Correlation between lactate dehydrogenase and QTc interval prolongation in maintenance hemodialysis patients: a cross-sectional study.

BACKGROUND: Corrected QT (QTc) interval prolongation is one of the common causes of sudden cardiac death in patients with maintenance hemodialysis (MHD) patients. However, there are few studies on QTc prolongation in MHD patients. The concentration of lactate dehydrogenase (LDH) in hemodialysis population increased, and LDH was associated with the mortality of MHD patients. This study aimed to investigate the relationship between QTc interval prolongation and LDH in MHD patients. METHODS: This is a cross-sectional observational study. Patients who underwent MHD for more than 3 months in the Second Affiliated Hospital of Nantong University from November 2012 to November 2019 with complete data were selected as the research subjects. The patients were divided into the normal QTc interval group and the QTc interval prolongation group. The general data of patients and clinical laboratory indicators were collected retrospectively from the electronic medical record system. Pearson correlation analysis and binary logistic regression were used to analyze the correlation between LDH and QTc interval prolongation; the cut-off value of LDH predicting QTc interval prolongation was calculated by receiver operating characteristic (ROC) curve. RESULTS: The LDH level in the prolonged QTc interval group was significantly higher than that in the normal group (301.96±110.91 vs. 215.39±67.65, t=-8.03, P<0.001). QTc interval and LDH (r=0.386) were positively correlated. Binary logistic regression analysis showed that LDH, serum potassium <4 mmol/L, serum phosphorus, and left ventricular end-diastolic diameter (LVDd) were independent related factors for QTc interval prolongation. The ROC curve results showed that LDH =220 U/L was the best cutoff point for predicting QTc interval prolongation in MHD patients, with a sensitivity of 81.45% and a specificity of 59.35%. Binary logistic regression analysis showed that the LDH >220 U/L group was 6.34 times more likely to have QTc interval prolongation than the LDH ≤220 U/L group (OR 6.34, 95% CI: 3.47-11.58, P<0.001). CONCLUSIONS: LDH in MHD patients is closely related to QTc interval prolongation. Serum LDH, ionic calcium, serum phosphorus and potassium may predict QTc interval prolongation. Monitoring related indicators can remind clinicians to intervene as soon as possible to reduce the potential risk of arrhythmia and sudden cardiac death (SCD).

Malignant prolongation of the QTc interval due to severe vitamin D deficiency: an unusual presentation.

Long QT syndrome with Torsades de Pointes (TdP) is a life-threatening polymorphic ventricular arrhythmia. The corrected QT (QTc) prolongation >500 milliseconds (ms) has been associated with TdP. Hypocalcaemia due to severe vitamin D deficiency is an uncommon cause of acquired long QT. We hereby present a case of a 40-year-old woman with sensorineural deafness and having symptoms of palpitations and presyncope. She had a QTc interval of 556 ms (reference range, QTc 451-470 ms in adult healthy woman) on 24-hour Holter analysis. Genetic analysis for congenital long QT syndrome was negative. She was diagnosed with severe hypocalcaemia secondary to severe vitamin D deficiency. After treatment with intravenous calcium gluconate, followed by oral vitamin D and calcium supplementation, the QTc became normalised and no further episode of palpitations or presyncope occurred. The causes of vitamin D deficiency was due to inadequate exposure to sunlight and a strict vegan diet.

Arrhythmogenic foods - A growing medical problem.

Arrhythmogenic ingredients in our diet such as mushrooms, licorice, toxic honey, liquid protein drinks, etc. have long been recognized as rare but important considerations in the differential diagnosis of arrhythmias. Anecdotal reports of torsades de pointes (TdP), arrhythmias and/or sudden death and small studies in normal subjects have suggested that simple ingredients such as grapefruit juice or ingredients in energy drinks marketed as dietary supplements could have direct arrhythmogenic actions, especially in patients with congenital long QT syndrome (cLQTS). Two recent studies that employed the industry-standard "thorough QT" trial design leave no doubt that grapefruit juice and some energy drinks can prolong the QTc interval and to exceed 500 msec. in some patients with cLQTS, a threshold known to signal imminent danger. These reports raise numerous clinically important questions such as which other patients may be at risk of arrhythmias. For example, patients with multiple clinical risk factors for TdP (hypokalemia, bradycardia, female sex, etc.) may be at risk from these and possibly other dietary ingredients ingested by millions of people each day. It is essential that further research evaluate the safety of these and similar food products and that vulnerable patients, especially those with cLQTS, be warned of this serious and emerging threat.

Molecular Autopsy Implicates Primary Carnitine Deficiency in Sudden Unexplained Death and Reversible Short QT Syndrome.

We report a case of sudden unexplained death in a young asymptomatic woman in whom postmortem genetic testing after a negative autopsy identified a homozygous pathogenic mutation in SLC22A5 which leads clinically to primary carnitine deficiency (PCD). Her brother was subsequently diagnosed clinically with short QT syndrome, received an implantable defibrillator, and was then found to carry the same pathogenic homozygous mutation and critically low levels of carnitine. His QT interval improved with the use of carnitine supplementation, highlighting the close relationship between electrophysiology and biochemistry, and the importance of postmortem genetic testing in the clinical management of surviving relatives.

Effectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patients.

BACKGROUND: We evaluated the effectiveness of a computer clinical decision support system (CDSS) for reducing the risk of QT interval prolongation in hospitalized patients. METHODS AND RESULTS: We evaluated 2400 patients admitted to cardiac care units at an urban academic medical center. A CDSS incorporating a validated risk score for QTc prolongation was developed and implemented using information extracted from patients' electronic medical records. When a drug associated with torsades de pointes was prescribed to a patient at moderate or high risk for QTc interval prolongation, a computer alert appeared on the screen to the pharmacist entering the order, who could then consult the prescriber on alternative therapies and implement more intensive monitoring. QTc interval prolongation was defined as QTc interval >500 ms or increase in QTc of ≥60 ms from baseline; for patients who presented with QTc >500 ms, QTc prolongation was defined solely as increase in QTc ≥60 ms from baseline. End points were assessed before (n=1200) and after (n=1200) implementation of the CDSS. CDSS implementation was independently associated with a reduced risk of QTc prolongation (adjusted odds ratio, 0.65; 95% confidence interval, 0.56-0.89; P<0.0001). Furthermore, CDSS implementation reduced the prescribing of noncardiac medications known to cause torsades de pointes, including fluoroquinolones and intravenous haloperidol (adjusted odds ratio, 0.79; 95% confidence interval, 0.63-0.91; P=0.03). CONCLUSIONS: A computer CDSS incorporating a validated risk score for QTc prolongation influences the prescribing of QT-prolonging drugs and reduces the risk of QTc interval prolongation in hospitalized patients with torsades de pointes risk factors.

Extreme but not life-threatening QT interval prolongation? Take a closer look at the neck!

We present the case of a 82-year-old woman with a history of total thyroidectomy who was admitted in hospital with severe hypocalcemia. A 12-lead surface ECG revealed atrial fibrillation along with an extremely prolonged QT interval of approximately 730ms. In the absence of any other possible cause of QT interval prolongation, hypocalcemia was attributed to surgical hypoparathyroidism and undue discontinuation of calcium supplementation. Surprisingly, no ventricular arrhythmias were recorded and calcium repletion was followed by normalization of QT interval.

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 50 mg/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.

Marine n-3 fatty acids, atrial fibrillation and QT interval in haemodialysis patients.

Patients treated with haemodialysis are at high risk of sudden cardiac death (SCD) often caused by arrhythmias. Atrial fibrillation (AF) is frequent among haemodialysis patients and is associated with increased mortality. Prolonged QTc is a risk marker of ventricular arrhythmia and is thereby associated with SCD. Studies have suggested that n-3 PUFA may have an antiarrhythmic effect, but the exact mechanism is not clear. The aim of this study was to examine whether AF was associated with n-3 PUFA in plasma phospholipids and whether supplementation with n-3 PUFA would shorten the QTc interval in haemodialysis patients compared to placebo. In a double-blinded randomised, placebo-controlled intervention trial 206 haemodialysis patients with CVD were treated with 1·7 g n-3 PUFA or placebo (olive oil) daily for 3 months. Blood samples and electrocardiogram evaluations were carried out at baseline and after 3 months. The QT interval, PQ interval and heart rate were measured in all patients with sinus rhythm (SR). At baseline 13 % of patients had AF. The content of the n-3 PUFA, DHA, was significantly lower (P < 0·05) in serum of patients with AF compared with patients with SR. Thus, the DHA content was independently negatively associated with AF. Supplementation with n-3 PUFA did not shorten the QT interval significantly compared to the placebo group (P = 0·42), although subgroup analysis within the n-3 PUFA group revealed a shortening effects on QTc (P = 0·01). In conclusion, an inverse association was found between the presence of AF and the plasma DHA in haemodialysis patients. Intervention with n-3 PUFA did not shorten the QTc interval compared to placebo.

The ketogenic diet and the QT interval.

Cardiac complications have been rarely reported associated with the ketogenic diet. Prolonged QT interval in the electrocardiogram and torsades de pointes arrhythmias have been described in a few cases. The effect of the ketogenic diet on QT interval has not been systematically evaluated. We obtained serial electrocardiograms in our patients on the ketogenic diet to look for changes in the mean QT interval. Twenty seven children aged 6 months to 5 years with refractory epilepsy were enrolled. Classic ketogenic diet was introduced using a non-fasting gradual initiation protocol. All patients were supplemented with oral calcium and selenium. Electrocardiograms were obtained at baseline and after 1, 3, 6, and 12 months on the ketogenic diet. There was no statistically significant change in the corrected QT interval over time. There were no ST segment changes or dysrhythmias in any of the electrocardiograms.

The effect of Turkish bath on QT dispersion.

OBJECTIVE: It is known that QT intervals might differ from each other on electrocardiogram (ECG). It is also known that diversity of QT interval between derivations is an indicator of heterogeneity of repolarization and it is a leading electrophysiological cause of ventricular arrhythmias and sudden heart death. In this study, we evaluated the effects of the Turkish bath on QT dispersion. METHODS: A total of 47 healthy volunteers were enrolled in the prospective study. The 12-lead ECG recordings were taken in all subjects before and after bath and QT dispersions were calculated. Blood pressure and the heart rate of each patient were recorded. QT dispersion was defined as the difference between the maximum and minimum QT intervals occurring in any of the 12 leads. Statistical analysis were performed using Wilcoxon rank test and paired t test. RESULTS: The mean age was 49.47+/-11.64 years; range was between 23-70 years. The mean temperature of the bath was 39.72+/-1.75 degrees C, mean humidity percent was 84.42+/-4.74%. QTc dispersion were respectively determined as 0.047+/-0.025 sec and 0.047+/-0.019 sec (p=0.981) before and after bath. We determined no correlation between duration time at bath and QTc dispersion (r=-0.069 p=0.646). CONCLUSION: In our study we found no meaningful difference in QTc dispersion in individuals who take bath. Our study is the first study in which we evaluated QTc dispersion in high temperature and humidity environment of the bath and we did not determine any effect on QTc dispersion.

Acute hypokalemia may not be an effective way to sensitize the in situ canine heart for sparfloxacin-induced long QT syndrome.

Extents of the sparfloxacin (3 - 10 mg/kg, i.v.)-induced QT interval prolongation under normokalemic and hypokalemic conditions were assessed in halothane-anesthetized beagle dogs (n = 5). The hypokalemic condition was induced by an oral administration of furosemide (200 mg/kg per day) for 3 days, which decreased the serum potassium concentration from 3.65 +/- 0.13 to 2.35 +/- 0.13 mM (P < 0.05). However, the decrease of potassium concentration by itself did not affect the extent of the sparfloxacin-induced QT interval prolongation. These results indicate that acute hypokalemia may not severely sensitize the in situ heart for drug-induced long QT syndrome as previously thought.

A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation derived from the effects of terfenadine, cisapride and E-4031 in the conscious chronic av node--ablated, His bundle-paced dog.

INTRODUCTION: Terfenadine, cisapride, and E-4031, three drugs that prolong ventricular repolarization, were selected to evaluate the sensitivity of the conscious chronic atrioventricular node--ablated, His bundle-paced Dog for defining drug induced cardiac repolarization prolongation. A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation was generated from these data. METHODS: Three male beagle dogs underwent radiofrequency AV nodal ablation, and placement of a His bundle-pacing lead and programmable pacemaker under anesthesia. Each dog was restrained in a sling for a series of increasing dose infusions of each drug while maintained at a constant heart rate of 80 beats/min. RT interval, a surrogate for QT interval in His bundle-paced dogs, was recorded throughout the experiment. RESULTS: E-4031 induced a statistically significant RT prolongation at the highest three doses. Cisapride resulted in a dose-dependent increase in RT interval, which was statistically significant at the two highest doses. Terfenadine induced a dose-dependent RT interval prolongation with a statistically significant change occurring only at the highest dose. The relationship between drug concentration and RT interval change was described by a sigmoid E(max) model with an effect site. Maximum RT change (E(max)), free drug concentration at half of the maximum effect (EC(50)), and free drug concentration associated with a 10 ms RT prolongation (EC(10 ms)) were estimated. A linear correlation between EC(10 ms) and HERG IC(50) values was identified. DISCUSSION: The conscious dog with His bundle-pacing detects delayed cardiac repolarization related to I(Kr) inhibition, and detects repolarization change induced by drugs with activity at multiple ion channels. A clinically relevant sensitivity and a linear correlation with in vitro HERG data make the conscious His bundle-paced dog a valuable tool for detecting repolarization effect of new chemical entities.

Drugs, hERG and sudden death.

Early recognition of potential QT/TdP liability is now an essential component of the drug discovery/drug development program. The hERG assay is an indispensable step and a high-quality assay must accompany any investigational new drug (IND) application. While it is the gold standard at present, the hERG assay is too labor-intensive and too low throughput to be used as a screen early in the discovery/development process. A variety of indirect high throughput screens have been used.

Effect of epicardial or biventricular pacing to prolong QT interval and increase transmural dispersion of repolarization: does resynchronization therapy pose a risk for patients predisposed to long QT or torsade de pointes?

BACKGROUND: The present study examined pacing site-dependent changes in QT interval and transmural dispersion of repolarization (TDR) and their potential role in the development of torsade de pointes (TdP). METHODS AND RESULTS: In humans, the QT interval, JT interval, and TDR were measured in 29 patients with heart failure during right ventricular endocardial pacing (RVEndoP), biventricular pacing (BiVP), and left ventricular epicardial pacing (LVEpiP). In animal experiments, pacing site--dependent changes in ventricular repolarization were examined with a rabbit left ventricular wedge preparation in which action potentials from endocardium and epicardium could be simultaneously recorded with a transmural ECG. In humans, LVEpiP and BiVP led to significant QT and JT prolongation. LVEpiP also enhanced TDR. Frequent R-on-T extrasystoles generated by BiVP and LVEpiP but completely inhibited by RVEndoP occurred in 4 patients, of whom 1 developed multiple episodes of nonsustained polymorphic ventricular tachycardia and another suffered incessant TdP. In rabbit experiments, switching from endocardial to epicardial pacing produced a net increase in QT interval and TDR by 17+/-5 and 22+/-5 ms, respectively (n=6, P<0.01), without parallel increases in ventricular transmembrane action potential durations. Epicardial pacing facilitated transmural propagation of early afterdepolarization, leading to the development of R-on-T extrasystoles and TdP in the presence of action potential duration-prolonging agents. CONCLUSIONS: LVEpiP and BiVP increase QT, JT, and TDR by altering the transmural sequence of activation of the intrinsically heterogeneous ventricular myocardium. Our data suggest that the resultant exaggeration of arrhythmic substrates can lead to the development of TdP in a subset of patients.

Torsade de pointes.

Torsade de pointes ventricular tachyarrhythmia in the long QT syndrome is a prime example of how molecular biology, ion channel, and cellular and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and the acquired long QT syndrome are caused by abnormalities (intrinsic, acquired, or both) of the ionic currents underlying ventricular repolarization. In this review, the continually unraveling molecular biology of congenital long QT syndrome is discussed. The various pharmacologic agents associated with the acquired long QT syndrome are listed. Although it is difficult to predict which patients are at risk for torsade de pointes, careful assessment of the risk to benefit ratio is important before prescribing drugs known to cause QT prolongation. The in vivo electrophysiologic mechanism of torsade de pointes in the long QT syndrome is described, using as a paradigm the anthopleurin-A canine model, a surrogate for LQT3. The characteristic association of torsade de pointes with T-wave alternans and short-long cardiac sequences is discussed, with emphasis on electrophysiologic mechanisms. Finally, the expanding knowledge of genetic mutations other than long QT syndrome associated with polymorphic ventricular tachyarrhythmia is emphasized.

Influence of QRS duration on the prognostic value of T wave alternans.

INTRODUCTION: T wave alternans (TWA) is a promising new noninvasive marker of arrhythmia vulnerability that quantifies beat-to-beat changes in ventricular repolarization. Secondary repolarization abnormalities are common in subjects with wide QRS complexes. However, the relationship between TWA and QRS prolongation has not been evaluated. The goal of this study was to determine if QRS prolongation influences the prevalence or prognostic value of TWA. METHODS AND RESULTS: The study consisted of 108 consecutive patients with coronary artery disease and left ventricular ejection fraction < or = 40% who were referred for electrophysiologic studies. Patients underwent TWA testing using bicycle ergometry in the absence of beta-blockers or antiarrhythmic drugs. The primary endpoint was the combined incidence of death, sustained ventricular arrhythmias, and appropriate implantable cardioverter defibrillator therapy. The prognostic value of TWA was assessed in the entire cohort and in two subgroups: QRS < 120 msec (normal, n = 62) and QRS > or = 120 msec (prolonged, n = 46). TWA (hazard ratio 2.2, P = 0.03) and QRS prolongation (hazard ratio 2.2, P = 0.01) were both significant and independent predictors of arrhythmic events. QRS prolongation had no effect on the prevalence of positive TWA tests (QRS < 120 msec: 48%, QRS > or = 120 msec: 50%, P = NS). TWA was a highly significant predictor of events in patients with a normal QRS (hazard ratio 5.8, P = 0.02). In contrast, TWA was not useful for risk stratification in subjects with QRS prolongation (hazard ratio 1.1, P = 0.8). CONCLUSION: TWA is useful only for risk stratification in the absence of QRS prolongation. The presence of QRS prolongation and left ventricular ejection fraction < or = 40% may be sufficient evidence of an adverse prognosis that additional risk stratification is not useful or necessary.

Ventricular tachycardia in structurally normal hearts.

This review focuses on four distinct syndromes of ventricular tachycardia that occur in the structurally normal heart. Recent advances in the fields of molecular biology and genetics, along with intracardiac mapping techniques, have led to a greater understanding of the underlying mechanisms of and therapeutic options for these syndromes. The cyclic AMP-mediated triggered activity tachycardias, including exercise-induced right ventricular outflow track tachycardia and repetitive monomorphic ventricular tachycardia, are the most common of these syndromes. Idiopathic left ventricular tachycardia, for which there is significant evidence for re-entry within the Purkinje network, is largely curable with catheter ablation. The long QT syndrome comprises a heterogeneous group of ion channel defects leading to prolongation of myocyte repolarization and Torsade de Pointes ventricular tachycardia. Brugada syndrome, a familial disorder of transmembrane ion transport, is felt to be the result of a group of sodium channel defects leading to characteristic electrocardiographic abnormalities, and syncope and sudden death. Primary focus is given to recent advances in our understanding of the underlying mechanism and current therapeutic approaches.

Atrio-sinus interaction demonstrated by blockade of the rapid delayed rectifier current.

BACKGROUND: Proper pacemaking of the heart requires a specific organization of the sinoatrial (SA) node. The SA node drives the surrounding atrium but needs to be protected from its hyperpolarizing influence, which tends to suppress pacemaker activity. It has been suggested that the hyperpolarizing atrial influence is minimal at the site of the central nodal area. METHODS AND RESULTS: Atrio-sinus interaction was assessed by specific depolarization of the SA node by blocking the HERG-encoded rapid delayed rectifier current (I(K,r)) with the drug E-4031. In the SA node, E-4031 (1 micromol/L) changed action potential configuration drastically but never resulted in pacemaker arrest. In the atrium, E-4031 did not affect the membrane resting potential, thereby leaving the normal hyperpolarizing load on the SA node intact. When the SA node was sectioned into strips and subsequently separated from the atrium, spontaneous electrical activity of the strip containing the primary pacemaker ceased on I(K,r) blockade. When not separated from the atrium, I(K,r) blockade never resulted in pacemaker arrest. A similar effective atrio-sinus interaction was demonstrated in computer simulations. CONCLUSIONS: Our results demonstrate that the atrium provides an effective hyperpolarizing load on the central SA nodal area and is at least one of the controlling mechanisms for normal pacemaking function. The present study can be of help in understanding why patients with long-QT2 syndrome secondary to a mutation in HERG do not show sinus arrest.

Mechanism of ventricular arrhythmias in the long QT syndrome: on hermeneutics.

Both the congenital and acquired long QT syndrome are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying repolarization. The prolongation of repolarization acts as a priming step for the generation of early afterdepolarizations. In the long QT syndrome, it also is associated with increased dispersion of repolarization. Focal early afterdepolarization-induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant ventricular tachycardia that sometimes has a characteristic twisting of the QRS axis, referred to as torsades de pointes.