A porcine model of skin wound infected with a polybacterial biofilm.

A clinically relevant porcine model of a biofilm-infected wound was established in 10 minipigs. The wounds of six experimental animals were infected with a modified polymicrobial Lubbock chronic wound biofilm consisting of Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Bacillus subtilis. Four animals served as uninfected controls. The wounds were monitored until they had healed for 24 days. The biofilm persisted in the wounds up to day 14 and significantly affected healing. The control to infected healed wound area ratios were: 45%/21%, 66%/37%, and 90%/57% on days 7, 10 and 14, respectively. The implanted biofilm prolonged inflammation, increased necrosis, delayed granulation and impaired development of the extracellular matrix as seen in histological and gene expression analyses. This model provides a therapeutic one-week window for testing of anti-biofilm treatments and for research on the pathogenesis of wound infections in pig that is clinically the most relevant animal wound healing model.

Evaluation of beat-to-beat ventricular repolarization lability from standard 12-lead ECG during acute myocardial ischemia.

BACKGROUND: Acute myocardial ischemia is a common cause of ventricular arrhythmias, yet recent ECG methods predicting susceptibility to ventricular tachyarrhythmia have not been fully evaluated during spontaneous ischemia. We sought to evaluate the clinical utility of alternans and non-alternans components of repolarization variability from the standard 10-second 12-lead ECG signals to risk stratify patients with acute chest pain. METHODS: We enrolled consecutive, non-traumatic, chest pain patients transported through Emergency Medical Services (EMS) to three tertiary care hospitals with cardiac catheterization lab capabilities in Pittsburgh, PA. ECG signals were manually annotated by an electrophysiologist, then automatically processed using a custom-written software. Both T wave alternans (TWA) and non-alternans repolarization variability (NARV) were calculated using the absolute RMS differences over the repolarization window between odd/even averaged beats and between consecutive averaged pairs, respectively. The primary study outcome was the presence of acute myocardial infarction (AMI) documented by cardiac angiography. RESULTS: After excluding patients with secondary repolarization changes (n=123) and those with excessive noise (n=90), our final sample included 537 patients (age 57±16years, 56% males). Patients with AMI (n=47, 9%) had higher TWA and NARV values (p<0.01). Mean RR correlated with TWA, and noise measures correlated with TWA and NARV, after adjusting for potential confounders. There was a high collinearity between TWA and NARV, and each was separately predictive of AMI after controlling for number of analyzed beats, noise measures, and other clinical variables. CONCLUSIONS: Despite limitations imposed by signal quality, TWA and NARV are higher in patients with AMI, even after correction for potential confounders. The clinical value of TWA and NARV derived from standard ECG using our time-domain RMS method is questionable due to the small number of beats and significant noise.

A model of cardiac ryanodine receptor gating predicts experimental Ca2+-dynamics and Ca2+-triggered arrhythmia in the long QT syndrome.

Abnormal Ca2+ handling is well-established as the trigger of cardiac arrhythmia in catecholaminergic polymorphic ventricular tachycardia and digoxin toxicity, but its role remains controversial in Torsade de Pointes (TdP), the arrhythmia associated with the long QT syndrome (LQTS). Recent experimental results show that early afterdepolarizations (EADs) that initiate TdP are caused by spontaneous (non-voltage-triggered) Ca2+ release from Ca2+-overloaded sarcoplasmic reticulum (SR) rather than the activation of the L-type Ca2+-channel window current. In bradycardia and long QT type 2 (LQT2), a second, non-voltage triggered cytosolic Ca2+ elevation increases gradually in amplitude, occurs before overt voltage instability, and then precedes the rise of EADs. Here, we used a modified Shannon-Puglisi-Bers model of rabbit ventricular myocytes to reproduce experimental Ca2+ dynamics in bradycardia and LQT2. Abnormal systolic Ca2+-oscillations and EADs caused by SR Ca2+-release are reproduced in a modified 0-dimensional model, where 3 gates in series control the ryanodine receptor (RyR2) conductance. Two gates control RyR2 activation and inactivation and sense cytosolic Ca2+ while a third gate senses luminal junctional SR Ca2+. The model predicts EADs in bradycardia and low extracellular [K+] and cessation of SR Ca2+-release terminate salvos of EADs. Ca2+-waves, systolic cell-synchronous Ca2+-release, and multifocal diastolic Ca2+ release seen in subcellular Ca2+-mapping experiments are observed in the 2-dimensional version of the model. These results support the role of SR Ca2+-overload, abnormal SR Ca2+-release, and the subsequent activation of the electrogenic Na+/Ca2+-exchanger as the mechanism of TdP. The model offers new insights into the genesis of cardiac arrhythmia and new therapeutic strategies.

Increased Nonalternans Repolarization Variability Precedes Ventricular Tachycardia Onset in Patients with Implantable Defibrillators.

BACKROUND: T-wave alternans (TWA) is associated with ventricular tachycardia (VT). Nonalternans repolarization variability (NARV) precedes VT in certain experimental models, but its link to clinical arrhythmia is unproven. This study was conducted to determine if NARV increases prior to VT in patients with implantable cardioverter defibrillators (ICDs). METHODS: TWA and NARV were calculated from shock-channel electrograms preceding onset of VT or non-VT events in patients with an ICD. In each patient, presence of both a VT and a non-VT event with the same QRS morphology before the event was required. Mixed linear model was used for data analysis, using heart rate (HR) and the number of analyzed beats as covariates. RESULTS: Five hundred and sixty-eight events from 64 patients (males/females 51/13, 67 ± 13 years) were analyzed. HR preceding non-VT events was higher than before VT events (RR interval 595 ± 159 vs 706 ± 111 ms; P < 0.0001). Both TWA and NARV increased with increasing HR (P < 0.001). TWA decreased with increasing number of analyzed beats. When controlled for number of analyzed beats and HR, both TWA and NARV were higher before VT than before non-VT events (P < 0.002 and P < 0.0005, respectively). CONCLUSIONS: NARV is elevated prior to spontaneous VT onset. Both NARV and TWA increase with HR. The decrease of TWA with increasing number of analyzed beats may indicate contamination with NARV or noise when only a small number of beats is available for analysis. NARV might be useful for VT prediction in the future.

Nonalternans repolarization variability and arrhythmia - the calcium connection.

Repolarization alternans precedes certain types of ventricular arrhythmias and its presence may be prognostically useful, but some ventricular arrhythmias are not preceded by repolarization alternans. Nonalternans changes of ventricular repolarization occur in patients with coronary artery disease and in subjects with congenital long QT syndrome. In animal experiments, nonalternans repolarization lability occurs in a canine model of chronic AV block with propensity to polymorphic ventricular tachycardia, in the perfused rabbit heart exposed to IKr block, and in a murine model of catecholaminergic polymorphic ventricular tachycardia. Optical mapping experiments indicate that heterogeneity of intracellular calcium handling underlies nonalternans repolarization variability. Detection of nonalternans repolarization lability poses specific challenges, since signal averaging does not increase the signal to noise ratio. Nonalternans repolarization lability may be erroneously reported as repolarization alternans by non-spectral methods applied to short data segments. Additional research will be needed to determine the role of nonalternans repolarization variability in mechanism of ventricular arrhythmias.

Nighttime instabilities of neurophysiological, cardiovascular, and respiratory activity: integrative modeling and preliminary results.

Unstable (cyclical alternating pattern, or CAP) sleep is associated with surges of sympathetic nervous system activity, increased blood pressure and vasoconstriction, heightened baroreflex sensitivity, and unstable heart rhythm and breathing. In susceptible persons, CAP sleep provokes clinically significant events, including hypertensive crises, sleep-disordered breathing, and cardiac arrhythmias. Here we explore the neurophysiology of CAP sleep and its impact on cardiovascular and respiratory functions. We show that: (i) an increase in neurophysiological recovery rate can explain the emergence of slow, self-sustained, hypersynchronized A1 CAP-sleep pattern and its transition to the faster A2-A3 CAP-sleep patterns; (ii) in a two-dimensional, continuous model of cardiac tissue with heterogeneous action potential duration (APD) distribution, heart rate accelerations during CAP sleep may encounter incompletely recovered electrical excitability in cell clusters with longer APD. If the interaction between short cycle length and incomplete, spatially heterogeneous repolarization persists over multiple cycles, irregularities and asymmetry of depolarization front may accumulate and ultimately lead to a conduction block, retrograde conduction, breakup of activation waves, reentrant activity, and arrhythmias; and (iii) these modeling results are consistent with the nighttime data obtained from patients with structural heart disease (N=13) that show clusters of atrial and ventricular premature beats occurring during the periods of unstable heart rhythm and respiration that accompany CAP sleep. In these patients, CAP sleep is also accompanied by delayed adaptation of QT intervals and T-wave alternans.

QT interval prolongation in end-stage liver disease cannot be explained by nonhepatic factors.

INTRODUCTION: QT interval prolongation in patients with end-stage liver disease (ESLD) is common. However, electrolyte abnormalities, renal insufficiency, treatment with QT-prolonging drugs, and other factors known to prolong QT interval independently of liver disease occur frequently in ESLD. Moreover, elevated heart rate may be present in ESLD and result in spurious QTc prolongation if the Bazett formula is used for rate correction. It thus remains unclear whether QT prolongation in ESLD is directly caused by liver failure, or indirectly by these confounding factors. METHODS: Medical records of all patients (n = 437) who received orthotopic liver transplantation (OLTx) at our institution between 2008 and 2011 were reviewed. Data from 51 patients with available pre-OLTx dobutamine stress echo (DSE), post-OLTx ECG and without nonhepatic factors affecting QT interval duration were analyzed. For each patient, QT versus RR regression line was calculated from ECG tracings obtained during DSE. The QT interval on post-OLTx ECG was compared with the pre-OLTx QT predicted by the regression line for the same RR interval. RESULTS: QT interval shortened significantly post-OLTx (from 394 ± 47 to 364 ± 45 ms at RR interval 750 ± 144 ms; P < 0.002) when compared using the regression method. Corrected QT intervals calculated by Bazett and Fridericia formulas also shortened. Patients with prolonged QT pre-OLTx had significantly higher INR and lower serum albumin. CONCLUSION: ESLD impairs ventricular repolarization even in the absence of other known factors affecting repolarization. QT prolongation in ESLD is associated with impaired synthetic liver function.

Bradycardia alters Ca(2+) dynamics enhancing dispersion of repolarization and arrhythmia risk.

Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca(2+) transients and APs were measured optically from Langendorff rabbit hearts at high (150 × 150 µm(2)) or low (1.5 × 1.5 cm(2)) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR = 50 beats/min). Western blots and pharmacological interventions were used to elucidate the regional effects of bradycardia. As a result, bradycardia (SHR 50 beats/min) increased APDs gradually (time constant τf→s = 48 ± 9.2 s) and caused a secondary Ca(2+) release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 ± 9.7 ms after the Ca(2+) transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca(2+) release events leading to subcellular Ca(2+) waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation (P < 0.01, n = 5), enhanced DOR (r = 0.9277 ± 0.03, n = 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening (P < 0.05, n = 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)propan-1-one (K201; 1 µM), suppressed SCR and reduced APD at the base, thereby reducing DOR (P < 0.02, n = 5). Ventricular ectopy induced by bradycardia (n = 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca(2+) channel protein (Cav1.2α), Na(+)-Ca(2+) exchange (NCX1), voltage-gated Na(+) channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca(2+) ATPase 2a] that correlate with the SCR distribution and explain the molecular basis for SCR heterogeneities. In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations.

Accelerated junctional rhythm and nonalternans repolarization lability precede ventricular tachycardia in Casq2-/- mice.

BACKGROUND: Calsequestrin-2 (CASQ2) is a Ca(2+) buffering protein of myocardial sarcoplasmic reticulum. CASQ2 mutations underlie a form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The CPVT phenotype is recapitulated in Casq2 -/- mice. Repolarization lability (RL)-beat-to-beat variability in the T wave morphology-has been reported in long-QT syndrome, but has not been evaluated in CPVT. METHODS AND RESULTS: ECG from Casq2 -/- mice was evaluated with respect to heart rate (HR) and RL changes prior to onset of ventricular tachycardia (VT) to gain insight into arrhythmogenesis in CPVT. Telemetry from unrestrained mice (3-month-old males, 5 animals of each genotype) and ECG before and after isoproterenol administration in anesthetized mice was analyzed. Average HR in sinus rhythm (SR), occurrence of nonsinus rhythm and RL were quantified. HR was slower in Casq2 -/- animals. Accelerated junctional rhythm (JR) occurred more frequently in Casq2 -/- mice and often preceded VT. In Casq2 -/- mice, HR increased prior to VT onset, prior to onset of JR and on transition from JR to VT. RL increased during progression from SR to VT and after isoproterenol administration in Casq2 -/-, but not in Casq2+/+ animals. Isoproterenol did not increase repolarization alternans in either genotype. CONCLUSIONS: Accelerated JR, likely caused by triggered activity in His/Purkinje system, occurs frequently in Casq2 -/- mice. The absence of CASQ2 results in increased RL. The increase in HR and in RL precede onset of arrhythmias in this CPVT model. Nonalternans RL precedes ventricular arrhythmia in wider range of conditions than previously appreciated.

Anesthetic management of electrophysiological procedures for heart failure.

Recent advances in EP enabled significant improvement in the care for cardiac patient. Implantation of PMs or ICDs, CRT, and RFA of tachyarrhythmias represent EP procedures that significantly improve quality of life and outcome in selected patient populations. The complexity of the procedure and the off-site EP laboratory environment create a new, challenging scenario for the anesthesiologist. A complex medical history and a current physical status of a patient presenting for a procedure must be carefully weighed in when discussing the options of anesthesia care. The roles of individual anesthetics and anesthesia techniques need to be further evaluated to facilitate the procedure and optimize patient care.

Exercise-induced atrial and ventricular tachycardias in a patient with left ventricular noncompaction and normal ejection fraction.

We report a patient with ventricular and atrial tachycardias reproducibly induced during exercise testing. Atrial tachycardia, but no sustained ventricular tachycardia, was induced during electrophysiological study. Catecholaminergic polymorphic ventricular tachycardia was considered because of normal echocardiogram, family history of sudden death, and polymorphic appearance of some of the nonsustained ventricular tachycardia episodes. However, most episodes of ventricular tachycardia were monomorphic. Cardiac magnetic resonance diagnosed isolated left ventricular noncompaction.

Slow QT interval adaptation to heart rate changes in normal ambulatory subjects.

BACKGROUND: Clinical formulas for QT correction utilize instantaneous HR. We showed previously that longer-term HR affects QT duration. We extend these findings, identifying more accurate models of QT behavior. METHOD: Multiple models of QT dependence on HR were tested in 2 independent populations. Holter recordings were analyzed in population A (healthy volunteers, n = 14, 6 males, age 26.9 ± 12.3 yr). The hypotheses generated in population A were tested in an independent group population B, healthy volunteers, n = 15, 9 males, age 52.9 ± 15.6 yr). Linear models of QT interval dependence on a weighted average of RR intervals in the preceding 3 minutes were compared to models based on the immediately preceding RR interval (instantaneous HR). RESULTS: In population A, linear models based on RR intervals over the preceding minute performed better than the best nonlinear model based on the single RR interval immediately preceding the QT interval. Linear models including HR values preceding the QT interval by more than 60 s further improved model fit. This model hierarchy was confirmed in population B. Linear formula for QT correction based on exponential decay of HR effect with 60 s time constant outperformed Bazett and Fridericia formulas in both populations. CONCLUSIONS: QT duration in normal ambulatory subjects is affected by noninstantaneous HR, including HR history dating back more than 60 s. Exponential decay of this "memory effect" with time constant of 1 minute provides an accurate description of QT adaptation. This may be of clinical importance when HR is not steady.

Focal monomorphic ventricular tachycardia as the first manifestation of amyloid cardiomyopathy.

52-year-old patient presented with palpitation and well tolerated monomorphic ventricular tachycardia. He had normal echocardiogram and coronary angiogram 3 months prior to presentation. Surface EKG revealed regular wide-complex tachycardia with right bundle branch block morphology and right inferior axis. In conjunction with recent negative cardiac evaluation, this suggested idiopathic focal ventricular tachycardia from anterolateral basal left ventricle. CARTO based activation mapping confirmed the presence of VT focus in that area. Radiofrequency ablation at the site of perfect pacemap resulted in a partial suppression of the focus. Echocardiogram was subsequently performed because of progressive dyspnea. It revealed asymmetrical thickening of posterolateral left ventricle, with delayed enhancement on contrast magnetic resonance imaging. Fine needle aspiration of abdominal fat stained with Congo red confirmed the diagnosis of systemic AL amyloidosis due to IgG lambda-light chain deposition. Consequently, the patient underwent placement of implantable defibrillator and hematopoetic stem cell transplantation. He remains in excellent functional status 18 months after presentation.

Predictors of complications of endovascular chronic lead extractions from pacemakers and defibrillators: a single-operator experience.

BACKGROUND: National trends in chronic lead extractions from cardiac rhythm management (CRM) devices are on the rise. OBJECTIVE: The main objective of the study was to identify the predictors of complications of chronic lead extractions. METHODS: All patients who underwent endovascular chronic CRM lead extraction at our institution between 2002 and 2008 were included in this analysis. Demographic data as well as details of the extraction procedure and its complications within the ensuing 30 days were collected on all patients. RESULTS: Data of 212 consecutive patients (456 leads, age = 65 +/- 17 years, men 75%, left ventricular ejection fraction = 36 +/- 16%, coronary artery disease 80%, defibrillators 49%) were analyzed. There were a total of 26 (11.8%) complications in 25 patients including 9 (4.2%) major complications (death 1, hemothorax 4, pneumothorax 2, tamponade 1, stroke 1) and 17 (8.0%) minor complications. Independent predictors of any complications included a higher number of explanted right ventricular leads (HR = 3.51, P = 0.013). Explantation of ICD as opposed to a pacemaker device showed a strong trend toward significance (HR = 2.57, P = 0.053). An elevated white blood cell count also predicted major complications (HR = 1.52, P = 0.005). CONCLUSION: Predictors of complications after lead extraction procedures include a higher number of extracted leads and the presence of defibrillator as opposed to pacemaker leads. A new paradigm of the removal of all leads not connected to a device may, therefore, reduce the risk of complications from lead extraction procedures and deserves to be tested prospectively.

Short-long sequences prior to ventricular tachycardia onset: analysis of VAST trial electrograms.

BACKGROUND: The recently published Ventricular Arrhythmia Suppression Trial (VAST) found no effect of rate-smoothing (RS) algorithm on frequency of ventricular tachycardia (VT) episodes in patients with implantable defibrillator. A similar recent trial reported an opposite result. In order to determine possible reasons for the discrepancy between the trials and achieve better understanding of events preceding VT onset, we analyzed stored device electrograms preceding 162 VT episodes from 50 VAST trial patients with dual-chamber devices. RESULTS: In this analysis, short-long sequences were more common prior to polymorphic VTs than before monomorphic VTs. The proportion of VT episodes preceded by short-long sequences was lower during randomization to RS ON (5.3% vs 31.3%, P < 0.001). For patients with multiple episodes of monomorphic VT, there was higher interpatient than intrapatient variability in preceding RR intervals. When adjusting for this similarity of RR interval sequences preceding VT onset in individual patients, the difference in proportion short-long sequences between RS ON and RS OFF programming was no longer significant. CONCLUSION: Episodes of VT were preceded by stereotypic, patient-specific sequences of RR intervals in several VAST trial patients. RS reduced the percentage of VTs preceded by short-long sequences, but did not change overall VT incidence.

QT interval variability and adaptation to heart rate changes in patients with long QT syndrome.

BACKGROUND: Increased QT variability (QTV) has been reported in conditions associated with ventricular arrhythmias. Data on QTV in patients with congenital long QT syndrome (LQTS) are limited. METHODS: Ambulatory electrocardiogram recordings were analyzed in 23 genotyped LQTS patients and in 16 healthy subjects (C). Short-term QTV was compared between C and LQTS. The dependence of QT duration on heart rate was evaluated with three different linear models, based either on the RR interval preceding the QT interval (RR(0)), the RR interval preceding RR(0) (RR(-1)), or the average RR interval in the 60-second period before QT interval (mRR). RESULTS: Short-term QTV was significantly higher in LQTS than in C subjects (14.94 +/- 9.33 vs 7.31 +/- 1.29 ms; P < 0.001). It was also higher in the non-LQT1 than in LQT1 patients (23.00 +/- 9.05 vs 8.74 +/- 1.56 ms; P < 0.001) and correlated positively with QTc in LQTS (r = 0.623, P < 0.002). In the C subjects, the linear model based on mRR predicted QT duration significantly better than models based on RR(0) and RR(-1). It also provided better fit than any nonlinear model based on RR(0). This was also true for LQT1 patients. For non-LQT1 patients, all models provided poor prediction of QT interval. CONCLUSIONS: QTV is elevated in LQTS patients and is correlated with QTc in LQTS. Significant differences with respect to QTV exist among different genotypes. QT interval duration is strongly affected by noninstantaneous heart rate in both C and LQT1 subjects. These findings could improve formulas for QT interval correction and provide insight on cellular mechanisms of QT adaptation.

B-Cell lymphoproliferative disorder of an ICD pocket: a diagnostic puzzle in an immunosuppressed patient.

We present a case of a patient with lymphoma in an ICD pocket in the setting of posttransplant immune suppression. Infection of the ICD system was suspected and the correct diagnosis was established by biopsy.

Spatial indices of repolarization correlate with non-ST elevation myocardial ischemia in patients with chest pain.

Mild-to-moderate ischemia does not result in ST segment elevation on the electrocardiogram (ECG), but rather non-specific changes in the T wave, which are frequently labeled as non-diagnostic for ischemia. Robust methods to quantify such T wave heterogeneity can have immediate clinical applications. We sought to evaluate the effects of spontaneous ischemia on the evolution of spatial T wave changes, based on the eigenvalues of the spatial correlation matrix of the ECG, in patients undergoing nuclear cardiac imaging for evaluating intermittent chest pain. We computed T wave complexity (TWC), the ratio of the second to the first eigenvalue of repolarization, from 5-min baseline and 5-min peak-stress Holter ECG recordings. Our sample included 30 males and 20 females aged 63 ± 11 years. Compared to baseline, significant changes in TWC were only seen in patients with ischemia (n = 10) during stress testing, but not among others. The absolute changes in TWC were significantly larger in the ischemia group compared to others, with a pattern that seemed to depend on the severity or anatomic distribution of ischemia. Our results demonstrate that ischemia-induced changes in T wave morphology can be meaningfully quantified from the surface 12-lead ECG, suggesting an important opportunity for improving diagnostics in patients with chest pain.

Recent heart rate history affects QT interval duration in atrial fibrillation.

QT interval prolongation is associated with a risk of polymorphic ventricular tachycardia. QT interval shortens with increasing heart rate and correction for this effect is necessary for meaningful QT interval assessment. We aim to improve current methods of correcting the QT interval during atrial fibrillation (AF). Digitized Holter recordings were analyzed from patients with AF. Models of QT interval dependence on RR intervals were tested by sorting the beats into 20 bins based on corrected RR interval and assessing ST-T variability within the bins. Signal-averaging within bins was performed to determine QT/RR dependence. Data from 30 patients (29 men, 69.3±7.3 years) were evaluated. QT behavior in AF is well described by a linear function (slope ~0.19) of steady-state corrected RR interval. Corrected RR is calculated as a combination of an exponential weight function with time-constant of 2 minutes and a smaller "immediate response" component (weight ~ 0.18). This model performs significantly (p<0.0001) better than models based on instantaneous RR interval only including Bazett and Fridericia. It also outperforms models based on shorter time-constants and other previously proposed models. This model may improve detection of repolarization delay in AF. QT response to heart rate changes in AF is similar to previously published QT dynamics during atrial pacing and in sinus rhythm.

The link between abnormal calcium handling and electrical instability in acquired long QT syndrome--Does calcium precipitate arrhythmic storms?

Release of Ca(2+) ions from sarcoplasmic reticulum (SR) into myocyte cytoplasm and their binding to troponin C is the final signal form myocardial contraction. Synchronous contraction of ventricular myocytes is necessary for efficient cardiac pumping function. This requires both shuttling of Ca(2+) between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca(2+) release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity. Recent optical mapping data indicate that abnormal Ca(2+) handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca(2+) handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca(2+) elevation (SSCE), as well as more complex abnormalities of intracellular Ca(2+) handling detected by subcellular optical mapping in Langendorff-perfused hearts. The regional heterogeneities in Ca(2+) handling cause action potential (AP) heterogeneities through sodium-calcium exchange (NCX) activation and eventually overwhelm electrical coupling of the tissue. Divergent Ca(2+) dynamics among different myocardial regions leads to temporal instability of AP duration and - on the patient level - in T wave lability. Although T-wave alternans has been linked to cardiac arrhythmias, non-alternans lability is observed in pre-clinical models of the long QT syndrome (LQTS) and CPVT, and in LQTS patients. Analysis of T wave lability may provide a real-time window on the abnormal Ca(2+) dynamics causing specific arrhythmias such as Torsade de Pointes (TdP).