Heart Rate Variability Density Analysis (Dyx) and Prediction of Long-Term Mortality after Acute Myocardial Infarction.

AIMS: The density HRV parameter Dyx is a new heart rate variability (HRV) measure based on multipole analysis of the Poincaré plot obtained from RR interval time series, deriving information from both the time and frequency domain. Preliminary results have suggested that the parameter may provide new predictive information on mortality in survivors of acute myocardial infarction (MI). This study compares the prognostic significance of Dyx to that of traditional linear and nonlinear measures of HRV. METHODS AND RESULTS: In the Nordic ICD pilot study, patients with an acute MI were screened with 2D echocardiography and 24-hour Holter recordings. The study was designed to assess the power of several HRV measures to predict mortality. Dyx was tested in a subset of 206 consecutive Danish patients with analysable Holter recordings. After a median follow-up of 8.5 years 70 patients had died. Of all traditional and multipole HRV parameters, reduced Dyx was the most powerful predictor of all-cause mortality (HR 2.4; CI 1.5 to 3.8; P < 0.001). After adjustment for known risk markers, such as age, diabetes, ejection fraction, previous MI and hypertension, Dyx remained an independent predictor of mortality (P = 0.02). Reduced Dyx also predicted cardiovascular death (P < 0.01) and sudden cardiovascular death (P = 0.05). In Kaplan-Meier analysis, Dyx significantly predicted mortality in patients both with and without impaired left ventricular systolic function (P < 0.0001). CONCLUSION: The new nonlinear HRV measure Dyx is a promising independent predictor of mortality in a long-term follow-up study of patients surviving a MI, irrespectively of left ventricular systolic function.

Heart rate variability density analysis (Dyx) for identification of appropriate implantable cardioverter defibrillator recipients among elderly patients with acute myocardial infarction and left ventricular systolic dysfunction.

AIMS: Dyx is a new heart rate variability (HRV) density analysis specifically designed to identify patients at high risk for malignant ventricular arrhythmias. The aim of this study was to test if Dyx can improve risk stratification for malignant ventricular tachyarrhythmias and to test if the previously identified cut-off can be reproduced. METHODS AND RESULTS: This study included 248 patients from the CARISMA study with ejection fraction ≤40% after an acute myocardial infarction and an analysable 24 h Holter recording. All patients received an implantable cardiac monitor, which was used to diagnose the primary endpoint of near-fatal or fatal ventricular tachyarrhythmias likely preventable by an implantable cardioverter defibrillator (ICD), during a period of 2 years. A Dyx ≤ 1.96 was considered abnormal. The secondary endpoint was cardiovascular death. At enrolment 59 patients (24%) had a Dyx ≤ 1.96 and 20 experienced a primary endpoint. A Dyx ≤ 1.96 was associated with a significantly increased risk for malignant arrhythmias [hazards ratio (HR) = 4.36 (1.81-10.52), P = 0.001] and cardiovascular death [HR = 3.47 (1.38-8.74), P = 0.008]. Compared with important clinical risk parameters (age >70 years and QRS > 120 ms), Dyx ≤ 1.96 significantly added predictive value (P = 0.0066). CONCLUSIONS: Dyx was a better predictor of ventricular tachyarrhythmias than the traditional measures of HRV and heart rate turbulence, particularly in the elderly. Dyx might be a useful tool for better selection of ICD candidates in the elderly population, since a normal Dyx in this group was associated with a very low risk for malignant ventricular arrhythmias.ClinicalTrials.gov Identifier NCT00145119.

The effect of ICD programming on inappropriate and appropriate ICD Therapies in ischemic and nonischemic cardiomyopathy: the MADIT-RIT trial.

INTRODUCTION: The MADIT-RIT trial demonstrated reduction of inappropriate and appropriate ICD therapies and mortality by high-rate cut-off and 60-second-delayed VT therapy ICD programming in patients with a primary prophylactic ICD indication. The aim of this analysis was to study effects of MADIT-RIT ICD programming in patients with ischemic and nonischemic cardiomyopathy. METHODS AND RESULTS: First and total occurrences of both inappropriate and appropriate ICD therapies were analyzed by multivariate Cox models in 791 (53%) patients with ischemic and 707 (47%) patients with nonischemic cardiomyopathy. Patients with ischemic and nonischemic cardiomyopathy had similar incidence of first inappropriate (9% and 11%, P = 0.21) and first appropriate ICD therapy (11.6% and 14.1%, P = 0.15). Patients with ischemic cardiomyopathy had higher mortality rate (6.1% vs. 3.3%, P = 0.01). MADIT-RIT high-rate cut-off (arm B) and delayed VT therapy ICD programming (arm C) compared with conventional (arm A) ICD programming were associated with a significant risk reduction of first inappropriate and appropriate ICD therapy in patients with ischemic and nonischemic cardiomyopathy (HR range 0.11-0.34, P < 0.001 for all comparisons). Occurrence of total inappropriate and appropriate ICD therapies was significantly reduced by high-rate cut-off ICD programming and delayed VT therapy ICD programming in both ischemic and nonischemic cardiomyopathy patients. CONCLUSION: High-rate cut-off and delayed VT therapy ICD programming are associated with significant reduction in first and total inappropriate and appropriate ICD therapy in patients with ischemic and nonischemic cardiomyopathy.

The predictive value of CHADS2 risk score in post myocardial infarction arrhythmias - a Cardiac Arrhythmias and RIsk Stratification after Myocardial infArction (CARISMA) substudy.

BACKGROUND: Previous studies have shown substantially increased risk of cardiac arrhythmias and sudden cardiac death in post-myocardial infarction (MI) patients. However it remains difficult to identify the patients who are at highest risk of arrhythmias in the post-MI setting. The purpose of this study was to investigate if CHADS2 score (congestive heart failure, hypertension, age ≥75 years, diabetes and previous stroke/TCI [doubled]) can be used as a risk tool for predicting cardiac arrhythmias after MI. METHODS: The study included 297 post-MI patients from the CARISMA study with left ventricular ejection fraction (LVEF) ≤40%. All patients were implanted with an implantable cardiac monitor (ICM) within 5 to 21 days post-MI and followed every three months for two years. Atrial fibrillation, bradyarrhythmias and ventricular tachycardias were diagnosed using the ICM, pacemaker or ICD. Patients were stratified according to CHADS2 score at enrollment. Congestive heart failure was defined as LVEF ≤40% and NYHA class II, III or IV. RESULTS: We found significantly increased risk of an arrhythmic event with increasing CHADS2 score (CHADS2 score=1-2: HR=2.1 [1.1-3.9], p=0.021, CHADS2 score ≥ 3: HR=3.7 [1.9-7.1], p<0.001). This pattern was identical when dividing the arrhythmias into subgroups of atrial fibrillation, ventricular tachycardias and bradyarrhythmias. CHADS2 score was similarly associated with the development of major cardiovascular events defined as reinfarction, stroke, and hospitalization for heart failure or cardiovascular death. CONCLUSION: In the post-MI setting, CHADS2 score efficiently identifies populations at high risk for cardiac arrhythmias.

Senior academic physicians and retirement considerations.

An increasing number of academic senior physicians are approaching their potential retirement in good health with accumulated clinical and research experience that can be a valuable asset to an academic institution. Considering the need to let the next generation ascend to leadership roles, when and how should a medical career be brought to a close? We explore the roles for academic medical faculty as they move into their senior years and approach various retirement options. The individual and institutional considerations require a frank dialogue among the interested parties to optimize the benefits while minimizing the risks for both. In the United States there is no fixed age for retirement as there is in Europe, but European physicians are initiating changes. What is certain is that careful planning, innovative thinking, and the incorporation of new patterns of medical practice are all part of this complex transition and timing of senior academic physicians into retirement.

High-degree atrioventricular block complicating ST-segment elevation myocardial infarction in the era of primary percutaneous coronary intervention.

AIMS: Primary percutaneous coronary intervention (pPCI) has replaced thrombolysis as treatment-of-choice for ST-segment elevation myocardial infarction (STEMI). However, the incidence and prognostic significance of high-degree atrioventricular block (HAVB) in STEMI patients in the pPCI era has been only sparsely investigated. The objective of this study was to assess the incidence, predictors and prognostic significance of HAVB in STEMI patients treated with pPCI. METHODS AND RESULTS: This study included 2073 STEMI patients treated with pPCI. The patients were identified through a hospital register and the Danish National Patient Register. Both registers were also used to establish the diagnosis of HAVB. All-cause mortality was the primary endpoint. During a median follow-up of 2.9 years [interquartile range (IQR) 1.8-4.0] 266 patients died. High-degree atrioventricular block was documented in 67 (3.2%) patients of whom 25 died. Significant independent predictors of HAVB included right coronary artery occlusion, age >65 years, female gender, hypertension, and diabetes. The adjusted mortality rate was significantly increased in patients with HAVB compared to patients without HAVB [hazard ratio = 3.14 (95% confidence interval 2.04-4.84), P< 0.001]. A landmark-analysis 30 days post-STEMI showed equal mortality rates in the two groups. CONCLUSION: The incidence of HAVB in STEMI patients treated with pPCI has been reduced compared with reports from the thrombolytic era. However, despite this improvement high-degree AV block remains a severe prognostic marker in the pPCI era. The mortality rate was only increased within the first 30 days. High-degree atrioventricular block patients who survived beyond this time-point thus had a prognosis equal to patients without HAVB.

Myocardial performance is reduced immediately prior to ventricular ectopy.

BACKGROUND: We recently demonstrated local voltage potentials indicating conduction impairment and block in the sinus beats preceding ventricular premature beats (VPBs) originating in the ventricular outflow tracts. OBJECTIVE: The purpose of this study was to test the hypothesis that impairment of impulse conduction would also lead to changes in the contractile performance of sinus beats preceding ventricular ectopy using Tissue Doppler echocardiography. METHODS: Twenty-three consecutive patients with VPBs were examined in the apical 4-chamber view with a frame rate of 150 Hz (GE VIVID VII). Eleven patients had no structural heart disease, 5 had dilated cardiomyopathy, 4 had ischemic heart disease, 2 had arrhythmogenic right ventricular dysplasia, and 1 had aortic stenosis. The ectopy originated in the ventricular outflow tracts in 15 patients and in the left ventricle 8. Eleven of the patients underwent radiofrequency ablation of the VPBs. RESULTS: Tissue Doppler imaging demonstrated a highly statistically significant decrease in myocardial performance in the last sinus beat before the VPB compared to earlier sinus beats. Thus, ejection time (time to peak end-systolic contraction) and peak systolic velocity shortened significantly (P <.001 for both) with a subsequent reduction in systolic shortening (end-systolic displacement; P <.001). CONCLUSION: Ventricular ectopy is preceded by a significant decrease in myocardial performance in the last sinus beat preceding VPBs as observed in consecutive patients with a broad variety of heart conditions pointing to a mutual underlying electrical mechanism (ie, localized conduction block confined to an area surrounding the ectopic pacemaker).

Treating cardiac arrhythmias detected with an implantable cardiac monitor in patients after an acute myocardial infarction.

OPINION STATEMENT: Using an implantable cardiac monitor (ICM) in patients with acute myocardial infarction (MI) allows continuous electrocardiogram monitoring and provides a much more detailed picture of the incidence of brady- and tachyarrhythmias than conventional follow-up. The CARISMA study was the first to use the ICM in post-MI patients with moderate to severe left ventricular systolic dysfunction. Atrial fibrillation (AF) events lasting longer than 30 s were associated with an almost threefold increase in the risk of major cardiac events. This confirms the current definition of clinically significant AF episodes, as patients with episodes of shorter duration were not at increased risk. The association of AF to progressive heart failure, reinfarction, and cardiovascular death underlines the need for an intensive follow-up of post-MI patients with new-onset AF in order to reveal underlying causes of AF such as progressive left ventricular dysfunction or myocardial ischemia. Asymptomatic, especially nightly, bradycardia episodes including high-degree 2°-3° atrioventricular (AV) block, sinus bradycardia, and sinus arrest were frequently documented by ICM in the CARISMA study. Ten percent of patients experienced high-degree 2°-3° AV block, of which the main part was nightly and asymptomatic, and 50% of all cardiovascular deaths occurred in this group, most from severe heart failure. Therefore, in post-MI patients with paroxysmal high-degree AV block, pacemaker implantation should be done, and in the case of left ventricular dysfunction (LVEF ≤ 35%), an implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator (ICD/CRT-D) may be indicated. Nonsustained ventricular tachycardia (VT) is very frequent in post-MI patients, and in the CARISMA study, high-risk patients with nonsustained VT were implanted with an ICD. Furthermore, in 10% of the patients, the ICM recorded nonsustained VT episodes of ≥ 16 beats per minute, resulting in a twofold increase in the risk for cardiac death. Thus, patients with nonsustained VT should undergo careful investigation, and we recommend a repeat echocardiography and electrophysiological stimulation in these patients. Patients with sustained VT or VF should receive an ICD.

Clinical significance of late high-degree atrioventricular block in patients with left ventricular dysfunction after an acute myocardial infarction--a Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) substudy.

BACKGROUND: High-degree atrioventricular block (HAVB) is a frequent complication in the acute stages of a myocardial infarction associated with an increased rate of mortality. However, the incidence and clinical significance of HAVB in late convalescent phases of an AMI is largely unknown. The aim of this study was to assess the incidence and prognostic value of late HAVB documented by continuous electrocardiogram (ECG) monitoring in post-AMI patients with reduced left ventricular function. METHODS: The study included 286 patients from the CARISMA study with AMI and left ventricular ejection fraction of 40% or less. An insertable loop recorder was implanted 5 to 21 days after AMI for incessant arrhythmia surveillance. Furthermore, ECG documentation was supplemented by a 24-hour Holter monitoring conducted at week 6 post-AMI. The clinical significance of HAVB occurring more than 21 days after AMI was examined with respect to development of major heart failure events and major ventricular tachyarrhythmic events. RESULTS: During a median follow-up of 1.9 years (interquartile range 0.9-2.0), late HAVB was documented in 30 patients. The risk of major heart failure events (hazard ratio [HR] 4.08 [1.38-12.09], P = .01) and major ventricular tachyarrhythmic events (HR = 5.41 [1.88-15.58], P = .002) were significantly increased in patients who developed late HAVB. CONCLUSION: High-degree atrioventricular block documented by continuous ECG monitoring occurring more than 3 weeks after AMI is a frequent complication in post-AMI patients with left ventricular dysfunction. Furthermore, HAVB is associated with ominous prognostic implications of both potentially lethal arrhythmias and heart failure.

Risk markers of late high-degree atrioventricular block in patients with left ventricular dysfunction after an acute myocardial infarction: a CARISMA substudy.

AIMS: High-degree atrioventricular block (HAVB) after acute myocardial infarction (AMI) is associated with increased risk of mortality. Risk markers and predictors of HAVB occurring after AMI are largely unknown. The aim of this study was to assess the predictive value of risk markers derived from a series of non-invasive and invasive tests for the development of HAVB documented by an implantable loop recorder (ILR) in late convalescent phases of an AMI. METHODS AND RESULTS: The study included 292 patients with AMI and subsequent left ventricular dysfunction without prior HAVB or implanted pacemaker. An ILR was implanted for continuous arrhythmia surveillance. Risk stratification testing was performed at inclusion and 6 weeks after AMI. The tests included echocardiography, electrocardiogram (ECG), 24 h Holter monitoring, and an invasive electrophysiological study. High-degree atrioventricular block was documented in 28 (10%) patients during a median follow-up of 2.0 (0.4-2.0) years. Heart rate variability (HRV) measures and non-sustained ventricular tachycardia occurring at the week 6 Holter monitoring were highly predictive of HAVB. Power law slope <-1.5 ms(2)/Hz was the most powerful HRV parameter (HR = 6.02 [2.08-17.41], P < 0.001). CONCLUSION: Late HAVB development in post-AMI patients with left ventricular dysfunction can be predicted by risk stratification tests. Measures of HRV reflecting autonomic dysfunction revealed the highest predictive capabilities.

Effects of postectopic heart rate turbulence on measures of heart rate variability in patients after an acute myocardial infarction.

BACKGROUND: Heart rate (HR) turbulence lasting up to 15 beats after ventricular premature beats (VPBs) may have profound effects on HR variability measures. Aim of this study was to examine the effects of HR turbulence on HR variability measures. METHODS: We developed an algorithm, which deletes 15 consecutive RR intervals after VPBs and examined the effects of the HR turbulence removal on the HR variability measures in patients after an acute myocardial infarction (AMI). Two hundred and sixty seven patients with left ventricular ejection fraction (LVEF) ≤ 0.40 and occurrence of VPBs were included in the study. Differences (%) between original HR data and HR turbulence edited data were compared. RESULTS: HR turbulence editing had variable effects on different HR variability indexes. Ultra low (ULF) and very low frequency (VLF) spectral components were mostly affected by the HR turbulence removal. Both ULF and VLF decreased significantly both at baseline Holter recordings (ULF: P = 0.006, VLF: P = 0.031) and at 6 weeks from AMI (ULF: P < 0.001, VLF: P = 0.001). The number of VPBs had a marked influence on results, e.g., when the number of VPBs exceeded the highest decile (≈50 VPBs/hour), the ULF and VLF spectral component were >30% lower after removal of turbulence. In addition, the prediction of arrhythmic events by ULF component improved after turbulence removal (AUC: 0.69 ->0.74). CONCLUSIONS: HR turbulence affects HR variability measures, especially the ULF and VFL spectral components. Editing of the HR turbulence should be considered when HR variability is measured from Holter recordings.

The incidence and prognostic significance of new-onset atrial fibrillation in patients with acute myocardial infarction and left ventricular systolic dysfunction: a CARISMA substudy.

BACKGROUND: The incidence and risk associated with new-onset atrial fibrillation (AF) occurring after discharge in patients with acute myocardial infarction (MI) remains unknown. OBJECTIVE: This study sought to describe the incidence and clinical risk associated with postdischarge new-onset AF in post-MI patients with left ventricular systolic dysfunction. METHODS: The population included 271 post-MI patients with left ventricular ejection fraction ≤ 40% and no history of previous AF from the Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction (CARISMA) study. All patients were implanted with an implantable cardiac monitor and followed up every 3 months for 2 years. Major cardiovascular events were defined as reinfarction, stroke, hospitalization for heart failure, or death. RESULTS: The risk of new-onset AF is highest during the first 2 months after the acute MI (16% event rate) and decreases until month 12 post-MI, after which the risk for new-onset AF is stable. The risk of major cardiovascular events was increased in patients with AF events ≥ 30 seconds (hazard ratio [95% CI] = 2.73 [1.35 to 5.50], P = .005), but not in patients with AF events lasting <30 seconds (hazard ratio [95% CI] = 1.17 [0.35 to 3.92], P = .80). More than 90% of all recorded AF events were asymptomatic. CONCLUSION: Using an implantable cardiac monitor, the incidence of new-onset AF was found to be 4-fold higher than earlier reported. In the study population, in which treatment with beta-blockers was optimized, the vast majority of AF events were asymptomatic, emphasizing the importance of using continuous monitoring for studies concerning AF in heart failure patients. A duration of 30 seconds or more identified clinically important AF episodes documented by an implantable cardiac monitor.

Autonomic dysfunction and new-onset atrial fibrillation in patients with left ventricular systolic dysfunction after acute myocardial infarction: a CARISMA substudy.

BACKGROUND: Atrial fibrillation (AF) increases morbidity and mortality in patients with previous myocardial infarction and left ventricular systolic dysfunction. The purpose of this study was to identify patients with a high risk for new-onset AF in this population using invasive and noninvasive electrophysiological tests. METHODS: The study included 271 patients from the Cardiac Arrhythmias and RIsk Stratification after Myocardial InfArction (CARISMA) study with an acute myocardial infarction (AMI) and left ventricular ejection fraction ≤40% without previous AF at enrollment. Within 21 days after the AMI, an implantable loop recorder was inserted and used to diagnose AF over the 2-year study duration. The following tests were performed: heart rate variability (HRV) and turbulence (HRT) analyses from repeated 24-hour Holter recordings, 2-dimensional (2D)-echocardiograms, exercise test, and programmed electrophysiologic stimulation. RESULTS: A total of 101 patients (37%) developed AF during the study. Predictive measures included several indexes of HRV including reduced low-frequency (LF) power from spectral HRV analysis (adjusted HR = 1.6, P = 0.034), HRT slope ≤2.5 (HR = 1.6, P = 0.032) and Detrended Fluctuation Analysis (DFA1) from HRV analysis (HR = 1.8, P = 0.011); all are measures of cardiac autonomic nervous system dysfunction. Combined with age >60 years, low values for LF, HRT slope, and DFA1 provided a powerful risk score for prediction of new-onset AF (1-2 points: HR = 4.3, P = 0.001, 3-4 points: HR = 7.0, P < 0.001). CONCLUSION: Abnormal HRV and HRT parameters, which are associated with disturbances in the cardiac autonomic regulation, are associated with increased risk of new-onset AF independently of conventional clinical risk variables.

Diastolic dysfunction predicts new-onset atrial fibrillation and cardiovascular events in patients with acute myocardial infarction and depressed left ventricular systolic function: a CARISMA substudy.

AIMS: The aim of this study was to investigate the association between diastolic dysfunction and long-term occurrence of new-onset atrial fibrillation (AF) and cardiac events in patients with acute myocardial infarction (AMI) and left ventricular (LV) systolic dysfunction. METHODS AND RESULTS: The study was performed as a substudy on the CARISMA study population. The CARISMA study enrolled 312 patients with an AMI and LV ejection fraction

Heart rhythm at the time of death documented by an implantable loop recorder.

AIMS: The aims of this study were to describe arrhythmias documented with an implantable loop recorder (ILR) in post-acute myocardial infarction (AMI) patients with left ventricular dysfunction at the time of death and to establish the correlation to mode of death. METHODS AND RESULTS: Post-mortem ILR device interrogations were analysed from patients dying in the CARISMA study. Mode of death was classified by a modified CAST classification. Twenty-six patients died with an implanted ILR. Of these, 16 had an electrocardiogram recorded at the time of death. Ventricular tachycardia (VT)/ventricular fibrillation (VF) was terminal rhythm in eight patients and bradyarrhythmias were observed in another eight patients. Of the deaths with peri-mortem recordings, seven were classified as sudden cardiac death (SCD). In six of these, VF was documented at the time of death. Six monitored deaths were classified as non-SCD (NSCD) of which only two had recordings of VT/VF, whereas four had bradyarrhythmias. All peri-mortem recordings in non-cardiac death (NCD) were bradyarrhythmia. CONCLUSION: Long-term monitoring in a population of post-AMI patients with left ventricular ejection fraction < or =40% showed that VT/VF and bradyarrhythmia each accounted for half of the recorded events at the time of death. The ILR confirmed that ventricular tachyarrhythmias are associated primarily with SCD, whereas bradyarrhythmias and electromechanical dissociation seems dominant in NSCD and NCD. The study was registered at ClinicalTrials.gov: NCT00145119.

T(peak)T(end) interval in long QT syndrome.

BACKGROUND: The T(peak)T(end) (T(p)T(e)) interval is believed to reflect the transmural dispersion of repolarization. Accordingly, it should be a risk factor in long QT syndrome (LQTS). The aim of the study was to determine the effect of genotype on T(p)T(e) interval and test whether it was related to the occurrence of syncope. METHODS: Electrocardiograms were taken in 95 patients with LQTS drawn from the Danish long QT registry (44 patients with KvLQT1, 43 with HERG, and 8 with SCN5A mutations) and manually evaluated for the QT, QT(peak), and RR interval. RESULTS AND CONCLUSION: (1) T(p)T(e) cannot be used to distinguish symptomatic from asymptomatic patients with LQTS; (2) HERG patients have longer T(p)T(e) than KvLQT1 patients; and (3) there is no need to heart rate-correct T(p)T(e) intervals in patients with LQTS.

Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.

INTRODUCTION: The Brugada Syndrome (BrS), an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in four different genes leading to a loss of function in sodium and calcium channel activity. Although the transient outward current (I(to)) is thought to play a prominent role in the expression of the syndrome, mutations in I(to)-related genes have not been identified as yet. METHODS AND RESULTS: One hundred and five probands with BrS were screened for ion channel gene mutations using single strand conformation polymorphism (SSCP) electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 (MiRP2) was detected in one proband. The R99H mutation was found 4/4 phenotype positive and 0/3 phenotype-negative family members. Chinese hamster ovary (CHO)-K1 cells were co-transfected using wild-type (WT) or mutant KCNE3 and either WT KCND3 or KCNQ1. Whole-cell patch clamp studies were performed after 48 hours. Interactions between Kv4.3 and KCNE3 were analyzed in co-immunoprecipitation experiments in human atrial samples. Co-transfection of R99H-KCNE3 with KCNQ1 produced no alteration in current magnitude or kinetics. However, co-transfection of R99H KCNE3 with KCND3 resulted in a significant increase in the I(to) intensity compared to WT KCNE3+KCND3. Using tissues isolated from left atrial appendages of human hearts, we also demonstrate that K(v)4.3 and KCNE3 can be co-immunoprecipitated. CONCLUSIONS: These results provide definitive evidence for a functional role of KCNE3 in the modulation of I(to) in the human heart and suggest that mutations in KCNE3 can underlie the development of BrS.

Electrophysiological study and 'slow' ventricular tachycardia predict appropriate therapy: results from a single-centre implantable cardiac defibrillator follow-up.

AIMS: To account for appropriate and inappropriate therapies and cardiac death (CD) in a cohort of consecutive implantable cardiac defibrillator (ICD) eligible patients and to identify baseline predictors of these outcomes. METHODS AND RESULTS: During follow-up of 288 consecutive ICD-treated patients, clinical, biochemical, echocardiographic, arteriographic, and electrophysiological (EP) data at baseline were individually matched with survival data and electrograms retrieved during device interrogation. Predictors of therapy and CD were identified by multivariate analyses. Eighty-eight per cent of cases were secondary prevention and 12% were primary prevention. About 770 patient-years of ICD follow-up were analysed. Median follow-up was 22.7 months. Forty-eight per cent of patients had appropriate therapy for at least one ventricular tachyarrhythmia. Seventy per cent of tachycardias were successfully treated with anti-tachy pacing alone. Overall risk of therapy was higher for patients with ischaemic heart disease (IHD) than with non-IHD (51 vs. 37%; P = 0.049). Low left ventricular ejection fraction (LVEF), positive EP study, and 'slow' ventricular tachycardia predicted appropriate therapy. Cardiac death was predicted by nephropathy, low LVEF, amiodarone use, and supraventricular tachycardia (SVT). Inappropriate therapy affected 12.2% of patients and was predicted by known SVT and IHD. CONCLUSION: Electrophysiological study and slow VT predicted appropriate therapy. Amiodarone use predicted CD. Inappropriate therapy remains an important issue largely predictable by SVT.