Ventricular Repolarization Duration Research Articles

Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.

Heart repair by stem cell treatment may involve life-threatening arrhythmias. Cardiac progenitor cells (CPCs) appear best suited for reconstituting lost myocardium without posing arrhythmic risks, being commissioned towards cardiac phenotype. In this study we tested the hypothesis that mobilization of CPCs through locally delivered Hepatocyte Growth Factor and Insulin-Like Growth Factor-1 to heal chronic myocardial infarction (MI), lowers the proneness to arrhythmias. We used 133 adult male Wistar rats either with one-month old MI and treated with growth factors (GFs, n = 60) or vehicle (V, n = 55), or sham operated (n = 18). In selected groups of animals, prior to and two weeks after GF/V delivery, we evaluated stress-induced ventricular arrhythmias by telemetry-ECG, cardiac mechanics by echocardiography, and ventricular excitability, conduction velocity and refractoriness by epicardial multiple-lead recording. Invasive hemodynamic measurements were performed before sacrifice and eventually the hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. When compared with untreated MI, GFs decreased stress-induced arrhythmias and concurrently prolonged the effective refractory period (ERP) without affecting neither the duration of ventricular repolarization, as suggested by measurements of QTc interval and mRNA levels for K-channel α-subunits Kv4.2 and Kv4.3, nor the dispersion of refractoriness. Further, markers of cardiomyocyte reactive hypertrophy, including mRNA levels for K-channel α-subunit Kv1.4 and β-subunit KChIP2, interstitial fibrosis and negative structural remodeling were significantly reduced in peri-infarcted/remote ventricular myocardium. Finally, analyses of BrdU incorporation and distribution of connexin43 and N-cadherin indicated that cytokines generated new vessels and electromechanically-connected myocytes and abolished the correlation of infarct size with deterioration of mechanical function. In conclusion, local injection of GFs ameliorates electromechanical competence in chronic MI. Reduced arrhythmogenesis is attributable to prolongation of ERP resulting from improved intercellular coupling via increased expression of connexin43, and attenuation of unfavorable remodeling.

QT interval analysis in type 2 diabetic patients

Background: The electrocardiographic QT interval has been extensively studied in diabetes mellitus. Recently, there has been increasing interest in the relationship between diabetes and QT abnormalities .The QT interval, which is easily obtained from a standard resting electrocardiogram( ECG), reflected the total duration of ventricular myocardial depolarization and repolarization. The heart rate corrected QT interval (QTc) by Bazett's formula on the electrocardiogram has been proposed as a risk factor for ventricular arrhythmias in diabetes mellitus. Dispersion of QT(QTd) is defined as the difference between maximum and minimum QT interval QT interval on 12 lead ECG, which reflected spatial ventricular repolarization in homogeneity ,has been report to increase in diabetic subjects compare with non diabetic subjects.Patients and Methods: Type 2 diabetic patients (n=80) and healthy subjects (n=25) were required to have 12-lead ECG suitable for QT analysis ,QT interval was measured in each lead tofound(maximum, minimum, and mean ).QT interval vary according to the heart rate, it can be corrected using Bazett's formula to give QTc interval, and to found (maximum, minimum, and mean).Dispersion of QT interval(QTd) was calculate using the difference between the maximum and minimum QT interval duration as same as for dispersion of corrected QT interval(QTcd).Result: There were significant difference in QT interval indices between type 2 diabetic and healthy subjects (P<0.05) as well as the correct QT interval indices. ROC curve analysis of QT and QTc interval duration parameters demonstrated that no QT parameters performs better than maximum and minimum of QT and QTc, areas under ROC curve were(0.69 and 0.66 P<0.001)for maximum and mean QT respectively and (0.80 and 0.75 P<0.001) for maximum and mean QTc respectively. From this result we can say that QTc parameters better than QT parameters in context of patients and control differences. In multiple linear regression models, maximum, mean, and dispersion of QT interval were significantly affect by diabetes mellitus after adjustment for age, gender, body mass index (BMI), and heart rate. Whereas, only maximum and mean QTc were significantly affected by diabetes mellitus after adjustment for age, gender, and BMI. Prolongation of QT interval (QTc and QTd) also seen in a diabetic subjects which significant different as compare to the healthy subjects.Conclusion: The result of this study indicate that corrected QT interval (maximum and mean)in a routine ECG is a useful marker to identify the QT abnormalities differentiating diabetes type 2 from healthy subjects.

Changes in Ventricular Repolarization Duration During Typical Daily Emotion in Patients With Long QT Syndrome

Intense emotions are known triggers of sudden cardiac death. However, the effect of typical daily emotion on repolarization has not been examined. We examined whether QT interval changes as a function of typical daily emotion in patients at risk for cardiac events in the context of emotion. We studied 161 patients (n = 114 females; mean age, 35 years) with the congenital form of the Long QT Syndrome during daily activities. Each day for 3 days, a 12-hour Holter recording was completed. Patients were paged ten times per day at random times and rated the intensity of 16 prespecified emotions during the preceding 5 minutes. Measurements of QT interval and interbeat intervals were synchronized with emotion ratings. Low Arousal Positive Affect was associated with significant increases in QT interval corrected for heart rate (using Fridericia's QTc) (p < .001), whereas higher arousal Activated Positive Affect (p < .001) and Activated Negative Affect (p < .01) were associated with significant decreases in QTc. Changes in QTc as a function of daily emotion ranged from 5-ms increases to 11-ms decreases. High-frequency heart rate variability (vagal tone) was positively correlated with QTc (p < .001). The effects of each positive emotion variable on QTc were greater in LQT2 than LQT1 patients (p < .001). Ventricular repolarization duration (QTc) changes dynamically as a function of daily emotion. These changes are relatively small and do not constitute a risk in themselves. In the context of other risk factors, however, they may contribute to ventricular arrhythmias in vulnerable populations.

Insights into the Molecular Mechanism of hERG1 Channel Activation and Blockade by Drugs

Blockade of the human ether-a-go-go related gene 1 (hERG1) channel has been associated with an increased duration of ventricular repolarization, causing prolongation of the time interval between Q and T waves (long QT syndrome, or LQTS). LQTS may result in serious cardiovascular disorders such as tachyarrhythmia and sudden cardiac death. Diverse types of organic compounds bind to the wide intracellular cavity in the pore domain of hERG channels, leading to a full or partial blockade of ion current through the pore. The drug-induced blockade of the hERG-related component of the potassium current is thought to be a major reason for drug-induced arrhythmias in humans. Identification of specific interactions governing the high-affinity blockade of cardiac potassium (K-) channels is crucial both for the prevention of unintended ion channel block and for the design of ion channel modulators. A plethora of ligand- and receptor-based models of K-channels have been created to address these challenges. In this paper, we review the current state of knowledge regarding the structure-function relationship of hERG and discuss progress in the use of molecular modeling for developing both blockers and activators of hERG.

RT variability unrelated to heart period and respiration progressively increases during graded head-up tilt

Open-loop linear parametric models were exploited to describe ventricular repolarization duration (VRD) variability during graded head-up tilt. Surface ECG and thoracic movements were recorded in 15 healthy humans (age: 24-54 yr, median: 28 yr; 6 women and 9 men). Tilt table inclinations ranged from 15 to 90 degrees and were varied in steps of 15 degrees . All subjects underwent recordings at every step in random order. Heart period was assessed as the time difference between two consecutive R-wave peaks (RR) and the respiratory signal (R) as the sampling of the thoracic movement signal at the R-wave peaks. VRD was measured automatically as the temporal difference between the R-wave peak and T-wave apex (RT(a)) or T-wave end (RT(e)). The best model decomposed RT variability as due to RR changes (RR-related RT variability) to direct respiratory-related inputs (R-related RT variability) and to unknown rhythmical sources unrelated to RR changes and R (RR-R-unrelated RT variability). Using this model, RT(e) variability was found to be less predictable than RT(a) variability and composed of a smaller fraction of RR-related RT variability and a larger fraction of RR-R-unrelated RT variability. Predictability progressively decreased with tilt table angles, suggesting increased complexity of RT regulation. RT variance progressively increased with tilt table inclination. This increase was characterized by a gradual rise of the amount of RR-R-unrelated RT variability, whereas the amount of RR-related RT variability remained unchanged. These results suggest that the amount of RT variability, complexity of RT dynamics, and amount of RR-R-unrelated RT variability increase with the magnitude of the sympathetic drive directly related to tilt table inclination. We propose the utilization of the amount of RR-R-unrelated RT variability instead of overall RT variability as an indirect measure of autonomic regulation directed to ventricles.

Mechanisms of myocardial depression in sepsis: Association of L-type calcium current density and ventricular repolarization duration*

Mechanisms of myocardial depression in sepsis: Association of L-type calcium current density and ventricular repolarization duration*

Increased prevalence of prolonged QT interval in males with primary or secondary hypogonadism: A pilot study

Symptoms and signs of male hypogonadism span all organ systems, including the cardiovascular apparatus. The electrocardiographic QT interval reflects cardiac ventricular repolarization and, if prolonged, increases the risk of malignant arrhythmias. QT interval duration is similar in boys and girls during childhood, but shortens in males after puberty and experimental studies suggest that testosterone is a major contributor to shortening of QT interval in men. The aim of the present pilot study was to assess the duration of ventricular repolarization in adult males with primary or secondary hypogonadism. Standard ECG recordings were performed in 26 men (mean age 39.2 +/- 2.17 years) with pituitary or testicular hypogonadism and repeated in 15 patients during testosterone replacement. Twenty-six age-matched control men were also analysed. Measured QT intervals were corrected for heart rate according to Bazzett's formula (QTc = QT/radical RR interval). The prevalence of prolonged QTc was considerably higher in hypogonadal patients (four of 26 men) than in control men (none, p < 0.05) and in the general, healthy population (<2.5%). QTc interval normalized on hormone replacement therapy in the four patients presenting prolonged QTc in the hypogonadal state. Heart rate and left ventricular mass did not differ among the two groups and no known QT-prolonging factor was apparent in patients with abnormal QTc interval. In conclusion, a high number prolonged QT interval measurements was observed in hypogonadal men who may therefore be at increased risk for cardiac arrhythmias. This observation reveals an additional feature of male hypogonadism, which may benefit from testosterone replacement therapy.

IKs restricts excessive beat-to-beat variability of repolarization during beta-adrenergic receptor stimulation

In vivo studies have suggested that increased beat-to-beat variability of ventricular repolarization duration (BVR) is a better predictor of drug-induced torsades de pointes than repolarization prolongation alone. Cellular BVR and its dynamics before proarrhythmic events are poorly understood. We investigated differential responses of BVR in single myocytes during I Ks blockade versus I Kr blockade and late- I Na augmentation, under the influence of β-adrenergic receptor stimulation. Transmembrane action potentials were recorded from isolated canine left-ventricular midmyocytes at various pacing rates. I Ks was blocked by HMR1556, I Kr by dofetilide. Late I Na was augmented by sea anemone toxin-II. Isoproterenol was added for β-adrenergic receptor stimulation. BAPTA-AM buffered intracellular Ca 2+. SEA0400 partially inhibited the Na +–Ca 2+ exchanger. BVR was quantified as variability of action-potential duration at 90% repolarization: Σ(|APD90; i + 1 minus APD90; i|) / [nbeats × √ 2] for 30 consecutive action potentials. Baseline BVR was significantly increased by I Kr blockade and late- I Na augmentation, especially at slow pacing rates. β-adrenergic stimulation restabilized these BVR changes. In contrast, I Ks blockade caused very little change in repolarization when compared to baseline conditions, but predisposed the myocyte to increased BVR during β-adrenergic stimulation, especially at fast rates. BAPTA-AM and SEA0400 reduced this excessive BVR and eliminated early afterdepolarizations. In conclusion, β-adrenergic receptor stimulation exaggerates BVR during I Ks blockade, indicating a BVR-stabilizing role of β-adrenergic-sensitive I Ks. Loss of I Ks plus overriding of Ca 2+-dependent membrane currents, including inward Na +–Ca 2 + exchange current, conspire to proarrhythmic BVR under these conditions.

Baseline Values and Sotalol‐Induced Changes of Ventricular Repolarization Duration, Heterogeneity, and Instability in Patients With a History of Drug‐Induced Torsades de Pointes

The authors investigated whether computerized parameters quantifying ventricular repolarization delay, heterogeneity, and instability characterize individuals who developed drug-induced Torsades de Pointes. Assessing an individual's propensity to Torsades de Pointes when exposed to a QT-prolonging drug is challenging because baseline QT prolongation has limited predictive value. Five-minute digital 12-lead electrocardiograms were acquired at baseline and after a sotalol challenge in 16 patients who had a history of Torsades de Pointes in the context of a QT-prolonging drug and 17 patients who did not have such history. Computerized measurements of QTc, T peak to T end intervals (TpTe), TpTe/QTc, and QT variability were implemented, and novel quantifiers of ventricular repolarization heterogeneity from the early (ERD) and late (LRD) part of the T wave were investigated. Compared with electrocardiograms of patients without a history of Torsades de Pointes, the baseline electrocardiograms of patients with a history of Torsades de Pointes had a longer QTc and an increased repolarization heterogeneity of the early part of the T wave (ERD30%: 44 +/- 13 vs 35 +/- 8 ms, P = .02). On sotalol, the electrocardiograms from individuals with Torsades de Pointes revealed a delay of the terminal part of the T wave that was not present in patients without Torsades de Pointes (TpTe: 27 +/- 40 vs -2 +/- 21 ms, P = .02; LRD70%: 20 +/- 29 vs 2 +/- 4 ms, P = .04). Results suggest that the electrocardiogram abnormalities characterizing patients with a history of Torsades de Pointes are (1) an increased repolarization heterogeneity at baseline and (2) a sotalol-induced prolongation of the terminal part of the T wave.

Ventricular electrophysiology in congestive heart failure and its correlation with heart rate variability and baroreflex sensitivity: a canine model study

This study investigated ventricular electrophysiological characteristics and the correlation between these parameters and heart rate variability (HRV) and baroreflex sensitivity (BRS) in a canine congestive heart failure (CHF) model. Haemodynamics, HRV, BRS, and ventricular electrophysiological variables were measured 4-5 weeks after sham operation (control dogs) and pacemaker implantation, and rapid right ventricular pacing at 240 bpm (CHF group). In the CHF group, significant differences from the control group in ventricular effective refractory period (VERP), monophasic action potential (MAP) duration (MAPD(90)), ventricular late repolarization duration (VLRD), the ratio of VERP to MAPD(90), dispersion of ventricular recovery time (VRT-D), and ventricular fibrillation threshold (VFT) were noted. Both BRS and the time and power domain parameters of HRV were significantly decreased in the CHF group compared with the control group, and a significant, positive correlation between HRV and BRS was identified in the CHF group. Heart rate variability and BRS were negatively and significantly correlated with VLRD and VRT-D, and were positively correlated with VERP/MAPD(90) and VFT in the CHF group. These results suggest that ventricular electrophysiological characteristics correlated with abnormal autonomic nerve function may have important effects on sudden cardiac death. Further research is warranted.

Catecholaminergic Effects on Ventricular Repolarization During Inhibition of the Rapid Component of the Delayed Rectifier Potassium Current in a Perfused Heart Model

To determine the catecholaminergic effects on the duration of ventricular repolarization during inhibition of the rapid component of the delayed rectifier potassium current (I(Kr)). Isolated perfused heart model. University research center. Eighteen male Dunkin-Hartley guinea pigs. Hearts were excised and perfused in a retrograde manner at a constant aortic pressure of 60 mm Hg and temperature of 37 degrees C. Thirteen hearts were administered sparfloxacin 20 microg/ml (an I(Kr) inhibitor) in a buffered solution; the remaining five hearts were perfused with only the buffered solution to act as controls for potential time-dependent changes in action potential duration (APD). Immediately after the sparfloxacin infusion, six of the 13 hearts were administered a bolus catecholamine infusion of an epinephrine 10 nM-norepinephrine 6 nM admixture; 10 minutes after the start of the first catecholamine infusion, these hearts received another bolus infusion of an epinephrine 5 nM-norepinephrine 3 nM admixture. The other seven hearts were administered only a buffered solution. Hearts were paced (240 beats/min), and left ventricular monophasic action potentials were recorded for determination of APD at 90% and 30% repolarization (APD(90) and APD(30), respectively). The APD(90) and APD(30) increased in all 13 hearts exposed to sparfloxacin. The mean +/- SD APD(90) increase from baseline at 15 minutes was 4.2 +/- 2.5% relative to the five control hearts. In the presence of I(Kr) inhibition, the epinephrine 5 nM-norepinephrine 3 nM and epinephrine 10 nM-norepinephrine 6 nM admixtures altered APD(90), with a mean +/- SD maximum increase in APD(90) of 3.1 +/- 1.2% and 4.5 +/- 3.6%, respectively. This corresponded to a statistically significant increase in APD(90) and APD(30) 2 minutes after the catecholamine infusion in the presence of I(Kr) inhibition. A net prolongation of ventricular repolarization was observed after a catecholamine surge in the presence of mild I(Kr) inhibition. This suggests that counteracting mechanisms may contribute to the apparent arrhythmogenic substrate during nonspecific adrenergic receptor activation in the presence of I(Kr) inhibition.

Electrophysiological effects of short-term antihypertensive therapy

Evaluation of: Porthan K, Viitasalo M, Hiltunen TP et al. Short-term electrophysiological effects of losartan, bisoprolol, amlodipine, and hydrochlorothiazide in hypertensive men. Ann. Med. DOI: 10.1080/07853890802195211 (2008) (Epub ahead of print).Left ventricular hypertrophy (LVH) detected by ECG has been shown to be associated with a higher prevalence of ventricular arrhythmias in members of the general population, in a case–control series of hypertensive patients and in never-treated hypertensive patients. In-keeping with this, it has been observed that hypertension-induced LVH increases the risk of sudden cardiac death. Furthermore, a consistent bulk of data suggests antihypertensive therapy targeted at regression or prevention of electrocardiographic LVH may reduce the incidence of arrhythmias. In this regard, recent clinical trials showed that antihypertensive therapy may delay or prevent the occurrence of cardiac arrhythmias and sudden cardiac death in patients with hypertension. Porthan et al. hypothesized that an antihypertensive therapy might also rapidly affect ventricular repolarization and sought to investigate the short-term electrophysiological effects of four common antihypertensive drugs, represented by an angiotensin II receptor blocker (losartan), a β-blocker (bisoprolol), a calcium channel blocker (amlodipine) and a thiazide diuretic (hydrochlorothiazide) in hypertensive men. Porthan et al. showed that losartan and bisoprolol favorably affected ventricular repolarization, with beneficial effects on ECG parameters of ventricular repolarization duration and heterogeneity. On the contrary, hydrochlorothiazide significantly increased repolarization heterogeneity, while amlodipine administration did not affect ECG repolarization measures. Thus, the observed findings suggest an intriguing hypothesis on the possible role of antihypertensive therapy in favouring or preventing cardiac arrhythmias.

A REAL-TIME QT INTERVAL DETECTION ALGORITHM

The QT interval is the electrocardiographic representation of the duration of ventricular depolarization and repolarization. In this paper, we have developed a new real-time QT interval detection algorithm for automatically locating the onset of QRS and the end of the T wave. The algorithm consists of several steps: signal-to-noise enhancement, QRS detection, QRS onset, and T-wave end definition. The detection algorithm is tested on electrocardiogram (ECG) signals from the universal MIT-BIH Arrhythmia Database. The resulting QRS detection algorithm has a sensitivity of 99.79% and a specificity of 99.72%. The QRS onset and T-wave detection algorithm is tested using several data records from the MIT/BIH Arrhythmia Database. The results obtained are shown to be highly satisfactory.

Effect of autonomic blockade on ventricular repolarization shortening: Response to behavioral stimulus in paced dogs

Autonomic tone has been suggested to be a significant determinant of ventricular repolarization duration with both rate dependent and independent effects. Using the His bundle-paced dog, a model that eliminates the need for QT correction factors, we explored the rate-independent effects of sympathetic and parasympathetic blockade on ventricular repolarization shortening following an excitatory stimulus. Six male His bundle-paced beagle dogs were paced at 80 bpm and fitted with jackets, surface ECG electrodes, and radiotelemeters. Dogs were given propranolol, atropine methyl nitrate, or the appropriate control in a four-period crossover design. Doses were based on literature reviews and unpublished pharmacokinetic/pharmacodynamic modeling to provide efficacious beta- and parasympathetic blockade throughout the data collection period. Data collection began at 11 am and concluded at 11 am the following day, with event stimuli provided by investigators entering the room at 5 pm and at 7 am the following morning. One minute of ECG data were sampled every 15 min and these means were averaged to generate hourly means for the 24 hour data collection period. Treatment with atropine attenuated RT interval shortening when compared with the vehicle group at both the 5 pm and 7 am stimulus. In contrast, propranolol was not associated with significant effects on RT interval duration at either time point. These results suggest that parasympathetic withdrawal is the primary factor responsible during both awake hours (5 pm) and in the transition from deep sleep to the awake state (7 am) in the facilitation of RT interval shortening following an excitatory stimulus. The attenuation of RT interval shortening following atropine treatment may be a direct effect, or an indirect effect requiring an excited state to become evident. The use of a model that eliminates the need to apply correction factors to repolarization indices helps to clarify the role of the autonomic nervous system on ventricular repolarization.

The Relationship between Ventricular Repolarization Duration and RR Interval in Normal Subjects and Patients with Myocardial Infarction

Objectives: When either ventricular myocardium becomes ischemic or autonomic nervous system activity changes with age, the relationship between ventricular repolarization duration and RR interval will change as well. We studied the relationship between ventricular repolarization duration and RR interval among normal subjects in different age groups and between patients with myocardial infarction (MI) and age-matched healthy subjects. Methods: Ventricular repolarization duration variability (RDV) spectra were separated into RR-dependent and RR-independent components. We compared spectral measures among normal subjects in different age groups and between patients with MI and age-matched healthy subjects. Results: The RR-dependent component of RDV spectra, which is correlated with autonomic nervous system activity, significantly decreased with age for healthy subjects. The RR-independent component significantly increased in MI patients compared to age-matched healthy subjects. Conclusions: We demonstrated the increase in RDV upon decreasing age and in the presence of MI. Our results support the idea that the RR-dependent part corresponds to the physiology-related part of the RDV spectra and the RR-independent part corresponds to the pathology-related part of the RDV spectra. Our study suggests that these spectral measures are likely to be helpful in the evaluation of a patient with MI and merit further investigation.

Electrolyte concentration during haemodialysis and QT interval prolongation in uraemic patients

To assess the effect of different combinations of potassium and calcium concentrations on QT interval in the dialysis bath in uraemic patients. Sixteen haemodialysis (HD) patients underwent a 24 h Holter recording before and during HD sessions with six randomized combinations of electrolytes concentrations of the dialysis bath (K(+), 2 and 3 mmol/L; Ca(2+), 1.25, 1.5, and 1.75 mmol/L). The effect of different dialysis baths on QT interval was significant (P < 0.05). The longest mean QTc was observed with the lowest K(+) (2 mmol/L) and Ca(2+) concentrations (1.25 mmol/L), whereas the shortest mean QTc was observed with the highest K(+) (3 mmol/L) and Ca(2+) concentrations (1.75 mmol/L). QTc was >440 ms in 9 of 16 patients (56%) at the lowest Ca(2+) and K(+) concentrations, and in 3 of 16 patients (18%) at the highest electrolytes level. Changes in QTc during the HD sessions were inversely correlated with that in total Ca and Ca(2+) plasma concentrations (P < 0.0001). Changes in ventricular repolarization duration associated with HD largely depend on the concentrations of Ca(2+) and K(+) in the dialysis bath. These findings may have important implications for the choice of the electrolytes concentration of the dialysis bath during the HD session.

If Inhibition with Ivabradine

Ivabradine belongs to a new class of specific heart rate reducing agents that inhibit spontaneous pacemaker activity of the sinus node by selectively and specifically inhibiting the I(f) current; thus, allowing heart rate reduction without affecting myocardial contractility, relaxation and peripheral vascular resistance. In clinical studies involving >3500 patients and 800 healthy volunteers, ivabradine demonstrated a good safety profile during its clinical development. The most common adverse events were visual symptoms in 16.4% (n = 270) and sinus bradycardia < or =55 beats per minute in 3.2% (n = 53) of all patients treated with recommended doses of 5 mg and 7.5 mg twice daily. However, because the heart rate reducing effect of ivabradine is proportional to the resting heart rate and is associated with a clear trend to a plateau-dose effect, severe sinus bradycardia is uncommon. Less than 1% of patients withdrew from therapy because of untoward sinus bradycardia. The QT interval is prolonged in accordance with the reduction in heart rate; however, after appropriate correction for heart rate and in direct comparisons of the QT interval when the influence of the heart rate was controlled by atrial pacing, no significant effect of ivabradine on ventricular repolarization duration was demonstrated. Consequently, ivabradine has no direct torsadogenic potential. Because ivabradine also inhibits h-channels, which carry the I(h) current in the eye, it may cause luminous phenomena (phosphenes). Visual symptoms are transient, do not interfere with quality of life and have led to few withdrawals (<1%; 24 of 2545 patients); symptoms resolved during treatment in 77.5% (383 of 491) of patients. Since constitutionally active I(f) and I(h) currents are confined to the sinus node, retina and CNS neurons (ivabradine does not cross blood-brain barrier), ivabradine does not affect other tissues. The safety of ivabradine will be further assessed by postmarketing surveillance and during on-going clinical trials.

QT Prolongation and Safety in the Indian Population

The QT interval in electrocardiogram (ECG) reflects the total duration of ventricular myocardial depolarization and repolarization. It has been well recognized that many condition may cause QT interval prolongation. Unfortunately, numbers of cardiac and non-cardiac drug prolong the QT interval and cause a distinctive polymorphic ventricular tachycardia termed torsade de pointes (TdP). TdP can degenerate into ventricular fibrillation, which leads to sudden cardiac death. Recently various regulatory and clinical bodies of Europe, USA, Canada and Australia have made their focus on the drugs that induce prolongation of QT interval. Committee for Proprietary Medicinal Products (CPMP) of the European Agency issued a document entitled 'Points to Consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products' [1, 2]. In addition, USFDA adopted the guideline 'Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-anti arrhythmic drugs' [3]. These documents and guidelines are primarily concern with development of novel agents and the new use or new dose of already approved drugs. The scope of this guideline is to study the effect of drugs on QT prolongation and give idea of evaluation of drug's effects on QT prolongation. Today more than 50 available drugs (both old and new) have been identify, which prolong the QT interval [1]. Several drugs have been withdrawn from many countries on this basis but many of these drugs are still available in Indian market and potentially creating life-threatening arrhythmias. This article will focus on recommendation of study on the normal limits of QT interval in Indian population and preparation of the database, which can be helpful in withdrawal of drugs from the market that produces QT prolongation.

A Principal Component Regression Approach for Estimating Ventricular Repolarization Duration Variability

Ventricular repolarization duration (VRD) is affected by heart rate and autonomic control, and thus VRD varies in time in a similar way as heart rate. VRD variability is commonly assessed by determining the time differences between successive R- and T-waves, that is, RT intervals. Traditional methods for RT interval detection necessitate the detection of either T-wave apexes or offsets. In this paper, we propose a principal-component-regression- (PCR-) based method for estimating RT variability. The main benefit of the method is that it does not necessitate T-wave detection. The proposed method is compared with traditional RT interval measures, and as a result, it is observed to estimate RT variability accurately and to be less sensitive to noise than the traditional methods. As a specific application, the method is applied to exercise electrocardiogram (ECG) recordings.

Calcium and potassium changes during haemodialysis alter ventricular repolarization duration: in vivo and in silico analysis

Alterations of ventricular repolarization duration, as measured by the QT interval, are frequently observed in haemodialysis (HD) patients. The nature and the sign of these changes are not yet fully understood. Different dialysate K(+) and Ca(2+) levels, leading to different end-HD plasma concentrations in the patient, have been tested in the present study in terms of their impact on QTc. A model of the human cardiomyocyte action potential (AP) has been used to assess in silico whether the changes in Ca(2+) and K(+) were able to justify at the cellular level the observed alterations of QTc. QTc was prolonged in HDs with low (1.25 mM) versus high (2 mM) Ca(2+) (424 +/- 33 versus 400 +/- 28 ms, P < 0.05) and in HDs with low (2 mM) versus high (3 mM) K(+) (420 +/- 35 versus 399 +/- 36 ms, P < 0.05). These alterations were confirmed at the cellular level by computational analysis showing prolongation of ventricular AP at low K(+) and low Ca(2+) at the same extent of the measured QTc variations. Numerical simulation predicted a critically long AP (and QT) when considering low K(+) and Ca(2+) simultaneously, suggesting the concurrent lowering of Ca(2+) and K(+) as a potential arrhythmogenic factor. Numerical simulations of the ventricular AP may be useful to quantitatively predict the complex dependence of AP duration on simultaneous changes in Ca(2+) and K(+). Moreover, Ca(2+) content in the dialysate should be designed not to critically lower serum Ca(2+), especially in sessions at risk of end-dialysis hypokalaemia.