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The phosphodiesterase-5 inhibitor sildenafil was developed for the treatment of pulmonary hypertension. The authors investigated the efficacy and safety of sildenafil in the early postoperative period after mitral valve surgery in patients with pulmonary hypertension.A double-blind, placebo-controlled randomized trial was performed.The trial was performed in a single tertiary referral center.Fifty consecutive patients who experienced pulmonary hypertension and underwent mitral valve surgery.Patients were randomly assigned to the following 2 groups: 25 patients received 20 mg sildenafil every 8 hours, and the remaining 25 patients received placebo during the same period. Hemodynamic parameters were studied by using a pulmonary artery catheter at baseline and every 6 hours up to 36 hours.Patients who received sildenafil showed a decrease in mean pulmonary pressure, from 32 ± 7 mmHg at baseline to 26 ± 3 mmHg after 36 hours, whereas no change was seen in patients who received placebo (mean pulmonary pressure 34 ± 6 mmHg at baseline and 35 ± 5 mmHg after 36 h) (p0.001). No significant changes in systemic hemodynamic and oxygenation were observed. Patients who received sildenafil compared with those who received placebo had a median mechanical lung ventilation time of 16 (10-31) hours versus 19 (13-41) hours (p = 0.431), intensive care unit stay of 74 (44-106) hours versus 91 (66-141) hours (p = 0.410), and a total hospitalization stay of 7 (5-10) days versus 11 (7-15) days (p = 0.009).The immediate postoperative administration of sildenafil after mitral valve surgery is safe. Sildenafil demonstrates a favorable decreasing effect on pulmonary vascular pressure without systemic hypotension and ventilation-perfusion mismatch.

Invagination is an innovative technique for closing the left atrial appendage (LAA) to reduce the risk of thrombi formation. The influence of LAA invagination on the flow fields in the atria was investigated based on a computational fluid dynamics. The simulation results demonstrated that the novel invagination process can eliminate low velocities (blood stasis) and low shear rate and thus decrease the risk of thrombus formation during atrial fibrillation. This innovative technique may enhance the clinical treatment of patients with atrial fibrillation by improving the atrial flow field while lowering the risk of creating emboli.

Background The recessive form of catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is caused by mutations in cardiac calsequestrin (CASQ2), leading to protein deficiency. Objectives The aims of this study were to develop a viral-delivered gene therapy for CPVT2 and to determine the relationship between CASQ2 expression and antiarrhythmic efficacy in a murine model. Methods We used a murine model of CPVT2 caused by the D307H human mutation (CASQ2 D307H ) or CASQ2 knockout (CASQ2 Δ/Δ ). Adeno-associated virus (AAV) particles containing the CASQ2 gene (AAV CASQ2 ) were injected into the heart or intraperitoneally to 12-week-old mice. A telemetry device was implanted, and mice underwent provocation testing 7–8 weeks after gene therapy. Results CASQ2 Δ/Δ mice injected intracardiacally with AAV CASQ2 expressed 40% ± 25% of the normal CASQ2 protein level, which was increased compared to untreated CASQ2 Δ/Δ mice (n = 10; P D307H (n = 12) and CASQ2 Δ/Δ (n = 4) mice. All control mice with CPVT2 had nonsustained ventricular tachycardia (VT) and 8 of 13 had sustained VT on provocation. Expressing ≥33% of the normal CASQ2 level was needed to protect from nonsustained VT as well as stress-induced premature ventricular contractions. Lower levels of expression prevented sustained VT in AAV CASQ2 -treated mice (0 of 26; P Conclusion AAV CASQ2 displays a long-lasting capacity to attenuate and potentially cure CPVT2. Systemic delivery is feasible and convenient, reproducibly providing adequate levels of transgene expression. Antiarrhythmic efficacy depends on the CASQ2 level: ≥33% of the normal CASQ2 level is needed to prevent arrhythmia. However, even lower levels of protein protect from sustained VT, thereby potentially reducing the risk of sudden death.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress‐provoked ventricular arrhythmia, which also manifests sinoatrial node (SAN) dysfunction. We recently showed that SK4 calcium‐activated potassium channels are important for automaticity of cardiomyocytes derived from human embryonic stem cells. Here SK4 channels were identified in human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) from healthy and CPVT2 patients bearing a mutation in calsequestrin 2 (CASQ2‐D307H) and in SAN cells from WT and CASQ2‐D307H knock‐in (KI) mice. TRAM‐34, a selective blocker of SK4 channels, prominently reduced delayed afterdepolarizations and arrhythmic Ca 2+ transients observed following application of the β‐adrenergic agonist isoproterenol in CPVT2‐derived hiPSC‐CMs and in SAN cells from KI mice. Strikingly, in vivo ECG recording showed that intraperitoneal injection of the SK4 channel blockers, TRAM‐34 or clotrimazole, greatly reduced the arrhythmic features of CASQ2‐D307H KI and CASQ2 knockout mice at rest and following exercise. This work demonstrates the critical role of SK4 Ca 2+ ‐activated K + channels in adult pacemaker function, making them promising therapeutic targets for the treatment of cardiac ventricular arrhythmias such as CPVT.

Response to cardiac resynchronization therapy (CRT) is well-established in patients with typical left bundle branch block (LBBB) but modest or even negative in those with intraventricular conduction delay (IVCD). However, IVCD pattern is heterogeneous, and it is possible that QRS patterns may also respond to CRT. Consecutive baseline ECGs of 239 patients implanted between 2007 and 2010 with CRT were analyzed. ECGs were classified into the following three groups: (a) typical LBBB (TLBBB) according to accepted guidelines (n = 67); (b) IVCD with LBBB pattern criteria in V1, 1, and aVL but with QS or rS in V5–V6 which we defined as atypical LBBB (ALBBB) (n = 74); and (c) all other IVCD (OIVCD) patterns (n = 98). Endpoints were 2 years mortality and echocardiographic response, defined as a decrease of ≥ 10% in indexed LVESV or an increase of ≥ 5% in left ventricular ejection fraction at 1 year of follow-up. Baseline clinical characteristics were similar among all the three groups. Rates of echocardiographic response were lower among those with OIVCD compared to those with LBBB and ALBBB (50% vs. 75% and 72%, respectively, p = 0.01 for both comparisons). A multivariable model showed a lower likelihood of echocardiographic response in OIVCD [HR = 0.40; (0.16–0.98)] and a similar likelihood in ALBBBB [HR = 0.98; (0.40–2.40)] compared to TLBBB. Cumulative 2-year survival was 88% in ALBBB, 86% in TLBBB, and 76% in OIVCD (p value = 0.011). Patients with ALBBB may have a favorable echocardiographic response to CRT and display similar survival rates to typical LBBB. This subgroup of IVCD should be considered for CRT. Atypical left bundle branch morphology defined as QS or rS in lead V1, broad R waves in lead I, and aVL but with QS or rS in V5–V6 is associated with favorable echocardiographic response to CRT and displays similar survival rates to typical LBBB patients.

Background Patients with coronary heart disease demonstrate changes in skin microcirculation and a decrease in cutaneous blood mass. Objective The goal of this study was to assess the feasibility of diagnosing myocardial ischemia based on peripheral microcirculatory variables. Methods The skin microcirculatory measurements were monitored using an LPT system comprising a Laser Doppler Flowmeter (LDF), a photoplethysmograph (PPG) and a transcutaneous oxygen tension device (tc-PO2). Concurrently, heart rate and blood pressure were monitored. Measurements were performed before and after exercise stress test. Subjects were divided into ischemic (20) and nonischemic (27) patients based on myocardial perfusion imaging (MPI). Results The results indicate differences in LPT variables between ischemic and nonischemic patients following exercise, while no differences in the central variable values were observed between the two groups. Conclusions Peripheral microcirculatory variables may be useful for non-invasive assessment of myocardial ischemia. The system has clinical potential for sensitive and noninvasive monitoring of vital variables during medical procedures in clinics, as well as in home care for patients who suffer from ischemic cardiac diseases.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia characterized by syncope and sudden death occurring during exercise or acute emotion. CPVT is caused by abnormal intracellular Ca(2+) handling resulting from mutations in the RyR2 or CASQ2 genes. Because CASQ2 and RyR2 are involved in different aspects of the excitation-contraction coupling process, we hypothesized that these mutations are associated with different functional and intracellular Ca(²+) abnormalities. To test the hypothesis we generated induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CM) from CPVT1 and CPVT2 patients carrying the RyR2(R420Q) and CASQ2(D307H) mutations, respectively, and investigated in CPVT1 and CPVT2 iPSC-CM (compared to control): (i) The ultrastructural features; (ii) the effects of isoproterenol, caffeine and ryanodine on the [Ca(2+) ]i transient characteristics. Our major findings were: (i) Ultrastructurally, CASQ2 and RyR2 mutated cardiomyocytes were less developed than control cardiomyocytes. (ii) While in control iPSC-CM isoproterenol caused positive inotropic and lusitropic effects, in the mutated cardiomyocytes isoproterenol was either ineffective, caused arrhythmias, or markedly increased diastolic [Ca(2+) ]i . Importantly, positive inotropic and lusitropic effects were not induced in mutated cardiomyocytes. (iii) The effects of caffeine and ryanodine in mutated cardiomyocytes differed from control cardiomyocytes. Our results show that iPSC-CM are useful for investigating the similarities/differences in the pathophysiological consequences of RyR2 versus CASQ2 mutations underlying CPVT1 and CPVT2 syndromes.

Background— Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing life-threatening arrhythmias whenever sympathetic activity increases. β-Βlockers are the mainstay of therapy; when they fail, implantable cardioverter-defibrillators (ICDs) are used but often cause multiple shocks. Preliminary results with flecainide appear encouraging. We proposed left cardiac sympathetic denervation (LCSD) as useful additional therapy, but evidence remains anecdotal. Methods and Results— We report 63 patients with CPVT who underwent LCSD as secondary (n=54) or primary (n=9) prevention. The median post-LCSD follow-up was 37 months. The 9 asymptomatic patients remained free of major cardiac events. Of the 54 patients with prior major cardiac events either on (n=38) or off (n=16) optimal medical therapy, 13 (24%) had at least 1 recurrence: 0 patients had an aborted cardiac arrest, 2 patients had syncope only, 10 patients had ≥1 appropriate ICD discharges, and 1 patient died suddenly. The 1- and 2-year cumulative event-free survival rates were 87% and 81%. The percentage of patients with major cardiac events despite optimal medical therapy (n=38) was reduced from 100% to 32% ( P P P Conclusions— LCSD is an effective antifibrillatory intervention for patients with CPVT. Whenever syncope occurs despite optimal medical therapy, LCSD could be considered the next step rather than an ICD and could complement ICDs in patients with recurrent shocks.

This study sought to determine the feasibility of using noninvasive cardiac hemodynamics (NICHE), a new noninvasive Doppler-based device, to monitor real-time, simultaneous tissue and blood-flow Doppler measurements in a clinical setting, and to obtain preliminary performance data compared to a commercially available system. Doppler-based measurements have been shown to correlate well with invasive hemodynamic data and diastolic function, but their use in clinical applications has been limited by various technical issues. The NICHE device was developed to obtain simultaneous tissue and blood-flow Doppler measurements automatically, in real-time and in a hands-free manner. Thirty participants (ten normal volunteers and 20 patients in a cardiac rehab program) underwent standard echocardiographic/Doppler studies followed immediately by NICHE monitoring. Early diastolic transmitral blood-flow velocity (E) and tissue Doppler myocardial wall velocity during early relaxation (E′) were acquired using a standard echo device; and E/E′ was derived post hoc. NICHE measurements included E, E′, and directly measured instantaneous E/E′. NICHE was successfully used in 28 participants. Measurements of ENICHE ranged from 40 cm/s to over 120 cm/s and correlated well with Eecho (R = 0.93). ENICHE′ ranged from 2 to 23 cm/s and correlated well with the averaged Eecho′ (R = 0.91). Directly measured E/ENICHE′ ratios ranged from 3 to 23 and correlated well with derived E/Eecho′ (R = 0.91). The NICHE device can monitor patients in a hands-free manner and can supply real-time Doppler derived measurements of hemodynamic parameters and diastolic function that correlate well with measurements from standard echo devices.

The aim of this study was to evaluate the effects of fish oils, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on ventricular tachyarrhythmic episodes (VTEs) in implantable cardioverter defibrillator (ICD) recipients with ischemic cardiomyopathy. One hundred five ICD recipients with ischemic cardiomyopathy received 3.6 g of EPA and DHA and placebo for 6 months, each at a random order, with a 4-month washout period between treatments. Eighty-seven patients completed the 16-month study protocol. The primary end point was any VTE (including sustained and non-sustained ventricular tachycardias at a rate of >150 bpm) as recorded by the ICDs. Secondary end points included device therapy (anti-tachycardia pacing (ATP) or shocks). During treatment with fish oils, there was a significant increase in EPA and DHA concentrations in red blood cells (RBCs) and subcutaneous fat tissue. Among 87 patients who completed the study protocol, the mean number of VTEs was significantly lower during treatment with fish oil (1.7) vs. placebo (5.6; p = 0.035). Appropriate device therapy for VTE occurred in 18 (21%) patients. Fish oil therapy was associated with a trend toward fewer VTEs terminated with ATP (2.8 ± 13.7 vs. 0.5 ± 2.1, respectively; p = 0.077). VTE terminated by ICD shocks, however, was rare, and rates were similar between both groups (0.11 ± 0.6 vs. 0.10 ± 0.4, p = not significant, respectively). Our data suggest that fish oil therapy may be associated with a reduction in the frequency of VTE in ICD recipients with ischemic cardiomyopathy.

Background Spontaneous calcium release evoking delayed afterdepolarization is believed to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a lethal human arrhythmia provoked by exercise or emotional stress. β-Adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation, and/or sympathetic denervation. Objective To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the homozygous calsequestrin knockout (CASQ2 Δ/Δ ) mouse model of CPVT2. Methods A heart telemetry device was implanted for continuous electrocardiographic recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by using Western blotting and confocal microscopy. Results Adult CASQ2 Δ/Δ mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. β-Adrenergic blockers, propranolol and metoprolol, attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with α-blocking activity, phentolamine or labetalol, abolished both exercise- and epinephrine-induced arrhythmia. In contrast, injection of α-adrenergic agonist phenylephrine reproducibly provoked ventricular tachycardia. Isolated cardiomyocytes from CASQ2 Δ/Δ mice had delayed calcium release waves upon exposure to sympathetic agonists, which were abolished by phentolamine. Hearts of calsequestrin-mutant mice expressed more α1-adrenergic receptor than did wild type control mice ( P Conclusion We identified a contribution of the α-adrenergic pathway to the pathogenesis of catecholamine-induced arrhythmia. α-Blockade emerges as an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to β-blockers.

CRT Response in Patients with Renal Dysfunction Introduction Renal dysfunction is associated with increased morbi-mortality in heart failure patients. Data regarding functional and clinical efficacy of cardiac resynchronization therapy (CRT) in this population are limited. Methods and Results We aimed to evaluate the rate of functional response to CRT in patients with renal dysfunction and its association with long-term mortality. Our study included a total of 179 consecutive patients implanted between 2007 and 2010. The rate of functional response to CRT (defined by a composite score using New York Heart Association functional class, 6-minute walk test, and quality of life) was compared between patients with and without renal dysfunction (defined as eGFR < or ≥60 mL/min/1.73 m2). Survival analysis estimates were constructed according to the Kaplan–Meier method, with results comparison using the log-rank test. During a median follow-up of 4.2 years, 73 patients (40%) died. Patients with low eGFR were older (72 ± 8 years vs. 64 ± 12 years; P < 0.001), and had higher prevalence of ischemic heart disease (75% vs. 53%; P = 0.003). Functional response rates did not differ significantly between patients with and without renal dysfunction (58% and 69%, respectively; P = 0.14). Despite overall higher mortality in patients with low eGFR (53.8% vs. 22.7%; P < 0.001), the presence of functional response at 1 year among patients with renal dysfunction was still independently associated with an improved long-term survival (HR = 0.49 [95%CI: 0.28–0.83]; P = 0.009). Conclusion Functional response to CRT at 1 year does not differ significantly between patients with or without kidney disease, and is an independent predictor of improved long-term survival in patients with renal dysfunction.

Aims Strategically chosen ventricular tachycardia (VT)/ventricular fibrillation (VF) detection and therapy parameters aimed at reducing shock deliveries were proven effective in studies that utilized single manufacturer devices with a follow-up of up to 1 year. Whether these beneficiary effects can be generalized to additional manufacturers and be maintained for longer periods is to be determined. Our aim was to evaluate the durability and applicability of the programming of strategic implantable cardioverter-defibrillators (ICDs) of various manufacturers, which is aimed at reducing the shock delivery burden in primary prevention ICD recipients. Methods and results A retrospective analysis of prospectively collected data of 300 ICD recipients of various manufacturers was conducted; 160 devices were strategically programmed to reduce shocks and 140 were not. The primary endpoint was the composite of death and appropriate shocks. Additional outcomes were inappropriate shocks, syncope events, and non-sustained VTs. At a median follow-up of 24 months, 19 patients died, 31 received appropriate shocks, and 41 received inappropriate shocks. Multivariate analysis showed that strategic programming dedicated to shock reduction was associated with a 64% risk reduction in the primary endpoint [hazard ratio (HR): 0.13–0.93; P = 0.03] and a 70% reduction in inappropriate shock deliveries (HR: 0.16–0.72; P = 0.01). Very few syncope events occurred (five patients, 1.6%), and there was no between-group difference in this outcome. Conclusion Utilization of strategically chosen VT/VF detection and therapy parameters was found to be effective and safe in ICDs of various manufacturers at a median follow-up period of 2 years among primary prevention patients.

Aims Absent left atrium (LA) mechanical contraction may occur following the modified Cox-maze operation, and was found to impose a potential risk for the occurrence of thrombo-embolic stroke. It is unknown whether certain morphological P-wave characteristics can surrogate absent LA mechanical activity. The aim of this study was to evaluate the morphological features of the P-waves on the surface electrocardiogram (ECG) of patients who underwent the maze operation and to relate them to the contractile profile of the LA. Methods and results Electrocardiogram tracings of 150 consecutive patients that were in sustained sinus rhythm following the maze operation were evaluated. P-waves were scrutinized for morphology, duration, axis, and amplitude. Clinical, surgery-related, and echocardiographic data were collected and analysed. Forty-seven patients (31%) had no evidence of LA contraction at 3 months after surgery (baseline assessment) and on follow-up echocardiography. Multivariate analysis showed that a positive-only P-wave deflection at lead V1 ( P = 0.03), a negative-only deflection at aVL, and a P-wave amplitude of ≤0.05 mV at the septal-anterior leads ( P < 0.001 for both) were associated with absent LA mechanical contraction. In a secondary analysis, a risk score involving the above three parameters was developed for the prediction of stroke occurrence. Patients at the high-risk score group had a 30% survival freedom of stroke compared with 70% for patients at intermediate risk ( P < 0.001). Conclusion Absent LA mechanical contraction following the modified maze operation may be accompanied by a distinguished pattern of the P-waves on the surface ECG.

Background: Contemporary implantable cardiac defibrillators (ICD) enable storage of multiple, preepisode R-R recordings in patients who suffered from ventricular tachyarrhythmia (VTA). Timely prediction of VTA, using heart rate variability (HRV) analysis techniques, may facilitate the implementation of preventive and therapeutic strategies. Aim: To evaluate the novel multipole method of the HRV analysis in prediction of imminent VTAs in ICD patients. Methods: We screened patients from the Biotronik HAWAI Registry (Heart Rate Analysis with Automated ICDs). A total of 28 patients from the HAWAI registries (phase I and II), having medical records, who had experienced documented, verified VTA during the 2-year follow-up, were included in our analysis. HRV during preepisode recordings of 4,500 R-R intervals were analyzed using the Dyx parameter and compared to HRV of similar length recordings from the same patients that were not followed by arrhythmia. Results: Our study population consisted mainly of men 25 of 28 (89%), average age of 64.8 ± 9.4 years, 92% with coronary artery disease. HRV during 64 preevent recordings (2.3 events per patient on average) was analyzed and compared with 60 control recordings. The multipole method of HRV analysis showed 50% sensitivity and 91.6% specificity for prediction of ventricular tachycardia/ventricular fibrillation in the study population, with 84.5% positive predictive value. No statistically significant correlation was found between various clinical parameters and the sensitivity of imminent VTA predetection in our patients. Conclusion: The multipole method of HRV analysis emerges as a highly specific, possible predictor of imminent VTA, providing an early warning allowing to prepare for an arrhythmic episode. (PACE 2013; 36:1342‐1347)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal ventricular arrhythmia evoked by physical or emotional stress. Recessively inherited CPVT is caused by either missense or null-allele mutations in the cardiac calsequestrin (CASQ2) gene. It was suggested that defects in CASQ2 cause protein deficiency and impair Ca2+ uptake to the sarcoplasmic reticulum and Ca2+-dependent inhibition of ryanodine channels, leading to diastolic Ca2+ leak, after-depolarizations, and arrhythmia. To examine the effect of exercise training on left ventricular remodeling and arrhythmia, CASQ2 knockout (KO) mice and wild-type controls underwent echocardiography and heart rhythm telemetry before and after 6 wk of training by treadmill exercise. qRT-PCR and Western blotting were used to measure gene and protein expression. Left ventricular fractional shortening was impaired in KO (33 ± 5 vs. 51 ± 7% in controls, P < 0.05) and improved after training (43 ± 12 and 51 ± 9% in KO and control mice, respectively, P = nonsignificant). The exercise tolerance was low in KO mice (16 ± 1 vs. 29 ± 2 min in controls, P < 0.01), but improved in trained animals (26 ± 2 vs. 30 ± 3 min, P = nonsignificant). The hearts of KO mice had a higher basal expression of the brain natriuretic peptide gene. After training, the expression of natriuretic peptide genes markedly decreased, with no difference between KO and controls. Exercise training was not associated with a change in ventricular tachycardia prevalence, but appeared to reduce arrhythmia load, as manifested by a decrease in ventricular beats during stress. We conclude that, in KO mice, which recapitulate the phenotype of human CPVT2, exercise training is well tolerated and could offer a strategy for heart conditioning against stress-induced arrhythmia.

Transvenous lead extraction can lead to tricuspid valve damage.To assess the incidence, risk factors and clinical outcome of tricuspid regurgitation (TR) following lead extraction.We prospectively collected data on patients who underwent lead extraction at the Sheba Medical Center prior to laser use (i.e., before 2012). Echocardiography results before and following the procedure were used to confirm TR worsening, defined as an echocardiographic increase of at least one TR grade. Various clinical and echocardiographic parameters were analyzed as risk factors for TR. Clinical and echocardiographic follow-up was conducted to assess the clinical significance outcome of extraction-induced TR.Of 152 patients who underwent lead extraction without laser before 2012, 86 (56%) (192 electrodes) had echocardiography results before and within one week following the procedure. New or worsening TR was discovered in 13 patients (15%). Use of mechanical tools and younger age at extraction were found on multivariate analysis to be factors for TR development (P = 0.04 and P = 0.03 respectively). Average follow-up was 22.25 ± 21.34 months (range 8-93). There were no significant differences in the incidence of right-sided heart failure (50% vs. 23%, P = 0.192) or hospitalizations due to heart failure exacerbations (37.5% vs. 11%, P = 0.110). No patient required tricuspid valve repair or replacement. Death rates were similar in the TR and non-TR groups (20% vs. 33%).TR following lead extraction is not uncommon but does not seem to affect survival or outcomes such as need for valve surgery. Its long-term effects remain to be determined.

We are glad to have the opportunity to respond to the points kindly raised by Drs Patane and Gow in reference to our recent article on catecholaminergic polymorphic ventricular tachycardia (CPVT).1 We are obviously aware of the article by Faggioni et al,2 which includes 1 of the coauthors of our article, Dr Wilde. We also have direct experience with a few CPVT patients who had a reduction or disappearance of the ventricular arrhythmias induced by exercise when heart rate increased further (usually to >140 bpm). We have not discussed atrial overdrive pacing simply because we do not believe that these data and observations have direct relevance to the ongoing clinical management of CPVT patients in everyday life. The concept of atrial high-rate pacing (>120 bpm) may be of potential value in the in-hospital management of emergencies, but we find it difficult to recommend that heart rate should be increased permanently, or during exercise, to >140 bpm. In addition, how would it be possible to exclude that such an intervention, activated in the out-of-hospital setting, would not precipitate ventricular tachycardia or ventricular fibrillation? Our article was focused on how to reduce the incidence of life-threatening arrhythmias in the safest way. Rate support of CPVT patients who have symptomatic bradycardia in response to therapeutic β-blockade is always a consideration in CPVT. We acknowledge the comments concerning the possibility of anatomic variations in the cervicothoracic ganglion. Dr Gow …

Introduction: Cases of ventricular tachycardia (TV) with hemodynamic compromise present a challenge in achieving non-inducibility by radiofrequency catheter ablation (RFCA). We report our experience of VT RFCA facilitated by elective mechanical circulatory support. Methods and results: Five patients with hemodynamically unstable, recurrent ventricular arrhythmias that were unresponsive to medical therapy underwent extracorporeal membrane oxygenation (ECMO) assisted RFCA of scar related VT. All underwent RFCA under general anesthesia and were connected to an ECMO circuit maintained at minimum flow of 1.5 L /min. In case of VT or VF the blood flow of the ECMO circuit was increased to 4 L/min to allow hemodynamic stability and adequate systemic organ perfusion. A total of 8 VTs were observed. In 4 cases, we mapped during VT the critical isthmus was found and ablated. Four VTs were targeted by substrate mapping only. Complete success, defined as non-inducibility with aggressive program stimulation of any VT, was achieved in 4 patients. In a single patient, a non-clinical VT was still inducible. He died of septic shock 24 hour after the procedure. The remaining 4 were free of ventricular arrhythmia as proven by implanted defibrillator interrogation, over a median follow up of 16 months. Conclusion: ECMO implantation for VTRFCA is safe and assists in reaching the desired endpoint of noninducibility. This approach should be considered in high risk patients who may not otherwise tolerate such procedures.

Aims The severity of tricuspid regurgitation (TR) is a predictor of outcome among heart failure patients. The interaction between cardiac resynchronization therapy (CRT) and TR has not been described. In this study, we examined the effect of pre-implant TR, and worsened TR post-implant, on response to CRT and overall survival. Methods and results We included all patients with successfully implanted CRT systems between 2007 and 2010. Patients were divided into two groups pre-implant: (Gp 1) no-or-mild TR; and (Gp 2) moderate-or-severe TR. Post-implant, patients were divided into two groups: (Gp A) improved or stable TR; and (Gp B) worsened TR. The clinical and echocardiographic outcome of all patients was assessed. The study included 193 patients. Thirty-five subjects (18%) had moderate or severe TR pre-implant (Gp 2). Baseline echo parameters and 6 min walk distance were worse in Gp 2 compared with Gp 1 (mild or no TR). There was no significant difference in clinical response to CRT between the two groups. However, Gp 2 had a significantly lower echocardiographic response (35 vs. 60%, P = 0.01) and higher mortality over 3 years (OR = 6.70, 95% CI = 1.8-24.5, P = 0.004). Post-implant, 25 patients (13%) developed worsened TR (Gp B), not associated with deterioration in right ventricle function or elevation in pulmonary artery pressure. Worsened TR predicted a reduced clinical response to CRT (42 vs. 70%, P = 0.006), when compared with Gp A. Conclusions The presence of baseline moderate or severe TR is associated with increased mortality but does not predict clinical or echocardiographic response to CRT. Patients with worsened TR following CRT are less likely to clinically respond to CRT. Pacing leads passing through the tricuspid valve may worsen TR. It is conceivable that avoidance of lead-induced TR by alternative implantation techniques could improve the response rate to CRT.

Introduction:Rate smoothing algorithms, while known to help prevent ventricular tachyarrhythmias in some patients, have been shown to result in underdetection of ventricular tachycardia (VT) due to interaction between bradycardia pacing and tachycardia detection parameters. A new algorithm named Bradycardia Tachycardia Response (BTR) has been developed in order to prevent rate smoothing-induced underdetection. The efficacy of BTR is not known. The aim of this study was to assess the effectiveness of BTR in preventing VT underdetection due to rate smoothing. Methods and Results:Two ICD models (TELIGEN and VITALITY AVT, Boston Scientific, St. Paul, MN, USA) bearing identical rate smoothing algorithms were connected to a VT simulator. Devices were programmed similarly except for the BTR feature that exists in TELIGEN only. The detection performance of both devices was tested using varying combinations of AV delay, rate smoothing down, and upper rate limit and compared between the two models. VT underdetection (delay or nondetection) occurred during pacing in 62% of the VT episodes with VITALITY AVT. In TELIGEN, all simulated VT episodes were detected appropriately as soon as their rates exceeded the programmed VT detection rate. Detection tended to be affected by higher upper rate, longer AV delays, and more aggressive rate smoothing. Conclusion:The BTR algorithm effectively counteracts VT detection delay caused by the interaction of rate smoothing with VT detection parameters, thus enabling safe use of the rate smoothing feature. (PACE 2012; 1–6)

Objectives The purpose of this study was to assess deformation dynamics and in vivo mechanical properties of the aortic annulus throughout the cardiac cycle. Background Understanding dynamic aspects of functional aortic valve anatomy is important for beating-heart transcatheter aortic valve implantation. Methods Thirty-five patients with aortic stenosis and 11 normal subjects underwent 256-slice computed tomography. The aortic annulus plane was reconstructed in 10% increments over the cardiac cycle. For each phase, minimum diameter, ellipticity index, cross-sectional area (CSA), and perimeter (Perim) were measured. In a subset of 10 patients, Young's elastic module was calculated from the stress-strain relationship of the annulus. Results In both subjects with normal and with calcified aortic valves, minimum diameter increased in systole (12.3 ± 7.3% and 9.8 ± 3.4%, respectively; p Conclusions The aortic annulus, generally elliptic, assumes a more round shape in systole, thus increasing CSA without substantial change in perimeter. Perimeter changes are negligible in patients with calcified valves, because tissue properties allow very little expansion. Aortic annulus perimeter appears therefore ideally suited for accurate sizing in transcatheter aortic valve implantation.

Background: Patients with atrial fibrillation sustain a significant lower exercise tolerance compared to those in sinus rhythm, even while seemingly in adequate rate-control. Methods: Exercise testing was performed during atrial fibrillation and after electric cardioversion for 30 patients who were initially treated with AV modifying agents and were considered in adequate rate control. Heart rate parameters were obtained during all exercise stages, and a graphic display of heart rate acceleration was obtained. For those patients who remained in sinus rhythm, an additional exercise test was performed after 1 month. Results: During atrial fibrillation, heart rate at the completion of Bruce stage 1 and the peak exercise heart rate were significantly higher when compared to sinus rhythm (120 ± 10 bpm vs. 98 ± 11 bpm and 164 ± 16 bpm vs. 129 ± 11 bpm respectively, p < 0.001 for both). The time to peak exercise heart rate was significantly shorter during atrial fibrillation (3.5 ± 1 min vs. 6.5 ± 1.5 min, p < 0.001), and the total exercise duration was subsequently shorter as well (6 ± 2 min vs. 8.5 ± 2 min, p < 0.001). Treatment with beta-blockers prior to exercise did not affect the earlier peaking of the heart rate. After 1 month, similar time to peak heart rate and similar exercise performance were observed among patients, who remained in sinus rhythm, when compared to to the post-cardioversion exercise test. Conclusions: In patients with atrial fibrillation, exercise heart rate acceleration displays a specific pattern of early peaking. Earlier heart rate peaking occurs regardless of ample rate control while at rest or mild physical activity and contributes to overall lower exercise performance. Ann Noninvasive Electrocardiol 2011;16(4):357–364

Aims KCNE1 encodes an auxiliary subunit of cardiac potassium channels. Loss-of-function variations in this gene have been associated with the LQT5 form of the long QT syndrome (LQTS), secondary to reduction of I Ks current. We present a case in which a D85N rare polymorphism in KCNE1 is associated with an LQT2 phenotype. Methods and results An 11-year old competitive athlete presented with mild bradycardia and a QTc interval of 470 ms. An LQT2 phenotype, consisting of low-voltage bifid T waves, was evident in the right precordial electrocardiogram leads. During the tachycardia phase following adenosine, QTc increased to 620 ms. Genetic analysis revealed a rare heterozygous polymorphism in KCNE1 predicting the substitution of asparagine for aspartic acid at position 85 of minK (D85N). Patch clamp experiments showed that KCNE1- D85N, when co-expressed with KCNH2 in TSA201 cells, significantly reduced I Kr. Homozygous co-expression of the mutant with KCNH2 reduced I Kr tail current by 85%, whereas heterozygous co-expression reduced the current by 52%, demonstrating for the first time a dominant-negative effect of D85N to reduce I Kr. Co-expression of the mutant with KCNQ1, either homozygously or heterozygously, produced no change in I Ks. Conclusions Our results suggest that a rare polymorphism KCNE1- D85N underlies the development of an LQT2 phenotype in this young athlete by interacting with KCNH2 to cause a dominant-negative effect to reduce I Kr. Our data provide further evidence in support of the promiscuity of potassium channel β subunits in modulating the function of multiple potassium channels leading to a diversity of clinical phenotypes.

Objectives We aimed to evaluate the relationship between echocardiographic response to cardiac resynchronization therapy (CRT) and the risk of subsequent ventricular tachyarrhythmias (VTAs). Background Current data regarding the effect of CRT on the risk of VTA are limited and conflicting. Methods The risk of a first appropriate implantable cardioverter-defibrillator (ICD) therapy for VTA (including ventricular tachycardia, ventricular fibrillation, and ventricular flutter) was compared between high- and low-echocardiographic responders to CRT defibrillator (CRT-D) therapy (defined as ≥25% and

Background— This study aimed to determine whether QRS morphology identifies patients who benefit from cardiac resynchronization therapy with a defibrillator (CRT-D) and whether it influences the risk of primary and secondary end points in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) trial. Methods and Results— Baseline 12-lead ECGs were evaluated with regard to QRS morphology. Heart failure event or death was the primary end point of the trial. Death, heart failure event, ventricular tachycardia, and ventricular fibrillation were secondary end points. Among 1817 patients with available sinus rhythm ECGs at baseline, there were 1281 (70%) with left bundle-branch block (LBBB), 228 (13%) with right bundle-branch block, and 308 (17%) with nonspecific intraventricular conduction disturbances. The latter 2 groups were defined as non-LBBB groups. Hazard ratios for the primary end point for comparisons of CRT-D patients versus patients who only received an implantable cardioverter defibrillator (ICD) were significantly ( P P P =0.257). The risk of ventricular tachycardia, ventricular fibrillation, or death was decreased significantly in CRT-D patients with LBBB but not in non-LBBB patients. Echocardiographic parameters showed significantly ( P Conclusions— Heart failure patients with New York Heart Association class I or II and ejection fraction ≤30% and LBBB derive substantial clinical benefit from CRT-D: a reduction in heart failure progression and a reduction in the risk of ventricular tachyarrhythmias. No clinical benefit was observed in patients with a non-LBBB QRS pattern (right bundle-branch block or intraventricular conduction disturbances). Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00180271.

Aims There are no data regarding the differential response to cardiac resynchronization therapy with defibrillator (CRT-D) by the aetiology of cardiomyopathy in mildly symptomatic patients. We evaluated the outcome of patients enrolled in MADIT-CRT by ischaemic and non-ischaemic aetiology of cardiomyopathy (ICM and non-ICM, respectively). Methods and results The clinical response to CRT-D was assessed among ICM ( n = 1046) and non-ICM ( n = 774) patients enrolled in MADIT-CRT during an average follow-up of 2.4 years, and echocardiographic response was assessed at 1 year. Cardiac resynchronization therapy with defibrillator vs. ICD therapy was associated with respective 34% ( P = 0.001) and 44% ( P = 0.002) reductions in the risk of heart failure or death among ICM and non-ICM patients ( P for interactio n = 0.455). In the ICM group, CRT-D was associated with mean (±SD) 29 ± 14% and 18 ± 10% reductions in left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV), respectively. In the non-ICM group, CRT-D was associated with significantly greater volume reductions compared with the ICM group [37 ± 16% and 24 ± 12% reductions in LVESV and LVEDV, respectively ( P < 0.001 for all)]. Risk subsets in the ICM group that showed a favourable clinical response to CRT-D included patients with QRS ≥150 ms, systolic blood pressure

Background Coronary revascularization (CR) may confer electrical stability in patients with ischemic cardiomyopathy. However, data regarding the effect of CR on the development of ventricular tachyarrhythmias in this population are limited. Objective The purpose of this study was to evaluate the association between CR and arrhythmic risk in postmyocardial infarction (post-MI) patients with left ventricular dysfunction. Methods The risk for life-threatening ventricular tachyarrhythmias (defined as a first appropriate defibrillator therapy for ventricular tachycardia [VT]/ventricular fibrillation [VF] or death) was compared between post-MI patients with and those without prior CR (n = 612 and 147, respectively) enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT). Results The 3-year cumulative rate of VT/VF or death was significantly higher among patients without prior CR (42%) than in patients who underwent prior CR (32%, P = .02). Multivariate analysis demonstrated that patients without prior CR had 48% increased risk ( P = .01) for VT/VF or death. Risk reduction associated with CR was related to elapsed time from CR, assessed both as a categorical variable (tertiles for time from CR: ≥7 years, hazard ratio [HR] = 1.93, P = .001; 1.5–7 years, HR=1.70, P = .01 vs P = .002, increased risk for VT/VF or death per 1-year increment of elapsed time from CR). The effect of CR on arrhythmic risk was similar in patients treated with a defibrillator alone or when combined with cardiac resynchronization therapy. Conclusion Post-MI patients with left ventricular dysfunction who undergo CR experience a time-dependent reduction in the risk for subsequent life-threatening ventricular tachyarrhythmias.

Purpose: We and others have shown that swimming exercise training performed before irreversible coronary occlusion improves the outcome of the heart injury and alters gene expression at the remodeling phase. The purpose of the current study was to identify temporal changes in the molecular response to myocardial infraction of prior exercise trained rats during the acute, the subacute, and the chronic phases postinfarction. Methods: Rats underwent a 7-wk swimming or sedentary protocol and were subjected to surgical induction of acute myocardial infarction (MI). Hearts were removed before and at 4 h, 2 d, and 4 wk after surgery. RNA extracted from the surviving myocardium of the MI hearts or from corresponding tissues in the non-MI hearts was subjected to multitranscript profiling. Results for representative transcripts were validated by reverse transcription and quantitative polymerase chain reaction amplification. Results: Global analysis of the 3686 detected transcripts generated a two-branch dendrogram that distinguished the pre-MI and the 4-h groups from the 2-d and the 4-wk groups and indicated that early after MI, the impact of infarction on the genes expressed overrides the training effect, whereas at 4 wk, the exercised hearts differ markedly from the nonexercised. Clustering the 1500 genes that showed the highest variance over time indicated differential expression of transcription regulators and proapoptotic genes 4 h and 2 d after MI and of stress-related and profibrotic genes 4 wk later in the exercised compared with sedentary hearts. Conclusion: Swimming exercise training conducted before acute MI reprograms the surviving myocardium for altered molecular response to MI that explains, in part, the protected cardiac phenotype of the exercised animals

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary electrical myocardial disease characterized by exercise- and stress-related ventricular tachycardia manifested as syncope and sudden death. The disease has a heterogeneous genetic basis, with mutations in the cardiac Ryanodine Receptor channel (RyR2) gene accounting for an autosomal-dominant form (CPVT1) in approximately 50% and mutations in the cardiac calsequestrin gene (CASQ2) accounting for an autosomal-recessive form (CPVT2) in up to 2% of CPVT cases. Both RyR2 and calsequestrin are important participants in the cardiac cellular calcium homeostasis. We review the physiology of the cardiac calcium homeostasis, including the cardiac excitation contraction coupling and myocyte calcium cycling. The pathophysiology of cardiac arrhythmias related to myocyte calcium handling and the effects of different modulators are discussed. The putative derangements in myocyte calcium homeostasis responsible for CPVT, as well as the clinical manifestations and therapeutic options available, are described.

A widened QRS interval is associated with increased mortality in patients with heart failure (HF). However, the prognostic significance of the type of bundle branch block (BBB) pattern in these patients is unclear. The data of 4,102 patients with HF hospitalized during a prospective national survey were analyzed to investigate the association between BBB type and 1-year mortality in 3,737 patients without pacemakers. Right BBB (RBBB) was present in 381 patients (10.2%) and left BBB (LBBB) in 504 patients (13.5%). RBBB and LBBB were associated with increased 1-year mortality on univariate analysis (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.15 to 1.81, and OR 1.20, 95% CI 0.97 to 1.47, respectively). In patients with systolic HF, after adjusting for multiple risk factors, only RBBB was found to be an independent predictor of mortality (RBBB vs no BBB OR 1.62, 95% CI 1.12 to 2.33, and RBBB vs LBBB OR 1.71, 95% CI 1.09 to 2.69). This correlation was stronger in patients with lower left ventricular ejection fractions and was also maintained in patients without acute myocardial infarctions. Analyzing the data for all patients with HF, there was a trend for increased mortality in the RBBB group only (adjusted OR 1.21, 95% CI 0.94 to 1.56). LBBB was not related to mortality in patients with either systolic HF or preserved ejection fractions. In conclusion, RBBB rather than LBBB is an independent predictor of mortality in hospitalized patients with systolic HF. This prognostic marker could be used for risk stratification and the selection of treatment.

Background:Vasovagal syncope is one of the most common medical conditions in young adults. Previous trials have shown effectiveness of tilt training in treating this condition. We conducted a prospective, randomized study in order to evaluate the role of tilt-training in young adults with vasovagal syncope. Methods:Forty-six soldiers (mean age 19.4 ± 0.8 years, 25 males), with a clinical diagnosis of vasovagal syncope supported by positive tilt test, were randomized to either three months of daily tilt training (treatment group), or no training (control group). Patients in both groups were instructed to increase fluid and salt intake, and to refrain from syncope-inducing situations, such as prolonged standing. Results:Compliance, defined as performing 50% or more of the tilt training daily sessions, was 91% during the first month, and declined to 58% during three months. Treatment group patients had a median (interquartile range) of 5.0 (0.5–16.0) syncope episodes during one-year follow up, compared to a median of 2.0 (0–6.0) episodes in the control group (P = 0.737). Also, there was no difference in time to first syncope after randomization between groups: a median of 1.0 (0.5–2.0) month in the treatment group, compared to 0.8 (0.5–2.0) month in the control group (P = 0.336). Conclusions:Adding daily three-month tilt training to modifications in lifestyle does not improve treatment results in young adults with vasovagal syncope. Good compliance is difficult to achieve in a tilt training program.

Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is a familial disorder caused by cardiac ryanodine receptor type 2 (RyR2) or calsequestrin 2 (CASQ2) gene mutations. To define how CASQ2 mutations cause CPVT, we produced and studied mice carrying a human D307H missense mutation (CASQ(307/307)) or a CASQ2-null mutation (CASQ(DeltaE9/DeltaE9)). Both CASQ2 mutations caused identical consequences. Young mutant mice had structurally normal hearts but stress-induced ventricular arrhythmias; aging produced cardiac hypertrophy and reduced contractile function. Mutant myocytes had reduced CASQ2 and increased calreticulin and RyR2 (with normal phosphorylated proportions) but unchanged calstabin levels, as well as reduced total sarcoplasmic reticulum (SR) Ca(2+), prolonged Ca(2+) release, and delayed Ca(2+) reuptake. Stress further diminished Ca(2+) transients, elevated cytosolic Ca(2+), and triggered frequent, spontaneous SR Ca(2+) release. Treatment with Mg(2+), a RyR2 inhibitor, normalized myocyte Ca(2+) cycling and decreased CPVT in mutant mice, indicating RyR2 dysfunction was critical to mutant CASQ2 pathophysiology. We conclude that CPVT-causing CASQ2 missense mutations function as null alleles. In the absence of CASQ2, calreticulin, a fetal Ca(2+)-binding protein normally downregulated at birth, remains a prominent SR component. Adaptive changes to CASQ2 deficiency (increased posttranscriptional expression of calreticulin and RyR2) maintained electrical-mechanical coupling, but increased RyR2 leakiness, a paradoxical response further exacerbated by stress. The central role of RyR2 dysfunction in CASQ2 deficiency unifies the pathophysiologic mechanism underlying CPVT due to RyR2 or CASQ2 mutations and suggests a therapeutic approach for these inherited cardiac arrhythmias.

Background: In this prospective, randomized, controlled study, we compared the performance of J-shaped active fixation (AF) atrial leads with J-shaped passive fixation (PF) leads, over a 1-year follow-up period. Methods: A total of 200 consecutive patients were prospectively randomized for implantation with a Medtronic 5568 AF lead model (n = 103; Minneapolis, MN, USA) versus a Medtronic 5592 PF model (n = 97), and all lead-related measurements and complications were recorded over one year. Results: All leads were successfully implanted with a nonsignificant difference in crossover rate to the alternative lead due to failed implantation (1 in the AF and 4 in the PF group, P = NS). Fluoroscopy time during implantation procedure was significantly shorter in the PF group (2.1 ± 3.6 vs 3.3 ± 4.5 minute, P < 0.05). Pacing thresholds during implantation were significantly lower in patients with PF leads (0.7 ± 0.3 V vs 0.9 ± 0.3 V, P < 0.001) and this difference persisted at 1-year follow-up (0.8 ± 0.6 V vs 1.3 ± 0.9 V in PF and AF leads respectively, P < 0.05). Lead-related complications occurred in PF and AF with similar frequency (4% and 9% respectively, P = 0.2). However, pericardial complications occurred only in the AF group (6 cases, P = 0.01). Lead dislodgement was observed in only two cases—both in the PF group (P = 0.3). Conclusion: Both types of J-shaped atrial leads had reasonable performance. PF leads required shorter fluoroscopy time for implantation, demonstrated a better pacing threshold over a 1-year follow-up period and had no pericardial complications, while AF lead implantation was complicated by pericardial irritation and/or effusion in 6% cases (P = 0.01).

Aims: To compare the clinical response of patients with right ventricular apical pacing (RVAP) upgraded to cardiac resynchronization therapy (CRT) to that of previously nonpaced heart failure (HF) patients who had de novo CRT implantation. Background: The role of CRT in patients with wide QRS and HF due to RVAP is less well established than in other CRT candidates. Methods: Ninety-eight consecutive patients with CRT were studied (mean age 70, mean ejection fraction 0.23). Group A: patients having RVAP prior to CRT implantation (n = 25), group B: patients without prior RVAP (n = 73). Clinical and echocardiographic parameters were recorded prior to, and 3 months after, CRT implantation. Results: Group A patients had a wider QRS at baseline compared to group B (203 ± 32 ms vs 163 ± 30 ms respectively, P < 0.001), and a shorter 6-minute walking distance (222 ± 118 m vs 362 ± 119 m, respectively, P < 0.005). Otherwise, clinical and echocardiographic parameters were not different. At follow up, group A patients had an average 0.7 ± 0.5 decrease in their NYHA functional class, compared to 0.3 ± 0.7 in group B patients (P < 0.05). Six-minute walking distance increased by 93 ± 113 m in group A, versus 36 ± 120 m in group B (P = 0.22). There was no difference in echocardiographic response to CRT between the groups. Conclusions: HF patients with prior RVAP demonstrate clinical improvement after upgrading to CRT that is comparable, and in some aspects, even better than that observed in HF patients with native conduction delay who undergo de novo CRT implantation.

Objectives To describe the incidence of atrial fibrillation induced by dobutamine stress echocardiography and characterize patients at risk of developing atrial fibrillation, by constructing a simple validated risk score index. Design An observational study using prospectively collected data. Methods 3800 consecutive patients in sinus rhythm undergoing dobutamine stress echocardiography were randomly divided to a case (2/3) and test group (1/3). Associations of predetermined demographic, clinical, electrocardiographic and echocardiographic variables were calculated in patients with and without atrial fibrillation induced by dobutamine stress echocardiography in the case group. Logistic regression analysis determined significant independent risk predictors, a scoring index was constructed and validated on the test group. Results There was a 2% incidence of dobutamine stress echocardiography-induced atrial fibrillation in the study population. Risk predictors of atrial fibrillation included: a history of atrial fibrillation (2 points), increased left atrial diameter, right bundle branch block, decreased rest heart rate and hypertension (1 point each). The case subgroup low-risk patients (score 0–2) had a 1% risk, moderate-risk patients (score 3) a 2.7% and high-risk patients (score 4–6) a 14.5% risk of developing atrial fibrillation during dobutamine stress echocardiography. The rates in the test subgroup were 1%, 3.8% and 15.3%, respectively. Conclusion Atrial fibrillation during dobutamine stress echocardiography is not common, the risk of developing atrial fibrillation during dobutamine stress echocardiography can be predicted by using a simple risk score system comprised of clinical, electrocardiographic and rest echocardiographic variables, which may be of help when planning a dobutamine stress echocardiography test in selected cases.

It was hypothesized that restricted diastolic leaflet motion is implicated not only in the mechanism of systolic mitral regurgitation (MR) but also in the mechanism of diastolic MR observed in patients with severe heart failure. Cardiac resynchronization therapy (CRT) can oppose increased mitral leaflet tethering by increasing transmitral pressure, thereby providing an opportunity to explore this hypothesis. A total of 26 consecutive candidates for CRT with diastolic MR were compared with 26 candidates without diastolic MR. Maximal diastolic mitral leaflet opening and inflow direction and measures of mitral valve apparatus (i.e., mitral annular diameters, calculated mitral annular area, and tethering distance) were assessed from the apical 4-chamber view before and during CRT. There were no significant differences in New York Heart Association functional class, ejection fraction, QRS duration, PR interval, systolic MR grade, or 2-dimensional geometry of the mitral valve apparatus between the groups. Patients with diastolic MR had more restricted maximal diastolic leaflet openings (54 degrees +/- 17 degrees vs 71 degrees +/- 11 degrees , p = 0.003) and substantially smaller inflow angles (66 degrees +/- 7 degrees vs 79 degrees +/- 9 degrees , p = 0.0003) compared with patients without diastolic MR. After the institution of CRT, diastolic MR was eliminated in all patients, although there were no significant changes in any of the parameters of mitral valve apparatus. In conclusion, abnormal mitral valve tethering is a constitutive element of the mechanism of diastolic MR in patients with left ventricular dysfunction. Its acute resolution after CRT does not seem to be caused by changes in mitral valve geometry but rather by an increase in transmitral closing forces.

Aims This study assesses short- and long-term performance of the S80TB ventricular lead manufactured by Sorin Biomedica, Italy. Methods and results Three hundred and thirty leads were implanted and had complete follow-up with us for a minimum of 60 months or up to failure, removal, and/or patient death (mean 40 months, range: 1 day to 81 months). Thirty-two patients (9.6%) had spontaneous lead-related complications: 7 (2.1%) occurred during the first week; 25 (7.6%) had chronic complications, of which 20 (6.1%) necessitated re-operations; 3 (0.9%) were lead material failures. Of the 110 re-operations (90 pacemaker replacements and 20 operations due to complications), 7 additional cases (6.4%) were complicated by unique connector damage that occurred during disconnection of the lead from the connector block. The Kaplan–Meier estimated 5-year lead survival free of lead material failure and free of any significant lead complication were 97.9 and 87%, respectively. Conclusion The S80TB lead demonstrates an acceptable rate of acute and chronic spontaneous complications and very few lead material failures over 5 years of follow-up. However, there seems to be a relatively high incidence of connector damage during disconnection from the connector block. Extra caution is required during those procedures in patients with this lead.

Objective: In this prospective, randomized, control study we compared performance of J-shaped (JL) and straight atrial leads (SL) with active (screw-in) fixation mechanism, over a 5-year follow-up period. Subjects and Methods: A total of 208 consecutive patients were randomized for implantation with a Medtronic 4568 JL model (n = 103) versus a Medtronic 4068 SL model (n = 105), and all lead-related measurements and complications were recorded. Results: Lead-related complications occurred in JL and SL with similar frequency (6% and 9%, respectively, P = 0.45). Lead dislodgment occurred in 8 (7.8%) cases in SL versus none in JL (P = 0.004). Lead malfunction and excessive pacing thresholds without macrodislodgment occurred more frequently in JL (11; 10.7%) than in SL (4; 3.8%), P = 0.055. Lead material failure (insulation break) occurred only once in SL at the 5-year checkup. Most complications occurred during the first year after implantation. Other events occurred in both leads with similar frequency and included: death in 39 and 35, loss of follow-up in 8 and 6, and development of atrial fibrillation in 9 and 15 patients, respectively. Of those who completed follow-up, lead impedance and pacing threshold increased significantly in both groups. P wave decreased in SL but not in JL. Conclusion: More dislocations occurred in SL, but were counterbalanced by more lead malfunctions and excessive pacing thresholds in the JL group. Both leads demonstrated minor deterioration in electrical measurements during follow-up, with only 1 case of lead material failure in SL. Overall, both groups demonstrated favorable lead performance throughout follow-up.

Objectives The aim of this research was to investigate the structural, functional, and molecular features of the remodeling heart in prior swim-trained infarcted rats. Background Physical exercise training is a known protective factor against cardiovascular morbidity and mortality. The structural and molecular aspects underlying this protection in the remodeling heart have not been investigated. Methods After seven weeks of swimming exercise training, rats underwent surgical ligation of the left coronary artery followed by a four-week sedentary period. Untrained control rats underwent the same surgical protocol. Left ventricular function was assessed by echocardiography four weeks after infarction, and hearts were sampled for histological and molecular analysis. Ribonucleic acid from the surviving left ventricle was analyzed by complementary deoxyribonucleic acid arrays followed by Northern blotting or quantitative reverse transcription polymerase chain reaction of selected messenger ribonucleic acids (mRNAs). Results Scar area was 1.6-fold smaller (p = 0.0002), arteriolar density was 1.7-fold higher (p = 0.0002), and left ventricular shortening fraction was 1.9-fold higher (p = 0.003) in the exercise-trained compared with sedentary hearts. Eleven genes whose expression level varied by at least ±1.5-fold distinguished the prior exercised rats from their sedentary counterparts. Compared with sedentary, the exercised hearts displayed 9- and 2.4-times lower levels of atrial natriuretic peptide and aldolase mRNA (p = 0.03 and 0.04, respectively), and a 2.7- and 1.9-fold higher abundance of cytochrome c-oxidase and fatty acid binding protein, respectively (p Conclusions Swimming exercise training before acute myocardial infarction reduces scar size, increases arteriole density, and manifests adaptation of stress- and energy-metabolism-related genes that may contribute to the improved heart function observed during remodeling.

This study examined left ventricular (LV) filling properties and exercise hemodynamics noninvasively before and after an exercise training program in patients with chronic heart failure (HF). Although exercise training did not improve LV filling properties in patients with advanced HF, LV filling properties determined the hemodynamic benefit attainable from exercise in this patient group.

ObjectivesThe aim of this study was to evaluate the significance of increased left atrial (LA) volume determined within the first 48 h of admission as a long-term predictor of outcome in patients with acute myocardial infarction (MI).BackgroundThe LA volume reflects left ventricular (LV) diastolic properties. Whereas other LV Doppler diastolic characteristics are influenced by acute changes in LV function, LA volume is stable and reflects diastolic properties before MI.MethodsClinical and echocardiographic parameters were prospectively collected in 395 consecutive patients with acute MI. Patients with LA volume index (LAVI) >32 ml/m2(normal + 2 standard deviations) were compared with those with LAVI ≤32 ml/m2. Independent clinical and echocardiographic prognostic risk factors for five years' mortality were determined by the Cox proportional hazard model.ResultsLeft atrial volume index >32 ml/m2was found in 63 patients (19%) who had a higher incidence of congestive heart failure on admission (24% vs. 12%, p < 0.01), a higher incidence of mitral regurgitation, increased LV dimensions, and reduced LV ejection fraction when compared with patients with LAVI ≤32 ml/m2. Their five-year mortality rate was 34.5% versus 14.2% (p < 0.001). Significant independent risk predictors of five years' mortality were age (10 years) (odds ratio [OR] 1.45; 95% confidence interval [CI]1.14 to 1.86), Killip class ≥2 on admission (OR 2.30; 95% CI 1.29 to 4.09), LAVI >32 ml/m2(OR 2.22; 95% CI 1.25 to 3.96), diabetes (OR 1.94; 95% CI 1.15 to 3.28), and LV restrictive filling pattern (OR 1.89; 95% CI 1.09 to 3.31).ConclusionsIn patients with acute MI, increased LA volume, determined within the first 48 h of admission, is an independent predictor of five-year mortality with incremental prognostic information to clinical and echocardiographic data.

Introduction: Evidence is inconclusive concerning the role of implantable cardioverter defibrillators (ICDs) to treat patients with hemodynamically stable ventricular tachycardia (VT). The goal of this study was to estimate future risk of unstable ventricular arrhythmias in patients who received ICDs for stable VT. Methods and Results: We reviewed complete ICD follow-up data from 82 patients (age 66.1 ± 11.3 years; left ventricular ejection fraction 32.3%± 11.2%; mean ± SD) who received ICDs for stable VT. During the follow-up period of 23.6 ± 21.5 months (mean ± SD), 15 patients (18%) died, and 10 (12%) developed unstable ventricular arrhythmia, 8 of whom had the unstable arrhythmia as the first arrhythmia after ICD placement. Estimated 2- and 4-year survival in the whole group was 80% and 74%, respectively. Estimated 2- and 4-year probability of any VT and unstable VT was 67% and 77% and 11% and 25%, respectively. There were no differences in age, ejection fraction, sex, underlying heart disease, cycle length, symptoms, baseline electrophysiologic study results, or QRS characteristics of qualifying VT between patients who developed unstable ventricular arrhythmia and patients who did not. Twenty-nine patients (35%) had at least one inappropriate shock, and 11 (13%) underwent further surgery for ICD-related complications. Conclusion: Patients who present with hemodynamically stable VT are at risk for subsequent unstable VT. ICD treatment offers potential salvage of patients with stable VT who subsequently develop unstable VT/ventricular fibrillation, although complications and inappropriate shocks are considerable. No predictors could be found for high and low risk for unstable arrhythmias. These findings support ICD treatment for stable VT survivors. (J Cardiovasc Electrophysiol, Vol. 15, pp. 658-664, June 2004)

This report describes the experience of a large pacemaker center during three successive replacement operations due to safety alerts involving three models from the same manufacturer. Between March 1993 and May 1999, 210 patients were implanted with three DDD pacemaker models (Sorin Biomedica, Saluggia, Italy) that were subsequently subject to safety alerts. Pacemaker records were reviewed for complications related to device malfunction, and those secondary to the replacement procedure. Pacemaker malfunction was observed in 16.4% of units despite much lower estimates from the company (range 1-4%). With the exception of one, all units were replaced. Malfunctions were discovered in 7 of 20 pacemakers following an urgent call for follow-up issued as a result of the alert. Twenty units implanted as substitutes for those replaced following the first alert turned out to be subject to the third alert. Significant clinical consequences of malfunction occurred in 5.3% of patients including a near fatal event in one case, while complications related to the replacement procedure occurred in 8.3% of patients, including one fatality. On the issuance of a safety alert, failure rates in a particular center may be higher than published by the manufacturer, and should prompt action by the center to weigh local incidence of device failure against complications of replacement procedures. When device failure mechanism is not entirely clear, particularly in cases of successive model failures, replacement devices from a different manufacturer should be considered.

The authors studied the involvement of IKr potassium current in ventricular fibrillation during perfusion. Electrophysiologic parameters were measured before and after dofetilide administration (2.5, 7.5, and 12.5 × 10 -7 M, n = 8) in isolated perfused feline hearts. During pacing, these parameters included epicardial conduction time, refractoriness, and the fastest rate for 1:1 pacing/response capture. During 8 minutes of electrically induced tachyarrhythmias, they included heart rate and normalized entropy reflecting the degree of organization. In all groups, arrhythmia rate was slower in the right ventricle than in the left ventricle. Dofetilide decreased the arrhythmia rate more than it increased organization, reduced its maintenance, or increased difficulty in initiation. Refractoriness was prolonged in a reverse use-dependent way which was less than 1:1 pacing/response capture. Unexpectedly, a moderate prolongation of conduction time was observed. Inverse correlation was found between the arrhythmia rate and changes in refractoriness and conduction time and between the degree of organization and refractoriness (both ventricles) and conduction time (right ventricle). Dofetilide, which intensively blocks IKr current and unexpectedly suppressed conduction, has different quantitative effects on fibrillation features. These changes in fibrillation suggest that these effects are mainly associated with refractoriness prolongation and do not seem to be attenuated by conduction suppression.