazole. Electrocardiograms from 15 patients with Cushing's disease (12 women, 3 men, age: 37.8 ± 2.66 years) on ketoconazole treatment (100 mg-800 mg qd) for 1 month to 12 years were reviewed retrospectively. QT interval was measured and corrected for heart rate (QTc). Measurements before and during ketoconazole treatment were compared and any abnormal QTc value recorded. Concurrent medical therapies were also documented. On average, QTc was superimposable before and during ketoconazole treatment (393.2 ± 7.17 versus 403.3 ± 6.05 msec. in women; 424.3 ± 23.54 versus 398.0 ± 14.93 msec. in men, N.S.). QTc normalized on ketoconazole in one man with prolonged QTc prior to treatment; no abnormal QTc was observed in any other patient during the entire observation period, even during concurrent treatment with other QT-prolonging drugs. In conclusion, long-term ketoconazole administration does not appear to be associated with significant prolongation of QT interval in patients with Cushing's disease. ECG monitoring can follow recommendations drawn for other low-risk QT-prolonging drugs with attention to specific risk factors, for example hypokalaemia and drug interactions.

A case of lithium toxicity with significant QT interval prolongation

Background Lithium toxicity has been associated with electrocardiographic abnormalities, such as QT interval prolongation.

Repeated Dermal Paraphenylenediamine Exposure Induces Systemic Biochemical and Histological Changes in Adult male Albino Rats

Paraphenylenediamine (PPD) is a synthetic compound that is widely used as a hair dye. This study investigated biochemical and histological effects after repeated PPD dermal application. 30 adult male albino rats (200± 20gms) were classified into two groups; group I, (control group) included negative and positive control subgroups, each consisted of 10 rats and group II (tested group). Tested group was subjected to repeated topical PPD application in a dose of 10mg/kg for 90 days. All groups were investigated for these laboratory biochemical parameters: Serum creatine phosphokinase CPK-MB, aspartate (AST) and alanine transferases (ALT), serum creatinine (S. Creat.), blood urea nitrogen (BUN) as well as serum potassium. All the mentioned parameters showed significant increase when compared to control group. ECG was done and revealed significant decrease of pulse rate and significant prolongation of PR, QRS and QT intervals in tested group. In-addition, to biochemical and ECG investigations; histological examination was done for; cardiac, hepatic, renal and testicular tissues. Cardiac, hepatic, renal, and testicular tissues of tested group showed evident changes. These changes were more obvious in Cardiac, renal, and testicular tissues when compared to control.

Acute Cardiotoxic Effects of Adjuvant Trastuzumab Treatment and Its Relation to Oxidative Stress

Our aim was to evaluate the acute cardiac toxicity of adjuvant trastuzumab treatment and its possible relation to changes in oxidative stress. Electrocardiographic and echocardiographic tissue Doppler imaging (TDI) parameters, activity of antioxidant enzymes (superoxide dismutase; SOD), and products of oxidative stress (malondialdehyde; MDA) were analyzed in 30 patients with early-stage breast cancer who had adjuvant trastuzumab treatment. There was a significant prolongation of QT interval after trastuzumab treatment. There was also a significant decrease in left ventricular ejection fraction (LVEF), TDI-derived S' parameters, and SOD enzyme activity and increase in MDA levels after trastuzumab infusion. There was a positive correlation between changes in SOD activity and LVEF and a negative correlation between changes in MDA levels and LVEF. This study demonstrated a correlation between decreases in LVEF and increases in products of the oxidative stress in patients who had adjuvant trastuzumab treatment.

THIS MONTH IN Anesthesiology

Recent insights into posttraumatic immune dysfunction have defined new targets for immunointervention that hold promise for improving outcomes in such critically ill patients.High inspired oxygen may be reasonable in lower risk surgery to improve wound oxygenation.Ultrasound imaging was an accurate technique for cervical zygapophysial joint nerve blocks in volunteers. See the accompanying Editorial View on page 236. Norketamine has an effect opposite to that of ketamine on pain relief.Emergence agitation, the associated risk factors, and its prevention and treatment are discussed.The proportion of anesthesiology residents from U.S. medical schools has more than doubled since 1995. This retrospective cohort study evaluated the 2010 and 2011 residency applicants to determine the factors associated with a successful admission to residency training programs. The sample represented 58% of the total national applicant pool; 66% of the applicants successfully matched to anesthesiology. The odds for a successful match were higher for applicants from U.S. medical schools, those with United States Medical Licensing Examination scores greater than 210, younger applicants, and females. Prior graduate education or peer-reviewed publications did not offer any advantage. This study suggests the potential for age and gender bias in the selection process. See the accompanying Editorial View on page 230 .The cause of rises in intrapartum maternal temperature is not known. In this prospective study of 81 women scheduled for labor induction, hourly oral temperatures were recorded and analyzed based on race, body mass index, duration of labor, and time to epidural. Overall, temperature rose in a significant linear trend over time. Positive temperature trends were associated with significantly longer time from membrane rupture to delivery and higher body mass index. Temperature slopes did not differ before compared with after epidural analgesia. This study suggests that epidural analgesia alone does not increase the risk of high temperatures in intrapartum women.Electrocardiograms (ECG) can identify abnormal cardiac repolarization by observation of a prolonged QT interval. QT interval prolongation is often caused by drugs and can result in sudden cardiac death. In this ancillary study to the Vitamins in Nitrous Oxide trial, serial postoperative 12-lead ECG were obtained from 469 patients undergoing major noncardiac surgery under general anesthesia. Eighty percent of patients experienced a significant QT interval prolongation, and approximately half had increases greater than 440 ms at the end of surgery. One patient developed torsade de pointes. Drugs associated with prolonged QT interval included isoflurane, methadone, ketorolac, cefoxitin, zosyn, unasyn, epinephrine, ephedrine, and calcium. Although the exact cause of the association between perioperatively administered drugs and QT interval prolongation is not known, further study is warranted to determine the clinical relevance.

Glucose and blood pressure lowering effects of Pycnogenol® are inefficient to prevent prolongation of QT interval in experimental diabetic cardiomyopathy

Diabetic cardiomyopathy shows ECG alterations related to cardiac repolarization and manifested by increased duration of QT interval. Although the mechanism is unknown, it is widely believed that the reduction of hyperglycaemia might prevent such alterations. To test this hypothesis, we used the standardized extract of French pine bark – Pycnogenol® (PYC) with hypoglycaemic and antioxidant properties in 8–9 week old rats with experimentally (streptozotocin) induced diabetes mellitus (DM). PYC was administered orally for 6 weeks in three different doses (10, 20, and 50mg/kg b.w., resp.). Experimental DM was manifested by hyperglycaemia (four to six-fold increase in plasma glucose concentration; p<0.05) and significantly increased mean arterial blood pressure (by 19%; p<0.05) measured using catheterization of carotid artery in vivo. Both abnormalities were dose-dependently reduced by PYC. In addition, diabetic cardiomyopathy was associated with a significant increase in left ventricular weight to body weight ratio (by 21%; p<0.05) and a significant decrease of the width of cardiomyocytes (by 23%; p<0.05) indicating cardiac edema on the one side, and hypotrophy of cardiomyocytes on the other. Both of these changes were not affected by PYC. Consequently to metabolic and hemodynamic alterations, significant prolongation of QT interval (by 20%; p<0.05) was present in diabetic rats, however, PYC failed to correct it. Conclusively, PYC fails to correct QT prolongation in spite of dose-dependent reduction of glycaemia and high blood pressure in streptozotocin-induced diabetic cardiomyopathy.

Abstract 315: Myocardial Repolarization Abnormalities During Therapeutic Hypothermia Do Not Affect Mortality and AICD Therapy in Cardiac Arrest Survivors

Background: We investigated changes in myocardial repolarization and associated outcomes in patients undergoing therapeutic hypothermia after cardiac arrest. Methods: Demographic, clinical, and ECG data on 19 consecutive cardiac arrest survivors (6 females, 59+/-15 years old, 3 with diabetes, 3 with cancer, 3 with CKD, 5 with pulmonary disease and 5 with cardiovascular disease) undergoing therapeutic hypothermia were collected. Absolute QT dispersion was calculated. ANOVA, chi-square, Kaplan-Meier and logistic regression analyses were used. The study was approved by the IRB. Results: Hypothermia resulted in significant prolongation of both minimum (baseline 277+/-74 vs. cooled 408+/-129 vs. re=warmed 313+/-82 msec, p&lt;0.001) and maximum QT intervals (392+/-60 vs. 549+/-147 vs. 453+/-90 msec, respectfully, p&lt;0.001, Figure) but no significant changes in QT dispersion. Age, gender, history of cancer, kidney, pulmonary, or cardiovascular disease, use of thiazide or loop diuretics, ACE inhibitors/ARBs, or potassium supplements had no effect on QT dispersion or hospital mortality . Similarly, Na, K, Mg, Cr, Ca, pH, or hematocrit on admission, during cooling or rewarming had no effect on QT dispersion or hospital mortality. In 7 survivors to hospital discharge QT changes at baseline, during hypothermia, or rewarming were not predictive of mortality or AICD discharges during long-term follow-up (27+/-8 months). Conclusion: Therapeutic hypothermia is associated with significantly prolonged QT intervals. However, these QT abnormalities do not translate into increased mortality and/or AICD therapy during short or long-term follow-up.

Electrophysiologic Profile of Dronedarone on the Ventricular Level

Dronedarone (D) is developed to maintain sinus rhythm in patients suffering from atrial fibrillation. The aim of the present study was to investigate, whether dronedarone also has an antiarrhythmic potential in the ventricle and to elucidate the mechanisms for its low proarrhythmic potential in an experimental whole heart model. Thirty-five rabbits underwent chronic treatment with D (n = 15; 50 mg · kg(-1) · d(-1)) and amiodarone (A; n = 20; 50 mg · kg(-1) · d(-1)). Hearts were perfused on a Langendorff apparatus. Results were compared with hearts acutely treated with sotalol (S; 50-100 μM; n = 14). A 12-lead electrocardiogram and up to 8 ventricular epi- and endocardial monophasic action potentials showed a significant prolongation of QT interval (D: +24 milliseconds, A: +28 milliseconds, S: +35 milliseconds (50 μM), +56 milliseconds (100 μM); P < 0.02) compared with baseline. In contrast to D and A, S led to a significant increase in dispersion of repolarization and exhibited reverse use dependence. D, A, and S increased refractory period, resulting in a significant increase in postrepolarization refractoriness (effective refractory period minus action potential duration; D = +12 milliseconds; A = +14 milliseconds; S = +25 milliseconds; P < 0.05). S led to a triangular action potential configuration, whereas D and A caused a fast phase 3 prolongation. After lowering of potassium concentration, 50% of S-treated hearts showed torsade de pointes, in contrast to an absence of torsade de pointes in D and A. Prolongation of myocardial repolarization and postrepolarization refractoriness by D may act antiarrhythmic. A fast phase 3 repolarization in the absence of both increased dispersion of repolarization and reverse use dependence prevents proarrhythmia.

Protease Inhibitor–Associated QT Interval Prolongation

To evaluate the literature on protease inhibitor (PI)-associated QT interval prolongation and risk for torsade de pointes in patients infected by HIV. Primary literature was identified through MEDLINE (1950-August 2011) and EMBASE (1980-August 2011), using the following search terms: antiretroviral agents, HIV, protease inhibitors, QTc, QT prolongation, and torsade de pointes. English-language case reports of antiretroviral therapy-associated QT interval prolongation, studies of healthy volunteers, or studies that evaluated the impact of PIs on QT interval in patients infected with HIV were reviewed and selected. Article bibliographies and conference abstracts were also reviewed. Several case reports, as well as in vitro data, have implicated PIs as a potential cause of QT interval prolongation and/or torsade de pointes. Saquinavir, therapeutically boosted with the potent CYP3A4 inhibitor ritonavir, was the only PI shown to be associated with significant QT interval prolongation in studies with healthy volunteers. While 1 case control study in HIV-infected patients found that nelfinavir or efavirenz, a nonnucleoside reverse transcriptase inhibitor, increased the risk of QT interval prolongation, larger prospective studies have not demonstrated any significant increase in QT interval following exposure to PIs. Similar risk factors for QT interval prolongation seen in non-HIV-infected patients, such as older age, female sex, ethnicity, cardiac conditions, diabetes mellitus, and concomitant use of other QT interval-prolonging medications, especially methadone, were risk factors identified in studies of HIV-infected patients. PIs do not appear to independently predispose patients to QT interval prolongation. However, other risk factors (both HIV-related and non-HIV-related) may increase the risk of QT interval prolongation. Available data suggest that baseline and follow-up electrocardiogram monitoring are unnecessary precautions, but may be considered in patients who are initiating PI therapy and are on multiple medications with proarrhythmic potential and/or have multiple comorbidities, increasing the risk.

Left cardiac sympathetic denervation for the treatment of methadone-induced long QT syndrome

Introduction Methadone remains one of the most common noncardiovascular drugs associated with the development of torsade de pointes (TdP), as QT interval prolongation can occur in up to 15% of methadone-maintenance patients. In fact, the overall use of methadone has increased significantly in the past decade, and it has also been found to be associated with an increased risk of sudden death in a community-based study. For patients with recurrent methadone-associated dP who are unable to discontinue the offending medicaion, an effective secondary prevention strategy is permaent pacing with defibrillator backup. However, there are ccasions when this treatment option is not clinically reaonable because of a high risk for cardiac device infection. e report one such case of an individual on methadone aintenance and a secondary-prevention implantable carioverter-defibrillator (ICD) who subsequently developed a evice infection. Given the patient’s clinical picture upon resentation, left cardiac sympathetic denervation (LCSD) as chosen as treatment. This case suggests that LCSD ight be an alternative to consider in patients on methadone ith significant QT interval prolongation, and thereby at isk for ventricular arrhythmias.

Significant QT interval prolongation and long QT in young adult ex-preterm newborns with extremely low birth weight

Background. The survival rate for extremely low birth weight (ELBW) infants born preterm is on an increasing upward trend, despite the possibility of neuro-cerebral consequences in later life. To date, scarce information is available on the effect of extreme prematurity on cardiovascular system.Aim. To verify the presence of standard echocardiographic and ECG alterations in ex-ELBW young healthy adults.Method. A color Doppler echocardiogram and an ECG were performed on 24 ex-ELBW (4 males and 20 females; mean: 23.2 ± 3.3 years), compared with 24 healthy subjects born at term (C). ECG parameters examined: PR, QT, QTc, and QT dispersion (QTd). Gestational age, birth weight, and duration of stay in neonatal intensive care unit were obtained from clinical records.Results. Transthoracic echocardiography did not reveal differences between ex-ELBW and C, while a significant difference was displayed by ex-ELBW with regard to PR (141.5 ± 13.4 ms vs. 164.2 ± 24.0 ms, p < 0.0003), QTc (417.0 ± 23.6 ms vs. 369.9 ± 19.5 ms, p = 0.00001), and QTd (30.4 ± 14.1 ms vs. 24.6 ± 8.2 ms, p < 0.00001). In two patients (8.3%), QTc exceeded the upper limit of normal range. A statistically significant inverse correlation was observed between QTc and gestational age (r = −0.67, p < 0.0003).Conclusions. QTc and QTd in ex-ELBW were found to be at the upper limit of normal range and correlated with gestational age and birth weight; in two cases, QTc exceeded the upper limit. This study, irrespective of the pathophysiological mechanism involved, underlines a potential risk for ex-ELBW of developing ventricular arrhythmias when using drugs capable of prolonging QT interval.Summary. QTc and QTd in young adults previously born preterm with an ELBW (401–1000 g) were generally found to be at the upper limit of normal range and correlated with gestational age and birth weight. This finding underlines a potential risk for ex-ELBW of developing ventricular arrhythmias when using drugs capable of prolonging QT interval.

The acute effects of ondansetron on the electrocardiogram in clinically normal dogs

This study was performed to determine the acute effects of a single intravenous dose of ondansetron on the electrocardiogram of dogs. Eight adult crossbreed dogs were used in this study. The electrocardiogram recording was obtained before the infusion of ondansetron and repeated at 5, 30, 60, and 120 min after treatment. The ECG measurements of heart rate, PR interval, QRS interval, ST segment, T-wave amplitude, and QT interval were taken from lead II. The JT interval was calculated as the QT interval minus the QRS interval. Rate-corrected QT and JT intervals (QTc and JTc) were obtained by using two formulas QTc = QT/3√R-R interval and JTc = JT/3√R-R interval. In comparison to the baseline values, mean heart rate significantly decreased at 5, 30, and 60 min after administration of intravenous ondansetron. There was significant prolongation of QT, QTc, and JT intervals at 30 and 60 min after infusion of drug. T-waves showed significant changes in its direction and amplitude at 60 and 120 min after treatment compared to the baseline values. In conclusion, ondansetron at standard dosages apparently causes ECG changes in healthy dogs. These include marked QT interval prolongation and reduction in heart rate. Although in current experiment, we did not observe serious arrhythmias in this group of dogs, it does not exclude the possibility of ventricular arrhythmias in prolonged use after reaching a certain cumulative dose.

Hypokalemia is associated with lengthening of QT interval in psychiatric patients on admission

Several studies have revealed a relatively high frequency of hypokalemia in the general psychiatric population. This may be explained by adrenergic stimulation observed in the acute phase of psychiatric disorders. Little is known about the effects of hypokalemia on cardiac repolarisation in these circumstances. The current study was designed to determine if the hypokalemia observed among patients with acute psychiatric disorders can cause significant QT interval prolongation, and thus increase the risk of ventricular arrhythmia. Electrocardiograms were obtained in 282 non-selected patients admitted to a psychiatric unit. Heart-rate adjusted QT intervals (QTc) were compared to serum potassium levels and to other risk factors for QT prolongation (bradycardia, age, gender, and administration of antipsychotics). Hypokalemia, diagnosed in more than 11% of the patients, was associated with a significantly longer QTc interval (means 423.5 ± 40 ms vs 408.5 ± 31 ms), as was female sex. Multiple linear regression analysis on the studied risk factors revealed that only hypokalemia and female sex were independently associated with lengthening of the QT interval. According to our results, hypokalemia seems to be one of the most important risk factors for QT prolongation. We therefore strongly recommend that psychiatric patients should be screened for hypokalemia on admission.

Influence of promethazine on cardiac repolarisation: a double‐blind, midazolam‐controlled study

Drugs used in anaesthesia may provoke torsadogenic changes in cardiac repolarisation. The aim of this study was to assess the effect of promethazine on the parameters of ventricular repolarisation: QTc interval and transmural dispersion of repolarisation. Forty patients were randomly allocated to receive promethazine (25 mg) or midazolam (2.5 mg). Changes in the ECG and arterial blood pressure were recorded. Correction of QT interval was calculated using Bazett's formula and Fridericia's correction; transmural dispersion of repolarisation was determined as T(peak)-T(end) time. Significant prolongation of QT interval, corrected with both formulae, was detected in patients receiving promethazine, while no change in the QTc value was observed in the midazolam group. There were no significant differences in T(peak)-T(end) time either between or within the groups. In conclusion, promethazine induces significant QTc prolongation but the lack of influence on transmural dispersion of repolarisation makes the risk of its torsadogenic action very low.

Identification of an ethnic-specific variant (V207M) of the KCNQ1 cardiac potassium channel gene in sudden unexplained death and implications from a knock-in mouse model

We performed mutation analysis for genes implicated in long QT syndrome (KCNQ1, KCNH2, and SCN5A) in 17 sudden unexplained death autopsy cases. Single-strand conformation polymorphism and subsequent DNA sequencing analyses revealed that in one case, there was a variant, V207M of KCNQ1, a gene encoding a cardiac potassium channel. This case, a 40-year-old African male, was shown to have a heterozygous missense mutation (V207M), which has been previously reported to be ethnic-specific. The heterozygous V207M mutation was found in one case (0.23%) of 444 alleles from African individuals. We developed a knock-in mouse model carrier of the Kcnq1-V206M mutation, the mouse equivalent to the KCNQ1-V207M mutation identified in the victim. Significant prolongation of QT intervals was observed in the Kcnq1(V206M/V206M) mice. These findings suggest that the KCNQ1-V207M mutation might be pathogenic and might have been associated with the cause of death in the present case.

Abstract 2965: QT Interval Prolongation during Severe Acute Rejection is Predictive of Sudden Cardiac Death in Heart Transplant Recipients

Background. QT interval prolongation is considered a risk factor for sudden cardiac death (SCD) in various non-transplant populations. Since acute allograft rejection is associated with a prolonged QT interval, we sought to investigate the effects of rejection-induced QT interval changes on SCD in heart transplant recipients. Methods. Of all patients who underwent heart transplantation between 1998 and 2007, we enrolled those with severe acute cellular rejection episodes (ISHLT grade 3A or higher, accompanied with hemodynamic compromise). In this cohort, baseline ECGs were obtained within 7 days after transplantation; follow-up ECGs were recorded at the time of the rejection episode. On all ECGs, QT interval was defined as the mean duration QT interval measurements in all leads, and corrected for heart rate with Bazett formula. A significant increase of QTc during rejection (dQTc) was defined as a relative change in QTc ≥10%. Patients were followed for SCD for 1 year after the rejection episode. Results. Of 80 patients with a severe rejection episode, 9 (11%) were excluded because of the inadequate quality of ECG recordings. Within the 1-year follow-up, 21 of 71 (30%) patients died. Of these, 14 (67%) died of SCD, and 7 (23%) died of other causes. Patients who died of SCD and survivors did not differ with regards to age (44 ± 12 years in SCD group vs. 46 ± 16 years in survivors, P = 0.61), gender (male: 83% vs. 58%, P = 0.06), incidence of infections (0.21 ± 0.43 vs. 0.20 ± 0.40, P = 0.91), malignancy (0% vs. 8%, P = 0.84), or allograft vasculopathy (29% vs. 26%, P = 0.85). No difference in Qtc prolonging drug was noted. During acute rejection, QTc interval was significantly longer in SCD group than in survivors (475 ± 57 ms vs. 437 ± 36 ms, P = 0.01), and the same was true for the incidence of dQTc &gt; 10% (50% vs. 16%, P = 0.008). SCD-free survival as evaluated by Kaplan-Meier analysis was significantly lower in patients with dQTc &gt; 10% (P = 0.013). On multivariate analysis, dQTc &gt; 10% was the only independent predictor of SCD (P = 0.02). The multivariate model included left ventricular dysfunction (LVEF &lt; 30%) and dQTc. Conclusion. Heart transplant recipients who display a significant (&gt; 10%) prolongation of QT interval during a severe acute rejection episode may be at increased risk for SCD.

Long-term amiodarone treatment causes cardioselective hypothyroid-like alteration in gene expression profile

The long-term cardiac effects of amiodarone resemble many aspects of hypothyroidism. The anti-arrhythmic potential of amiodarone may therefore be the result of a drug-induced, local hypothyroid-like condition. To investigate this controversial issue, we compared gene expression profiles in the hearts of rats treated with amiodarone with those of rats with hypothyroidism. Wistar male rats were assigned to 3 groups ( n = 6–8): Control, systemic hypothyroidism (Hypothyroidism) and amiodarone treatment (Amiodarone, 150 mg/kg/day, p.o., 4 weeks). Electrocardiogram (ECG) recordings, gene profiling by DNA microarray and Northern blotting were carried out. Amiodarone, like Hypothyroidism, caused significant prolongation of RR and QT intervals in ECGs. Microarray analysis of 8435 genes in the left ventricular myocardium revealed a significant similarity in expression profiles between Hypothyroidism and Amiodarone ( R = 0.63, p < 0.00001). The gene expression profiles of Hypothyroidism and Amiodarone showed closer correlation when top 100 up-regulated and 100 down-regulated genes in Hypothyroidism (total 200 genes) were analyzed ( R = 0.78, p < 0.00001). Northern blots of left ventricular myocardium showed a parallel decrease in mRNAs for myosin heavy chain (MHC)-alpha and a parallel increase for myosin heavy chain (MHC)-beta in Hypothyroidism and Amiodarone. In the liver and pituitary, in contrast, Northern blots showed quite different changes in the transcripts of the representative T3-responsive genes in the Hypothyroidism and Amiodarone. In conclusion, long-term treatment with amiodarone causes cardioselective hypothyroid-like alterations in gene expression profiles. The potent anti-arrhythmic activity of amiodarone may be attributable, in part at least, to this unique transcriptional remodeling.

Droperidol-induced Proarrhythmia

Droperidol-induced Proarrhythmia