Cardiac resynchronization therapy improves psycho-cognitive performance in patients with heart failure.

BACKGROUND: Reduced cognitive performance and high prevalence of depression have been reported in patients with congestive heart failure (CHF) and severe left ventricular dysfunction. However, effects of contemporary device therapy on cognitive performance and depression symptoms have not been studied thoroughly. METHODS: Seventy-four consecutive CHF patients-45 receiving a biventricular defibrillator (CRT-D) and 29 receiving an implantable single or dual-chamber defibrillator (ICD) as a control group-were enrolled in this investigator-initiated, prospective, controlled, and investigator-blinded study. A set of neuropsychological tests (mini-mental state examination, DemTect, age-concentration test, and Beck depression inventory) was performed before, at 3 and at 6 months after device implantation. RESULTS: DemTect-score improved significantly (F = 7.8; P = 0.007) after CRT-D-implantation compared with ICD. Age-concentration test revealed better concentration ability after CRT-D-implantation (F = 8.3; P = 0.005) compared with ICD. Under CRT-D mini-mental state examination showed a significant improvement (F = 4.2; P = 0.043). CRT with defibrillator therapy also improved depression revealed by beck depression inventory (F = 14.7; P< 0.001) compared with ICD. CONCLUSION: This prospective study is the first to demonstrate psycho-cognitive improvement by resynchronization therapy in CHF patients with severe left ventricular dysfunction. In contrast to ICD therapy, the beneficial effect of CRT-D on psycho-cognitive performance might be attributed to improved cardiac function and haemodynamics.

Clinical relevance of slow ventricular tachycardia in heart failure patients with primary prophylactic implantable cardioverter defibrillator indication.

AIMS: Implantable cardioverter defibrillators (ICDs) have shown to reduce all-cause mortality in heart failure patients. In SCD-HeFT study, ICDs were programmed with a detection zone of ≥ 187 b.p.m. Thus, the incidence and clinical significance of slower ventricular tachycardias (VTs) in these patients remains largely unknown, though clinically important for device selection, programming, and follow-up. METHODS AND RESULTS: We prospectively studied symptomatic heart failure patients with an indication for a primary prophylactic ICD with or without concomitant resynchronization therapy according to SCD-HeFT inclusion criteria. Devices were programmed to an additional monitor zone for slow VTs at heart rates 130-186 b.p.m. Two hundred consecutive patients (86% male) were followed for a mean of 509 ± 308 days. One hundred and thirty-seven patients (68.5%) were New York Heart Association class III, 75 patients (37.5%) were on cardiac resynchronization therapy, and 124 (62%) had ischaemic cardiomyopathy. We observed 473 VT episodes in 36 patients (18%) and 131 ventricular fibrillation episodes in 30 patients (15%). Ventricular tachycardia overall occurred in 40 patients (20%). The incidence of slow VTs was low in only 12 patients (6%). No patient with slow VT suffered from syncope, palpitation, or decompensation leading to hospitalization. We did not find any reliable predictor for increased long-term risk of slow VTs. CONCLUSION: Incidence of slow VTs in a typical heart failure population with primary prophylactic ICD-implantation ± resynchronization therapy is very low. Slow VTs detected in the ICD monitor zone remained clinically asymptomatic. Thus, single chamber and atriobiventricular ICDs with a VT/ventricular fibrillation zone of ≥ 187 b.p.m. and one burst before shock delivery might be sufficient and pragmatic for the vast majority of these patients.

Stable cystatin C serum levels confirm normal renal function in patients with dronedarone-associated increase in serum creatinine.

Dronedarone is a new antiarrhythmic drug for patients with nonpermanent atrial fibrillation (AF). A relatively consistent finding in all trials studying dronedarone was a moderate but significant elevation of serum creatinine. Since dronedarone competes for the same organic cation transporter in the distal renal tubule with creatinine, serum creatinine and its derived estimated glomerular filtration rate might not reflect true renal function in patients on dronedarone. We therefore investigated alternative markers for renal function in these patients. We prospectively included 20 patients with nonpermanent AF in whom dronedarone 400 mg twice daily was started. Patients had normal renal function and serum creatinine; serum cystatin C and creatinine clearance were measured before treatment and 10 and 90 days after treatment started. Mean serum creatinine level for all 20 patients at baseline (day 0) was 84.55 ± 12.14 and 87.8 ± 17.59 µmol/L on day 10. This slight increase in all patients was not significant. Patients were now divided into the predefined groups of "increased creatinine" (increase in serum creatinine level > 1 standard deviation) and "not increased creatinine." Patients with increased creatinine levels (n = 5) showed a significant elevation of serum creatinine levels from day 0 to day 10 (82.4 ± 9.18 to 104.4 ± 12.74 µmol/L; P = .003), whereas change in serum creatinine levels in the not increased creatinine group (n = 15) was not significant. Serum cystatin C levels remained stable in both of these groups (increased creatinine group: 0.76 ± 0.08 to 0.78 ± 0.08 mg/L; P = .65; not increased creatinine group: 0.77 ± 0.108 to 0.77 ± 0.107 mg/L; P = .906). In conclusion, cystatin C represents an easily available and reliable biomarker for estimation of true renal function in patients on dronedarone treatment.

Ablation of typical right atrial flutter in patients with pulmonary hypertension.

BACKGROUND: RF ablation for cavotricuspid isthmus (CTI) dependent flutter is an established therapy. Right atrial hypertrophy and enlargement are associated with the occurrence of cavotricuspid isthmus dependent flutter. Therefore, patients with pulmonary hypertension (PAH) are prone to atrial arrhythmias like cavotricuspid isthmus dependent flutter. However, the influence of PAH on typical atrial flutter ablation procedure has not been systematically examined. METHODS: In a retrospective single-centre analysis data of patients undergoing an ablation procedure for cavotricuspid isthmus dependent flutter between January 2007 and October 2009 at Hannover Medical School, Germany were analysed. Only procedures performed by experienced electrophysiologists with an 8mm RF-ablation catheter were included. Data for 196 patients were analysed. Thirty-eight patients were identified with PAH and were compared to 158 patients without PAH for procedural ablation parameters, procedure time, ablation time, ablation points and fluoroscopy time. RESULTS: A bidirectional block of the CTI was achieved in all patients. Patients with severe PAH had a significantly longer procedure time (78±40 min vs. 62±29 min; p=0.033), total ablation time (20±11 min vs. 15±9 min; p=0.02) and more ablation lesions (26±16 vs. 19±12; p=0.018) as compared to patients without PAH. CONCLUSION: Cavotricuspid isthmus dependent flutter ablation in patients with PAH is associated with longer procedure duration and a greater amount of cumulative tissue ablation needed to achieve bidirectional block of the CTI compared to patients without pulmonary hypertension.

Sustained risk of recurrent thromboembolic events in patients with patent foramen ovale and paradoxical embolism: long-term follow-up over more than 15 years.

BACKGROUND: Patients with patent foramen ovale (PFO) and cryptogenic stroke are at risk of recurrence. Therapeutic regimens range from no treatment to anticoagulation treatment to surgical or interventional closure. However, long-term follow-up is only available for up to 4 years. METHODS: Among ~5,000 transesophageal echocardiographies in stroke/TIA-patients between 1988 and 1997, a PFO was found and considered a possible mediator for the neurological event in 97 patients. In these patients, the PFO was judged to be responsible for the neurological event. Patients with cardiac or other reasons for embolism were excluded. The therapy for stroke was chosen by the attending physician. Follow-up information was obtained through telephone interviews. RESULTS: Follow-up was available for 86 patients (89%) with a mean period of 15.4 years (range, 11.2-25.9 years). Thirteen patients (15%) suffered from recurrent ischemic events (7 TIAs, 5 strokes, 1 peripheral embolism) after a mean period of 4.9 years. Four patients died, not associated with recurrent thromboembolism. The risk of recurrence was increased over the entire length of the mean follow-up period. The occurrence of recurrent events was not associated with differences in baseline data, the presence of ASA, PFO size or the chosen treatment. CONCLUSION: In patients with paradoxical embolism, recurrent ischemic events are frequent despite medical therapy. These events are not limited to the early years after the index event; this long-term follow-up revealed a risk of occurrence over the entire follow-up. These patients have a sustained risk of recurrence, requiring lifetime protection, which should be considered in tailoring individual therapeutic strategies.

The impact of cardiac resynchronization therapy on the incidence of ventricular arrhythmias in mild heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) decreases mortality, improves functional status, and induces reverse left ventricular (LV) remodeling in selected populations. However, the effect of CRT on ventricular arrhythmias is controversial. This is particularly important among patients with mild heart failure (HF), in whom sudden death is a leading cause of mortality. OBJECTIVE: This study sought to assess the impact of CRT on ventricular arrhythmias in mild HF. METHODS: The REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study is a multicenter randomized, double-blind trial of CRT among patients with mild systolic HF. The time to first appropriate, treated ventricular tachycardia/ventricular fibrillation (VT/VF) episode or spontaneous sustained VT in cardiac resynchronization therapy plus defibrillation device (CRT-D) patients was compared between groups, as were predictors of VT/VF. RESULTS: The study randomized 508 patients who received CRT-D devices. There were no significant demographic differences between groups. There were no differences in VT/VF episodes or VT storm between groups. Specifically, in the CRT ON group, the estimated event rate was 18.7% at 2 years, compared with 21.9% in the CRT OFF group (hazard ratio 1.05, P = .84). However, among CRT ON patients, those with reverse remodeling had a reduced incidence of VT/VF compared with those without remodeling (5.6% vs. 16.3%, hazard ratio 0.31, P = .001). CONCLUSION: CRT for up to 2 years does not impact VT/VF in mild HF despite marked clinical and remodeling effects of pacing. This neutral effect may be attributable to competing antiarrhythmic effects of reverse remodeling and proarrhythmic effect of pacing. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov/ct2/show/NCT00271154.

Left ventricular assist improves autonomic imbalance in patients with persistent myocardial dysfunction.

BACKGROUND: Left ventricular assist devices (LVAD) are an effective therapeutic option for end-stage heart failure (HF). Reduced heart rate variability (HRV) as a result of autonomic derangement is evident in chronic heart failure and several studies have established the independent prognostic value of HRV in chronic heart failure. OBJECTIVE: In the present study we investigated whether autonomic function is restored in patients after LVAD implantation with persistent, severely depressed left ventricular function. METHODS: Ambulatory Holter ECG recordings were collected in heart failure patients with an LVAD (n=8) und age-matched heart failure patients without an LVAD (n=7) both on optimal medical therapy. Cardiac dimensions and function were assessed by echocardiography or angiography. RESULTS: Analysis for heart rate variability revealed reduced SDNN (67±4 ms), SDANN (56±4 ms) and triangular index (18±1) in heart failure patients on optimal medical therapy. However patients with LVAD demonstrated a restoration in heart rate variability with normal SDNN (108±9 ms), SDANN (103±8 ms) and triangular index (29±2). Compared to patients without LVAD this difference was statistically significant (p<0.01). CONCLUSIONS: In end-stage heart failure patients autonomic imbalance indicated by severely reduced heart rate variability is restored after LVAD implantation with unloading of the failing heart.

Cryoballoon pulmonary vein isolation temporarily modulates the intrinsic cardiac autonomic nervous system.

PURPOSE: Modulation of the intrinsic cardiac autonomic nervous system (ICANS) has been described to occur during radiofrequency pulmonary vein (PV) isolation for paroxysmal atrial fibrillation (AF) and has been controversially proposed to increase clinical success. Energy source used for PV isolation might influence ICANS modulation. The effect of balloon-delivered cryoenergy on the ICANS is unknown. We conducted a study investigating acute periprocedural effect on ICAN as well as changes in heart rate variability (HRV) for standard deviation of normal-to-normal intervals (SDNN) and triangular index (TI) as surrogates for ICANS modulation after cryoballoon PV isolation. METHODS: Fourteen consecutive patients without structural heart disease underwent cryoballoon PV isolation for paroxysmal atrial fibrillation. Acute changes in heart rate requiring pacing during the procedure were recorded. HRV was tested by Holter ECG for SDNN and TI before ablation and after 1 week, 1 month, and 3 months following ablation. RESULTS: Fifty-five out of 56 PV were isolated (98%) with short-term 6-month freedom from paroxysmal AF of 64% by one single procedure. Five patients (36%) showed significant bradycardia during balloon thawing requiring temporary pacing. HRV decreased significantly immediately after PV isolation for both SDNN and TI until 1 month, gradually normalizing toward 3 months follow-up. HRV modulation was not different between patients with or without AF recurrences. CONCLUSIONS: Cryoballoon PV isolation significantly modulates the ICANS, but only temporarily for up to 3 months, measured by HRV changes after ablation.

Implantable defibrillator therapy for ventricular tachyarrhythmia in left ventricular assist device patients.

AIMS: Ventricular arrhythmias (VA) occur frequently after permanent left ventricular assist device (LVAD) implantation in end stage heart failure. Left ventricular assist device patients require rhythm control in contrast to patients with biventricular support. However, the rationale for implantable cardioverter-defibrillator (ICD) utilization in LVAD patients remains unclear. This study investigated the safety and efficacy of primary prevention ICD therapy and the rate of appropriate ICD interventions in LVAD patients. METHODS AND RESULTS: We prospectively collected data from patients receiving LVADs. Patients without previous ICD received an ICD after LVAD implantation for primary prevention. Sixty-one patients with LVAD and ICD were followed prospectively for 365 +/- 321 days. Nine patients died from thromboembolism or haemorrhage. Overall, the rate of appropriate ICD interventions was 34%, mostly for treatment of monomorphic VT in 52%, polymorphic VT in 13%, and VF in 35%. Seventy-one percent of VA were terminated by overdrive pacing, 29% by shock. Patients with a history of VA before LVAD implantation had a significantly higher 1-year rate for ICD therapy compared with LVAD patients with a primary prevention ICD indication LVAD patients (50 vs. 24%). Similarly, patients with non-ischaemic cardiomyopathy had a significantly higher risk for ICD therapy than patients with ischaemic heart disease (50 vs. 22%). CONCLUSION: Implantable cardioverter-defibrillator therapy is safe and effective in LVAD patients. Ventricular arrhythmias leading to ICD intervention occur frequently in 34% of LVAD patients after 1 year, with large variations depending on the underlying cardiac disease and previous arrhythmia history. Primary prevention ICD indication after LVAD implantation yields high rates of ICD intervention. A history of previous VA strongly predicts future use of ICD treatment after LVAD implantation.

A prospective experience with the lead integrity alert: new certainties and new uncertainties.

Lead fracture is one of the major complications in implantable cardioverter defibrillator (ICD) therapy often leading to a series of inadequate shocks and thus greatly impairing quality of life of patients. The novel lead integrity alert algorithm by Medtronic (Medtronic Inc., Minneapolis, MN, USA) is addressing this problem. We report a case of a lead failure being correctly predicted by shifting lead impedances about 4 weeks before the first episode of oversensing. Additionally, our case illustrates the new problem of how to clinically handle a patient with a highly probable, but not completely certain, ICD-lead failure.

Arrhythmia susceptibility in mice after therapy with beta-catenin-transduced hematopoietic progenitor cells after myocardial ischemia/reperfusion.

BACKGROUND: Hematopoietic progenitor cells (HPCs) can improve cardiac function after myocardial infarction. However, occurrence of arrhythmias is a potential limitation of cell therapy. In this study, we investigated the cardiac electrophysiological properties of ex vivo expanded HPCs, generated by beta-catenin gene transfer, after transcoronary delivery in a murine model of ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: To assess arrhythmia inducibility of ex vivo expanded HPCs, mice were subjected to I/R and assigned to sham operation (n = 8), I/R (n = 21) and HPC (n = 15) treatment. Six weeks later, mice were subjected to long-term electrocardiogram recording and in vivo transvenous electrophysiological study. After I/R, mice showed a significant prolongation of conduction and repolarization compared with sham-operated mice. There was a marked increase in ventricular ectopic activity in infarcted mice as compared with sham-operated mice. Cardiac electrophysiological parameters and ventricular ectopic activity were not altered in mice treated with HPCs in comparison with control I/R mice. CONCLUSION: Transcoronary delivery of genetically ex vivoexpanded HPCs did not alter the electrophysiological properties in mice after I/R. Therefore, ex vivo beta-catenin-mediated HPC expansion may represent an attractive therapeutic option for cell transplantation treatment of myocardial infarction without electrophysiological side effects.

Morphology of current of injury does not predict long term active fixation ICD lead performance.

BACKGROUND: Currents of injury (COI) have been associated with improved lead performance during perioperative measurements in pacemaker and ICD implants. Their relevance on long term lead stability remains unclear. METHODS: Unipolar signals were recorded immediately after active fixation ICD lead positioning, blinded to the implanting surgeon. Signals were assigned to prespecified COI types by two independent investigators. Sensing, pacing as well as changes requiring surgical intervention were prospectively investigated for 3 months. RESULTS: 105 consecutive ICD lead implants were studied. All could be assigned to a particular COI with 48 type 1, 43 type 2 and 14 type 3 signals. Pacing impedance at implant was 703.8+/-151.6 Ohm with a significant COI independent drop within the first week. Sensing was 10.6mV+/- 3.7mV and pacing threshold at implant was 0.8+/-0.3mV at 0.5ms at implant. There was no significant difference between COI groups at implant and during a 3 months follow up regarding sensing, pacing nor surgical revisions. CONCLUSIONS: Three distinct patterns of unipolar endocardial potentials were observed in active fixation ICD lead implant, but COI morphology did not predict lead performance after 3 months.

Implantable defibrillator with left ventricular assist device compatibility.

Implanted defibrillator (ICD) and HeartMate-II (Thoratec, Pleasanton, CA, USA) left ventricular assist device (LVAD) incompatibilities have been reported. In order to show which ICD would function regularly in Heart Mate II recipients, we conducted a systematic review of 39 consecutive patients with implanted ICD and HeartMate-II from our institution's LVAD registry. Forty-six ICDs were identified without device interactions in most ICD devices. However, loss of ICD to programmer telemetry was observed in four patients with V-193, V-196 and V-350 (St Jude Medical, Sunnyvale, CA, USA) and one patient with an Ovatio DR (Sorin, Milan, Italy) requiring ICD replacement. The majority of all investigated ICDs operated without LVAD to ICD interaction. However, surgeons implanting the Heart Mate II in ICD patients should be aware of possible interactions and incompatible devices should not be recommended in HeartMate-II recipients.

Left atrial substrate ablation in addition to pulmonary vein isolation in paroxysmal atrial fibrillation using a large 28-mm cryoballoon.

We report a case of successful isolation of all pulmonary veins (PV) for symptomatic paroxysmal atrial fibrillation using a 23-mm cryoballoon with continued paroxysmal atrial fibrillation during a 3-month follow-up. Left atrial-to-PV-junction ablation was then performed 3 months after the first procedure using a larger 28-mm balloon despite unrecovered isolation of all four PV, thereby curing symptomatic atrial fibrillation in this case.

Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3.

The sinus node (or sinoatrial node [SAN]), the pacemaker of the heart, is a functionally and structurally heterogeneous tissue, which consists of a large "head" within the right caval vein myocardium and a "tail" along the terminal crest. Here, we investigated its cellular origin and mechanism of formation. Using genetic lineage analysis and explant assays, we identified T-box transcription factor Tbx18-expressing mesenchymal progenitors in the inflow tract region that differentiate into pacemaker myocardium to form the SAN. We found that the head and tail represent separate regulatory domains expressing distinctive gene programs. Tbx18 is required to establish the large head structure, as seen by the existence of a very small but still functional tail piece in Tbx18-deficient fetuses. In contrast, Tbx3-deficient embryos formed a morphologically normal SAN, which, however, aberrantly expressed Cx40 and other atrial genes, demonstrating that Tbx3 controls differentiation of SAN head and tail cardiomyocytes but also demonstrating that Tbx3 is not required for the formation of the SAN structure. Our data establish a functional order for Tbx18 and Tbx3 in SAN formation, in which Tbx18 controls the formation of the SAN head from mesenchymal precursors, on which Tbx3 subsequently imposes the pacemaker gene program.

Effect of restoring sinus rhythm on sleep apnea in patients with atrial fibrillation or flutter.

Sleep apnea (SA) is more prevalent in patients with atrial fibrillation (AF), but the impact of cardioversion on disordered breathing is unknown. Thus, we investigated the influence of restoring sinus rhythm in patients with AF and atrial flutter (AFlut) on SA. The 16 patients (mean age 63.1 +/- 11.2) with AF (n = 6) or AFlut (n = 10) and SA (apnea-hypopnea index >10) received cardioversion or ablation of cavotricuspid isthmus. We compared the severity of SA by sleep polygraphy under AF/Aflut with the first night after restoring sinus rhythm and after 4 weeks. Apnea-hypopnea index before and immediately after restoring sinus rhythm was similar (31.7 +/- 13.2 vs 30.1 +/- 15.7, p = NS) despite a significantly reduced heart rate (86.7 +/- 26.5 vs 67.8 +/- 11.9 beats/min, p <0.02). After 4 weeks, apnea-hypopnea index remained unchanged (38.1 +/- 18.1, p = NS) although heart rate was further reduced (61.8 +/- 8.8 beats/min, p <0.003). In our study, SA could not be improved by cardioversion of AF/AFlut. Therefore, although it is well known that SA leads to AF, eliminating AF does not cure or improve SA. In conclusion, our study shows that AF should be regarded more as an innocent bystander than a causative or aggravating condition in SA.

Efficacy of pulmonary vein isolation by cryoballoon ablation in patients with paroxysmal atrial fibrillation.

BACKGROUND: Radiofrequency ablation of pulmonary veins (PVs) has emerged as an effective treatment for patients with paroxysmal atrial fibrillation (AF). However, serious complications raise concern about an even wider application. In terms of safety, cryoenergy has advantages compared with radiofrequency. A new cryoenergy balloon catheter has been recently developed to make AF ablation shorter and safer. OBJECTIVE: The purpose of this study was to test the 6-month efficacy of this new device for ablation of paroxysmal AF. METHODS: Twenty-one patients with highly symptomatic paroxysmal AF, normal left atrial size, and frequent episodes of AF were included. All PVs were targeted during cryoballoon ablation. Patients received 24-hour Holter electrocardiograms (ECGs) and event recorder during follow-up after 1, 3, and 6 months. RESULTS: A total of 81 (95%) of 85 PVs could be completely isolated with a single-balloon technique. Procedure time was 165 +/- 35 minutes, and fluoroscopy time was 39 +/- 9 minutes. After 6 months, 86% of the patients were free of symptomatic AF. In two of three patients with recurrence of AF, complete PV isolation has not been achieved initially. After a second procedure (1.04 procedures per patient), 90% of the patients were free of symptomatic AF. Three phrenic nerve palsies occurred during ablation of the right superior PV; two completely resolved after 6 and 9 months, and one is still persisting after 2 months. CONCLUSION: This is the first study that reports the results of the new cryoballoon AF ablation approach showing 86% freedom from AF recurrence after 6 months. Cryoballoon PV ablation promises to be effective for patients with paroxysmal AF and normally sized left atria.

Right ventricular pacing is an independent predictor for ventricular tachycardia/ventricular fibrillation occurrence and heart failure events in patients with an implantable cardioverter-defibrillator.

AIMS: There is increasing evidence that right ventricular (RV) pacing may have detrimental effects by increasing morbidity and mortality for heart failure in implantable cardioverter-defibrillator (ICD) patients. In this study we prospectively tested the hypothesis that cumulative RV pacing increases ventricular tachycardia/ventricular fibrillation (VT/VF) occurrence (primary endpoint) and hospitalization and mortality for heart failure (secondary endpoint) in a predominantly secondary prophylactic ICD patient population. METHODS AND RESULTS: Two hundred and fifty patients were divided into two groups according to the median of cumulative RV pacing (< or =2 vs. >2%) and prospectively followed-up for occurrence of primary and secondary endpoints for 18 +/- 4 months. Established predictors for VT/VF occurrence and heart failure events such as age, left ventricular ejection fraction (EF), QRS duration, history of atrial fibrillation, and NT-proBNP were collected at enrollment. Multivariate Cox regression analysis revealed that cumulative RV pacing > 2% and EF < 40% were independent predictors for VT/VF occurrence and heart failure events. Kaplan-Meier analysis showed that patients with >2% cumulative RV pacing more frequently suffered from VT/VF occurrence and heart failure hospitalization. CONCLUSION: Cumulative RV pacing > 2% and EF < 40% are independent predictors for VT/VF occurrence and mortality and hospitalization for heart failure in predominantly secondary prophylactic ICD patients. Our data show that algorithms capable of reducing cumulative RV pacing should be used more frequently in clinical practice.

Reduced delayed rectifier K+ current, altered electrophysiology, and increased ventricular vulnerability in MLP-deficient mice.

BACKGROUND: Mice with a knockout (KO) of muscle LIM protein (MLP) exhibit many morphologic and clinical features of human cardiomyopathy. In humans, MLP-expression is downregulated both in ischemic and dilative cardiomyopathy. In this study, we investigated the effects of MLP on the electrophysiologic phenotype in vivo and on outward potassium currents. METHODS AND RESULTS: MLP-deficient (MLPKO) and wild-type (MLPWT) mice were subjected to long-term electrocardiogram (ECG) recording and in vivo electrophysiologic study. The whole-cell, patch-clamp technique was applied to measure voltage dependent outward K+ currents in isolated cardiomyocytes. Long-term ECG revealed a significant prolongation of RR mean (108 +/- 9 versus 99 +/- 5 ms), P (16 +/- 3 versus 14 +/- 1 ms), QRS (17 +/- 3 versus 13 +/- 1 ms), QT (68 +/- 8 versus 46 +/- 7 ms), QTc (66 +/- 6 versus 46 +/- 7 ms), JT (51 +/- 7 versus 34 +/- 7 ms), and JTc (49 +/- 5 versus 33 +/- 7 ms) in MLPKO versus MLPWT mice (P < .05). During EP study, QT (80 +/- 8 versus 58 +/- 7 ms), QTc (61 +/- 6 versus 45 +/- 5 ms), JT (62 +/- 9 versus 43 +/- 6 ms), and JTc (47 +/- 5 versus 34 +/- 5 ms) were also significantly prolonged in MLPKO mice (P < .05). Nonsustained VT was inducible in 9/16 MLPKO versus 2/15 MLPWT mice (P < .05). Analysis of outward K+ currents in revealed a significantly reduced density of the slowly inactivating outward K+ current IK, slow in MLPKO mice (11 +/- 5 pA/pF versus 18 +/- 7 pA/pF; P < .05). CONCLUSION: Mice with KO of MLP exhibit significant prolongation of atrial and ventricular conduction and an increased ventricular vulnerability. A reduction in repolarizing outward K+ currents may be responsible for these alterations.