ZnT1 induces a crosstalk between T-type and L-type calcium channels through interactions with Raf-1 kinase and the calcium channel ß2 subunit.

ZnT1 is a major zinc transporter that regulates cellular zinc homeostasis. We have previously shown that ZnT1 has additional functions that are independent of its activity as a Zn2+ extruder. These include inhibition of the L-type calcium channel (LTCC) through interaction with the auxiliary ß-subunit of the LTCC and activation of the Raf-ERK signaling leading to augmented activity of the T-type calcium channel (TTCC). Our findings indicate that ZnT1 increases TTCC activity by enhancing the trafficking of the channel to the plasma membrane. LTCC and TTCC are co-expressed in many tissues and have different functions in a variety of tissues. In the current work, we investigated the effect of the voltage-gated calcium channel (VGCC) ß-subunit and ZnT1 on the crosstalk between LTCC and TTCC and their functions. Our results indicate that the ß-subunit inhibits the ZnT1-induced augmentation of TTCC function. This inhibition correlates with the VGCC ß-subunit-dependent reduction in ZnT1-induced activation of Ras-ERK signaling. The effect of ZnT1 is specific, as the presence of the ß-subunit did not change the effect of endothelin-1 (ET-1) on TTCC surface expression. These findings document a novel regulatory function of ZnT1 serving as a mediator in the crosstalk between TTCC and LTCC. Overall, we demonstrate that ZnT1 binds and regulates the activity of the ß-subunit of VGCC and Raf-1 kinase and modulates surface expression of the LTCC and TTCC catalytic subunits, consequently modulating the activity of these channels.

Shifting from vitamin K antagonists to non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: predictors, patterns and temporal trends.

BACKGROUND: Non-Vitamin K antagonist oral anticoagulants (NOACs) emerged as an alternative with comparable or superior efficacy and safety to vitamin K antagonists (VKAs) for stroke prevention in patients with non-valvular atrial fibrillation (AF). OBJECTIVES: The aim of the current study was to investigate the patterns, predictors, timelines and temporal trends of shifting from VKAs to NOACs. METHODS: In this retrospective observational study, the computerized database of a large healthcare provider in Israel, Maccabi Healthcare Services, was searched to identify patients with AF for whom either a VKA or NOAC was prescribed between 2012 and 2015. Time from diagnosis to therapy initiation and to shifting between therapies was evaluated. RESULTS: Out of 6987 eligible AF incident patients, 2338 (33.4%) initiated treatment with a VKA and 2221 (31.7%) with a NOAC. In addition, 5259 prevalent patients were analyzed. During the study period, NOAC prescriptions proportion among the newly diagnosed cases increased from 32 to 68.4% (p for trend <  0.001). The median time from diagnosis to first dispensing was greater in NOAC than VKA and decreased among patients treated with NOAC during the study period (2012: 1.9 and 0.3 months, 2015: 0.7 and 0.2 months, respectively). During follow-up, 3737 (49%) patients (54.3% and 47.1% of the incident and prevalent cases, respectively), shifted from a VKA to a NOAC, after a median of 22 months and 39 months in the incident and prevalent cases, respectively, decreasing throughout the study period. Female gender, younger age, southern district, higher CHADS2 and CHA2DS2-VASC score, non-smoking, and treatment with antiplatelets were associated with a greater likelihood for therapy shift. Shifting from a NOAC to a VKA decreased over time from 8 to 4.5% in 2012 to 0.5% and 0.7% in 2015 in the incident and prevalent groups, p <  0.001 respectively. CONCLUSIONS: Shifting from VKA to NOAC occurred in 50% of the cases, more frequently among incident cases, and younger patients with greater stroke risk. Shifting from a NOAC to a VKA was much less frequent, yet it occurred more often in incident cases and decreased over time. A socially and economically sensitive program to optimize the initiation of OAC therapy upon diagnosis is warranted.

Sex-specific contemporary trends in incidence, prevalence and survival of patients with non-valvular atrial fibrillation: A long-term real-world data analysis.

INTRODUCTION: Atrial fibrillation (AF) is a major increasing public health problem worldwide, with clinical and epidemiological differences between men and women. However, contemporary population-level data on incidence and survival are scarce. AIM: To evaluate sex-specific contemporary trends in the incidence, prevalence, and long-term survival of non-valvular AF in a real-world setting. METHODS: AF patients diagnosed between 2007-2015, insured by a large, state-mandated health organization in Israel (Maccabi Healthcare Services) were included. AF was diagnosed based on registered diagnoses. Patients with valvular disease, active malignancy, cardiac surgery ≤ 6 months, or recent pregnancy, were excluded. Annual incidence rate, period prevalence, and 5-year survival for each calendar year during the study period, were calculated. RESULTS: A total of 15,409 eligible patients (8,288 males, 7,121 females) were identified. Males were more likely to be younger, have higher rates of underlying diseases (ischemic heart disease, heart failure, and chronic obstructive pulmonary disease), but with lower rates of hypertension and chronic kidney diseases as compared to female patients. During the study period, age-adjusted incidence decreased both in men: (-0.020/1,000-person year, p-for trend = 0.033) and, women (-0.025/1,000 person-year p = 0.009). The five-year survival rate was significantly higher among men vs. women (77.1% vs. 71.5%, respectively, p<0.001). Age-adjusted prevalence increased significantly among men (+0.102 per year, p-for trend<0.001) yet decreased among women (-0.082 per year, p-for trend = 0.005). A significant trend toward improved long-term survival was observed in women and not in men. CONCLUSIONS: The current study shows significant sex-related disparities in the incidence, prevalence, and survival of AF patients between 2007-2015; while the adjusted incidence of both has decreased over-time, prevalence and mortality decreased significantly only in women.

Multisite cardiac resynchronization therapy for traditional and non-traditional indications.

PURPOSE: Multisite cardiac resynchronization therapy (MSCRT) with dual-vein left ventricular (LV) pacing has theoretical advantages over conventional CRT in faster and more physiological LV activation. We aimed to define indications, feasibility, safety, acute, and long-term results of MSCRT. METHODS: All patients implanted with MSCRT during 2008-2014 in a single center were reviewed and analyzed. RESULTS: Thirty-nine patients (90% CRT-defibrillators, 64 ± 9 years, 85% male, 74% ischemic etiology) were included. Four groups of indications were recognized: (1) significant tricuspid regurgitation (TR) in patients planned for device implantation without right ventricular lead (n = 3). Follow-up (f/u) of 4 ± 3 years showed major symptomatic improvement in all, with stable LV size and function and deferral of valve surgery; (2) severe heart failure with reduced ejection fraction (HFrEF) and refractory ventricular tachycardia (VT) (n = 4). Except for 1 early death for acute renal failure, all others showed no VT episodes and HF improvement (f/u 4.5 ± 0.5 years); (3) severe HFrEF and wide QRS (≥ 150 ms) or failure of biventricular pacing to narrow QRS during implantation (n = 5). One patient had periprocedural mortality. The others had major clinical improvement; (4) severe HF and narrow QRS/RBBB (n = 27). 23/24 patients with available f/u of 3 ± 1.7 years improved clinically and 57% had EF improvement. In 3 patients, LV1 was disabled and one had LV2 dislodgement. CONCLUSIONS: MSCRT is feasible, safe, and valuable in selected patients with a need to avoid RV lead during device implantation, refractory VT with no other solution, severe HFrEF with wide QRS or CRT non-responsiveness, and severe HF without LBBB. Randomized controlled studies are required.

Reduction in operator radiation exposure during transradial coronary procedures using a simple lead rectangle.

OBJECTIVES: Transradial access for percutaneous coronary intervention (PCI) reduces procedural complications however, there are concerns regarding the potential for increased exposure to ionizing radiation to the primary operator. We evaluated the efficacy of a lead-attenuator in reducing radiation exposure during transradial PCI. METHODS AND RESULTS: This was a non-randomized, prospective, observational study in which 52 consecutive patients were assigned to either standard operator protection (n = 26) or the addition of the lead attenuator across their abdomen/pelvis (n = 26). In the attenuator group patients were relatively older with a higher prevalence of peripheral vascular disease (67.9 vs 58.7 p = 0.0292 and 12% vs 7.6% p < 0.001 respectively). Despite similar average fluoroscopy times (12.3 ± 9.8 min vs. 9.3 ± 5.4 min, p = 0.175) and average examination doses (111866 ± 80790 vs. 91,268 ± 47916 Gycm2, p = 0.2688), the total radiation exposure to the operator, at the thyroid level, was significantly lower when the lead-attenuator was utilized (20.2% p < 0.0001) as compared to the control group. Amongst the 26 patients assigned to the lead-attenuator, there was a significant reduction in measured radiation of 94.5% (p < 0.0001), above as compared to underneath the lead attenuator. CONCLUSIONS: Additional protection with the use of a lead rectangle-attenuator significantly lowered radiation exposure to the primary operator, which may confer long-term benefits in reducing radiation-induced injury. ADVANCES IN KNOWLEDGE: This is the first paper to show that a simple lead attenuator almost completely reduced the scattered radiation at very close proximity to the patient and should be considered as part of the standard equipment within catheterization laboratories.

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

AIMS: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. METHODS AND RESULTS: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. CONCLUSION: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Safety, efficacy, and clinical applicability of pulmonary vein isolation with circular multi-electrode ablation systems: PVAC® vs. nMARQ™ for atrial fibrillation ablation.

AIMS: We compare our experience with available circular multi-electrode catheters for atrial fibrillation (AF) ablation: PVAC(®), a phased radiofrequency system, and nMARQ™, an irrigated tip-CARTO-based technology. METHODS AND RESULTS: Prospective observational study of 175 consecutive patients with follow-up duration of at least 5 months who underwent pulmonary vein isolation (PVI) for symptomatic AF using PVAC(®) (n = 93, age 61.4 ± 9.8 years; 60% male, 13% persistent AF) vs. nMARQ™ (n = 82, age 63.2 ± 10.6 years; 67% male, 24% persistent AF). Procedure and radiation times were 94 ± 27 and 33 ± 13 min for PVAC(®) and 81 ± 18 and 30 ± 8.5 for nMARQ™ (P = 0.0008 and P = 0.18), respectively. The number of applications and the total burning time (min) were 20 ± 7 and 19 ± 6.7 for PVAC(®) and 16 ± 5.6 and 11 ± 4 for nMARQ™ (P < 0.0001 for both), respectively. In two nMARQ™ patients with small atria and pulmonary veins (PVs) and in two PVAC(®) patients with large PVs, the procedure failed; switching to the alternative technology was successful. Acute success rate was 97% for PVAC(®) and 95% for nMARQ™. There was one tamponade in nMARQ™ group and non-significant different minor complications for both techniques. One-year freedom from AF was 79 and 80.7% with PVAC(®) vs. nMARQ™, after one PVI, and 88 vs. 87.7% after two PVIs. CONCLUSION: Both technologies have short procedure and fluoroscopy times, comparable complication rates, and comparable acute and 1-year success rates. The number of applications and total procedure and burning times were shorter with nMARQ™. nMARQ™ was more suitable for larger atria and PVs. Thus, a patient-based pre-ablation anatomy definition is probably warranted for appropriate selection of technology type.

INO-8875, a highly selective A1 adenosine receptor agonist: evaluation of chronotropic, dromotropic, and hemodynamic effects in rats.

Selective pharmacological activation of the adenosine 1 receptor (A(1)R) is a promising new approach to achieve a potent block of atrioventricular (A-V)-nodal conduction without significant cardiovascular side effects. The purpose of the present study was to evaluate the cardiovascular profile of INO-8875, a highly selective A(1)R agonist, and to compare its properties with N-[3(R)-tetrahydrofuranyl]-6-aminopurine riboside (CVT-510), which has already been shown to induce negative dromotropic effects with minimal cardiovascular side effects in animals and in clinical studies. Dose-response experiments in the isolated hearts of rats were used to evaluate the functional selectivity of INO-8875 for the slowing of A-V-nodal conduction. Ventilated adult rats were used to study the effects of INO-8875, in vivo, on arterial blood pressure as well as on supraventricular electrophysiology. Ex vivo, INO-8875 (100 nM to 3 µM) progressively prolonged A-V-nodal conduction without reducing left ventricular function or coronary resistance. In vivo, INO-8875 up to a dose of 50 µg/kg did not reduce the carotid arterial blood pressure (n = 4). INO-8875 (1-50 µg/kg) and CVT-510 (20 and 50 µg/kg) both induced a dose-dependent decrease in heart rate and atrial refractoriness, as well as slowing of A-V-nodal conduction. However, compared with CVT-510, the activity of INO-8875 was more pronounced in A-V-nodal function. INO-8875 exhibited a greater duration of action, lasting up to 2.5 hours post dosing, whereas the effects of CVT-510 dissipated over 1 hour. INO-8875 demonstrates functional properties of a highly selective A(1)R agonist. INO-8875 exhibits an increased dromotropic effect and greater duration of action compared with CVT-510.

[Brain natriuretic peptide (BNP) level predicts long term ventricular arrhythmias in patients with moderate to severe left ventricular dysfunction].

BACKGROUND: Brain natriuretic peptide (BNP) is a powerful predictor of mortality in patients with left ventricular dysfunction. Since malignant ventricular arrhythmias such as sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) are a major cause of death among those patients, we postulated that BNP levels can predict their long-term occurrence. OBJECTIVES: To study the association between malignant ventricular arrhythmias and BNP level over a long term follow-up. METHODS: We prospectively followed 94 patients with ischemic heart disease and left ventricular dysfunction, all implanted with an implantable cardioverter defibrillator (ICD). BNP level was measured at baseline and ICD interrogation and clinical status were recorded at 6 months intervals for a median of 3.5 years. RESULTS: Patients with BNP levels in the highest quartile experienced significantly more arrhythmic events than those at the lower three quartiles (OR 2.2, 95% C.I 1.2-4.2). In a multivariate analysis only BNP level predicted arrhythmic events. Among patients implanted for primary prevention of sudden cardiac death, BNP at the lowest quartile significantly predicted low event rate. CONCLUSION: While high BNP level is predictive of malignant ventricular arrhythmias, low levels among patients implanted for primary prevention can identify a low risk subgroup for which the ICD might be of borderline therapeutic benefit.

ZnT-1 enhances the activity and surface expression of T-type calcium channels through activation of Ras-ERK signaling.

Zinc transporter-1 (ZnT-1) is a putative zinc transporter that confers cellular resistance from zinc toxicity. In addition, ZnT-1 has important regulatory functions, including inhibition of L-type calcium channels and activation of Raf-1 kinase. Here we studied the effects of ZnT-1 on the expression and function of T-type calcium channels. In Xenopus oocytes expressing voltage-gated calcium channel (CaV) 3.1 or CaV3.2, ZnT-1 enhanced the low-threshold calcium currents (I(caT)) to 182 ± 15 and 167.95 ± 9.27% of control, respectively (P < 0.005 for both channels). As expected, ZnT-1 also enhanced ERK phosphorylation. Coexpression of ZnT-1 and nonactive Raf-1 blocked the ZnT-1-mediated ERK phosphorylation and abolished the ZnT-1-induced augmentation of I(caT). In mammalian cells (Chinese hamster ovary), coexpression of CaV3.1 and ZnT-1 increased the I(caT) to 166.37 ± 6.37% compared with cells expressing CaV3.1 alone (P < 0.01). Interestingly, surface expression measurements using biotinylation or total internal reflection fluorescence microscopy indicated marked ZnT-1-induced enhancement of CaV3.1 surface expression. The MEK inhibitor PD-98059 abolished the ZnT-1-induced augmentation of surface expression of CaV3.1. In cultured murine cardiomyocytes (HL-1 cells), transient exposure to zinc, leading to enhanced ZnT-1 expression, also enhanced the surface expression of endogenous CaV3.1 channels. Consistently, in these cells, endothelin-1, a potent activator of Ras-ERK signaling, enhanced the surface expression of CaV3.1 channels in a PD-98059-sensitive manner. Our findings indicate that ZnT-1 enhances the activity of CaV3.1 and CaV3.2 through activation of Ras-ERK signaling. The augmentation of CaV3.1 currents by Ras-ERK activation is associated with enhanced trafficking of the channel to the plasma membrane.

Distinguishing "benign" from "malignant early repolarization": the value of the ST-segment morphology.

BACKGROUND: Means for distinguishing the very common "benign early repolarization" from the very rare but malignant form are needed. Recently, the presence of early repolarization with "horizontal ST segment" was found to predict arrhythmic death during long-term follow-up in a large population study. We therefore speculated that the combination of "J waves with horizontal ST segment" would correlate with a history of idiopathic ventricular fibrillation (VF) better than the mere presence of J waves. OBJECTIVES: To determine whether the morphology of the ST segment adds diagnostic value to the mere presence of J waves in a case-control series of idiopathic VF. METHODS: We reanalyzed our case-control study showing that the presence of J waves strongly correlates with a history of idiopathic VF among 45 patients with this disorder, 124 controls matched for age and gender ("matched-control" group), and 121 young athletes. This time we focused only on those patients with J waves and graded their ST-segment morphology as either "horizontal" or "ascending" according to predefined criteria. RESULTS: The presence of J waves was associated with a history of idiopathic VF with an odds ratio of 4.0 (95% confidence intervals = 2.0-7.9), but having both J waves and horizontal ST segment yielded an odds ratio of 13.8 (95% confidence intervals = 5.1-37.2) for having idiopathic VF. CONCLUSIONS: We report, for the first time, that the combination of J waves with horizontal/descending ST segment improved our ability to distinguish patients with idiopathic VF from controls matched by gender and age.

ZnT-1 protects HL-1 cells from simulated ischemia-reperfusion through activation of Ras-ERK signaling.

Activation of ERK signaling may promote cardioprotection from ischemia-reperfusion (I/R) injury. ZnT-1, a protein that confers resistance from zinc toxicity, was found to interact with Raf-1 kinase through its C-terminal domain, leading to downstream activation of ERK. In the present study, we evaluated the effects of ZnT-1 in cultured murine cardiomyocytes (HL-1 cells) that were exposed to simulated-I/R. Cellular injury was evaluated by lactate dehydrogenase (LDH) release and by staining for pro-apoptotic caspase activation. Overexpression of ZnT-1 markedly reduced LDH release and caspase activation following I/R. Knockdown of endogenous ZnT-1 augmented the I/R-induced release of LDH and increased caspase activation following I/R. Phospho-ERK levels were significantly increased following I/R in cells overexpressing ZnT-1, while knockdown of ZnT-1 reduced phospho-ERK levels. Pretreatment of cells with the MEK inhibitor PD98059 abolished the protective effect of ZnT-1 following I/R. Accordingly, a truncated form of ZnT-1 lacking the C-terminal domain failed to induce ERK activation and did not protect the cells from I/R injury. In contrast, expression of the C-terminal domain by itself was sufficient to induce ERK activation and I/R protection. Interestingly, the C-terminal of the ZnT-1 did not have protective effect against the toxicity of zinc. In the isolated rat heart, global ischemic injury rapidly increased the endogenous levels of ZnT-1. However, following reperfusion ZnT-1 levels were found to be decreased. Our findings indicate that ZnT-1 may have important role in the ischemic myocardium through its ability to interact with Raf-1 kinase.

Acute transient phlebitis during eptifibatide intravenous injection: case report.

We present a 56-year-old man who developed acute transient phlebitis of the right cephalic vein during an intravenous injection of eptifibatide (Integrilin, Schering Plough, Kenilworth, NJ). The eptifibatide injections were discontinued, and signs of phlebitis disappeared within minutes. The patient's course was uneventful, and he was discharged home after 8 days. As far as we know, this is the first report of acute transient phlebitis during intravenous eptifibatide injections in the English-language medical literature.

INO-8875, a Highly-Selective A1 Adenosine Receptor Agonist: Evaluation of Chronotropic, Dromotropic and Hemodynamic Effects in Rats.

Publication of this article is suspended until the authors can provide full identification and verification of the chemical structure of INO-8875.

Association between mitral and aortic valve calcification and preferential left or right coronary artery disease.

BACKGROUND AND AIM OF THE STUDY: Mitral annular calcification (MAC) and aortic valve calcification (AVC) are predictive of coronary artery disease (CAD). However, no data exist concerning the association between preferential CAD side localization to the left or right coronary arteries and MAC or AVC. METHODS: A cohort analysis was performed of 1,000 consecutive coronary angiographies recorded in patients with CAD. The angiographies were divided according to the distribution of CAD to the isolated right coronary tree disease, left coronary tree disease, or both. The echocardiograms were reviewed for MAC, AVC or combined valvular calcification (CVC). RESULTS: Significant CAD (lumenal stenosis > 70%) was observed in 688 patients, among whom 167 had isolated (right or left) CAD and 521 double-sided coronary tree disease. Valvular calcification (VC) was observed in 70 (42%) of the isolated CAD patients; of these, 41 had isolated left CAD and 29 isolated right CAD. Among the isolated left CAD patients with VC, 13 (32%) had AVC, 22 (53%) had CVC, and only six (15%) had MAC (p < 0.01). Among the isolated right CAD patients with VC, 18 (62%) had MAC, nine (31%) had CVC, and only two (7%) had AVC (p < 0.01). VC was observed in 266 patients (51%) with mixed CAD; of these, 152 (57%) had CVC, 103 (39%) had AVC, and 11 (4%) had MAC (p < 0.01). CONCLUSION: Isolated left CAD is associated with AVC or CVC more frequently than with MAC. In contrast, isolated right CAD is associated with MAC or CVC, but rarely with AVC.

B-type natruiretic peptide levels stratify the risk for arrhythmia among implantable cardioverter defibrillator patients.

BACKGROUND: We sought to study the association between brain natriuretic peptide (BNP) levels and the occurrence of ventricular arrhythmias in patients with left ventricular dysfunction (LVD) and an implantable cardioverter defibrillator (ICD). METHODS: This was a prospective study of consecutive, stable, ambulatory patients with moderate and severe ischemic LVD and an ICD. A plasma BNP level was obtained at recruitment. Patients were evaluated every 3-6 mo for a minimum of 1 y. The primary end point was the occurrence of malignant ventricular arrhythmia or sudden cardiac death (SCD). RESULTS: The cohort consisted of 94 subjects (6 women) with a mean +/- standard deviation (SD) age of 69 +/- 10 y. The ICD implantation indication was primary and secondary prevention of SCD in 49% and 51% of subjects, respectively. A primary end point occurred in 27 patients (29%), and was more frequent in symptomatic heart failure patients and those implanted for secondary prevention of SCD. The median BNP level was significantly higher among patients who experienced an end point (191 pg/ml versus 142 pg/ml, p = 0.03). After controlling for New York Heart Association heart failure class and ICD implantation indication, the odds ratio (OR) for experiencing an adverse outcome among the upper BNP quartile versus all others was 3.5 (95% confidence interval [CI]: 1.2-10.2). Among patients implanted for primary prevention of SCD, none of the patients in the lower BNP quartile (BNP < 91 pg/ml) experienced an adverse outcome. CONCLUSIONS: These results suggest that abnormally high BNP levels not only predict cardiac death, but also arrhythmic death in this patient population, and a low BNP level can serve to identify low risk patients. (c)

A simple test of one minute heart rate variability during deep breathing for evaluation of sympatovagal imbalance in hyperthyroidism.

BACKGROUND: Heart rate variability is a sensitive marker of cardiac sympathetic activity. OBJECTIVES: To determine whether long-term hyperthyroidism induced by thyroxine suppressive therapy affects HRV. METHODS: Nineteen patients treated with suppressive doses of thyroxin for thyroid cancer and 19 age-matched controls were enrolled. Thyroid function tests and 1 minute HRV were performed on all subjects and the results were compared between the groups. The 1 minute HRV was analyzed during deep breathing and defined as the difference in beats/minute between the shortest and the longest heart rate interval measured by eletrocardiographic recording during six cycles of deep breathing. RESULTS: One minute HRV during deep breathing was significantly lower among thyroxine-treated patients compared to healthy controls (25.6 +/- 10.5 vs. 34.3 +/- 12.6 beats/min, P < 0.05). There were no significant differences in mean, maximal and minimal heart rate between the groups. CONCLUSIONS: Thyroxine therapy administered for epithelial thyroid cancer resulted in subclinical hyperthyroidism and significantly decreased HRV due to autonomic dysfunction rather than basic elevated heart rate.

[Incidence and predictors of atrial fibrillation after coronary artery bypass grafting in the Negev--are we different from the rest of the world?].

BACKGROUND: Atrial fibrillation (AF) remains a common problem after coronary artery bypass grafting (CABG). AF increases the risk for stroke and is associated with increased length of hospitalization and mortality. AIM: This study aimed to determine incidence, timing and predictors of post CABG AF in a prospectively evaluated cohort of patients undergoing CABG in the Negev. METHODS: Preoperative clinical data, intraoperative, intensive care and postoperative events including AF episodes were prospectively evaluated in 156 consecutive patients undergoing CABG during a nine month period ending on July 2003. RESULTS: Mean age was 64.9 years (SD = 9.7, range 41 - 84 years); 76.3% (119) were male. The in-hospital mortality was 1.2% (2 patients). The incidence of AF was 32.1% (50), with 40% of the AF episodes occurring on the second postoperative day (range 1-6 days). Univariate analyses identified the following variables as risk factors for AF: female gender, older age, ethnic origin, BMI > 30, hypertension, dyslipidemia, pre CABG nitrate, Ca blockers and furosemide treatment, left atrial diameter, renal failure and post CABG respiratory complications (p <0.05). By multivariate analysis, three variables were identified as independent predictors: BMI>30 (odds ratio 2.4; 95% CI 1.2-4.8); Sephardic Jews (OR 11.2; CI 1.0-114); enlarged left atrium (OR 4.6; CI 1.5-14.1). CONCLUSIONS: Consistent with previous studies, enlarged left atrium was a predictor of post CABG AF. In addition ethnic origin (Sephardic Jews) and BMI> 30 were also found to be important predictors of post CABG AF. In comparison with other studies, we not found moderate differences in outcomes and mortality in population that underwent CABG in the Negev in comparison to studies of the world.

Correlation between atrial ZnT-1 expression and atrial fibrillation in humans: a pilot study.

BACKGROUND: Until recently, the membrane protein ZnT-1 was studied mainly in the context of zinc homeostasis. However, new findings indicate that it acts as an inhibitor of L-type calcium channels. We recently found that acute rapid pacing of the rat atria in vivo augments the expression of ZnT-1, while knockdown of ZnT-1 in culture can oppose the inhibition of L-type calcium channels following rapid pacing. This pilot study, the first to assess cardiac ZnT-1 in humans, was designed to look for possible correlation between the atrial expression of ZnT-1 and atrial fibrillation. METHODS: Right atrial appendage tissue was collected from 39 patients (27 with sinus rhythm and 12 with atrial fibrillation; 6-permanent, 6- paroxysmal or persistent) undergoing open-heart surgery. The expression of ZnT-1 was analyzed by Western blot utilizing beta-actin as an internal loading control and a standard rat heart sample (STD) for inter-blot comparison. RESULTS: Overall atrial fibrillation patients (n = 12) had median ZnT-1/beta-actin of 1.80 STD (inter-quartile range 1.26 to 2.85) versus 0.73 STD (0.24 to 1.64) in the sinus rhythm group (P = 0.002). No association was found between ZnT-1 level and most other clinical parameters tested. Multivariate analysis determined that atrial fibrillation and increased body mass index were the only independent variables clearly associated with higher ZnT-1 levels (Standardized coefficients Beta = 0.62, 0.31; P = 0.002, P = 0.04, respectively). CONCLUSIONS: This pilot study provides evidence for increased ZnT-1 expression in the atria of patients with atrial fibrillation.

Atrial fibrillation and plasma troponin I elevation after cardiac surgery: relation to inflammation-associated parameters.

BACKGROUND: Recent studies have demonstrated correlation between inflammation to plasma troponin (cTnI) levels elevation and atrial fibrillation (AF) in noncardiac surgery settings. The goal of this prospective study was to examine the relation between inflammation associated parameters (IAPs) to post cardiac surgery cTnI elevation and AF. METHODS: A single post CABG cTnI measurement was assessed in 156 consecutive patients. Clinical, operative and postoperative data, IAPs (hypophosphatemia, preoperative statin treatment, immediate postoperative fever, and prolonged mechanical ventilation) and in-hospital AF episodes were prospectively recorded. RESULTS: Mean cTnI level was 14.4 +/- 12.4 ng/mL. In the two in-hospital deaths (1.2%) cTnI concentration was less than 12 ng/mL. Cardiac troponin-I levels were significantly higher in patients not preoperatively treated with statins (21.6 +/- 4.1 vs. 13.3 +/- 0.9, p = 0.05), in patients who needed intraoperative cardioversion (16.7 +/- 2.2 vs. 12.2 +/- 0.9, p = 0.07), in patients with postoperative hypophosphatemia (16.9 +/- 10.0 vs. 11.1 +/- 13.7, p = 0.04), postoperative fever (18.6 +/- 3.0 vs. 13.7 +/- 1.0, p = 0.07) and postoperative respiratory complications (23.9 +/- 4.3 vs. 13.5 +/- 1.0, p = 0.04). Step-wise logistic regression analysis revealed the following parameters as independently associated with elevated cTnI levels: preoperative statin treatment (CI 95%-15.9; -1.7, p = 0.02), intraoperative ventricular arrhythmia (CI 95%-0.7; 13.8, p = 0.08), hypophosphatemia (CI 95% 0.9; 8.6, p = 0.02), postoperative fever (CI 95% 0.9; 11.0, p = 0.02), and postoperative respiratory complications (CI 95% 0.1; 0.5, p = 0.01). Of the 156 patients, 50 (32.1%) had postoperative AF. The first episode of AF occurred between postoperative day 1 and 6 (mean-day 2). Mean duration of AF was 21.8 +/- 8.1 hours. Postoperative AF was significantly associated with age above 75 (50% vs. 29.4%, p = 0.01), hypertension (37% vs. 18%, p = 0.02), preoperative calcium channel blockers treatment (44% vs. 26%, p = 0.02), furosemide treatment (58% vs. 30%, p = 0.05), and preoperative left atrial diameter above 40 mm (56% vs. 29%, p = 0.01). Postoperatively, AF was significantly associated with postoperative renal failure (70% vs. 29%, p = 0.01), respiratory complications (61% vs. 29%, p = 0.02), and prolonged hospital stay (OR 1.1; CI 1.0-1.3; p < 0.05). No association was found between troponin levels and postoperative AF. Multivariable analysis found only left atrial enlargement and prolonged hospital stay independently associated with AF. CONCLUSIONS: A significant correlation between clinical IAPs and cTnI plasma level elevation was found after cardiac surgery. There was no correlation between these parameters and postoperative AF, and there was no correlation between postoperative plasma cTnI levels and the occurrence of AF. Preoperative treatment with statins may be beneficial in reducing postoperative inflammatory response but further study has to be carried out.