Left Atrial Appendage Occlusion versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation-One-Year Survival.

Aim To compare the 1-year survival rate of patients with atrial fibrillation (AF) following left atrial appendage occluder (LAAO) implantation vs. treatment with novel oral anticoagulants (NOACs). METHODS: We have conducted an indirect, retrospective comparison between LAAO and NOAC registries. The LAAO registry is a national prospective cohort of 419 AF patients who underwent percutaneous LAAO between January 2008 and October 2015. The NOACs registry is a multicenter prospective cohort of 3138 AF patients treated with NOACs between November 2015 and August 2018. Baseline patient characteristics were retrospectively collected from coded diagnoses of hospitalization and outpatient clinic notes. Follow-up data was sorted from coded diagnoses and the national civil registry. Subjects were matched according to propensity score. Baseline characteristics were compared using Chi-Square and student's t-test. Survival analysis was performed using Kaplan-Meier survival curves, log-rank test, and multivariable Cox regression, adjusting for possible confounding variables. RESULTS: This study included 114 subjects who underwent LAAO implantation and 342 subjects treated with NOACs. The mean age of participants was 77.9 ± 7.44 and 77.1 ± 11.2 years in the LAAO and NOAC groups, respectively (p = 0.4). The LAAO group had 70 (61%) men compared to 202 (59%) men in the NOAC group (p = 0.74). No significant differences were found in baseline comorbidities, renal function, or CHA2DS2-VASc score. One-year mortality was observed in 5 (4%) patients and 32 (9%) patients of the LAAO and NOAC groups, respectively. After adjusting for confounders, LAAO was significantly associated with a lower risk for 1-year mortality (HR 0.38, 95%CI 0.14-0.99). In patients with impaired renal function, this difference was even more prominent (HR 0.21 for creatinine clearance (CrCl) < 60 mL/min). CONCLUSIONS: In a pooled analysis of two registries, we found a significantly lower risk for 1-year mortality in patients with AF who were implanted with LAAO than those treated with NOACs. This finding was more prominent in patients with impaired renal function. Future prospective direct studies should further investigate the efficacy and adverse effects of both treatment strategies.

Significance of Anteroseptal Late Gadolinium Enhancement Among Patients With Acute Myocarditis.

Anteroseptal location of late gadolinium enhancement (LGE) in patients with acute myocarditis (AM) detected by cardiovascular magnetic resonance may indicate an independent marker of unfavorable outcomes according to recent data. We aimed to evaluate the clinical characteristics, management, and inhospital outcomes in patients with AM with positive LGE based on its presence in the anteroseptal location. We analyzed data from 262 consecutive patients hospitalized with a diagnosis of AM with positive LGE within 5 days of hospitalization (n = 425). Patients were divided into 2 groups: those with anteroseptal LGE (n = 25, 9.5%) and those with non-anteroseptal LGE (n = 237, 90.5%). Except for age that was higher in patients with anteroseptal LGE, the demographic and clinical characteristics did not differ significantly between both groups including past medical history, clinical presentation, electrocardiogram parameters, and lab values. Moreover, patients with anteroseptal LGE were more likely to present with reduced left ventricular ejection fraction and to receive congestive heart failure treatments. Although univariate analysis showed that patients with anteroseptal LGE were more likely to have inhospital major adverse cardiac events (28% vs 9%, p = 0.003), there was no difference inhospital outcomes on multivariable analysis between both groups (hazard ratio, 1.17 [95% confidence interval, 0.32 to 4.22], p = 0.81). A higher left ventricular ejection fraction in either echocardiography or cardiovascular magnetic resonance corresponded to better inhospital outcomes regardless of the presence or absence of anteroseptal LGE. In conclusion, the presence of anteroseptal LGE did not confer additional prognostic value for inhospital outcomes.

An objective tool for quantifying atrial fibrillation substrate in rats.

The utility of rodents for research related to atrial fibrillation (AF) is growing exponentially. However, the obtained arrhythmic waveforms are often mixed with ventricular signals and the ability to analyze regularity and complexity of such events is limited. Recently, we introduced an implantable quadripolar electrode adapted for advanced atrial electrophysiology in ambulatory rats. Notably, we have found that the implantation itself leads to progressive atrial remodeling, presumably because of mechanical loading of the atria. In the present study, we developed an algorithm to clean the atrial signals from ventricular mixing and thereafter quantify the AF substrate in an objective manner based on waveform complexity. Rats were sequentially examined 1-, 4-, and 8-wk postelectrode implantation using a standard AF triggering protocol. Preburst ventricular mixing was sampled and automatically subtracted based on QRS detection in the ECG. Thereafter, the "pure" atrial signals were analyzed by Lempel-Ziv complexity algorithm and a complexity ratio (CR) was defined for each signal by normalizing the postburst to the preburst values. Receiver operating characteristic (ROC) curve analysis indicated an optimal CR cutoff of 1.236 that detected irregular arrhythmic events with high sensitivity (94.5%), specificity (93.1%), and area under the curve (AUC) (0.96, 95% confidence interval, 0.945-0.976). Automated and unbiased analysis indicated a gradual increase in signal complexity over time with augmentation of high frequencies in power spectrum analysis. Our findings indicate that CR algorithm detects irregularity in a highly efficient manner and can also detect the atrial remodeling induced by electrode implantation. Thus, CR analysis can strongly facilitate standardized AF research in rodents.NEW & NOTEWORTHY Rodents are increasingly used in AF research. However, because of technical difficulties including atrial waveform mixing by ventricular signals, most studies do not discriminate between irregular (i.e., AF) and regular atrial arrhythmias. Here, we develop an unbiased computerized tool to "pure" the atrial signals from ventricular mixing and thereafter analyze AF substrate based on the level of irregularity in an objective manner. This novel tool can facilitate standardized AF research in rodents.

The Association between Marital Status and Outcomes of Patients Hospitalized with Heart Failure.

BACKGROUND: Little is known about the association between marital status and long-term outcomes of patients hospitalized with heart failure (HF). We aimed to examine the association between marital status and early as well as long-term outcomes of patients hospitalized with HF. METHOD: We analyzed data of 4089 patients hospitalized with HF and were enrolled in the multicenter national survey in Israel between March and April 2003 and were followed until December 2014. Patients were classified into married (N = 2462, 60%) and unmarried (N = 1627, 40%). RESULTS: Married patients were more likely to be males, younger, and more likely to have past myocardial infarction and previous revascularization. Also, they tended to have higher rates of diabetes mellitus (DM) and dyslipidemia, as well as smokers. Survival analysis showed that unmarried patients had higher mortality rates at 1 and 10 years (33% vs. 25%, at 1 year, 89% vs. 80% at 10 years, all p < 0.001). Consistently, multivariable analysis showed that unmarried patients had independently 44% and 35% higher risk of mortality at 1- and 10-year follow-up respectively (1-year HR = 1.44; 95%CI 1.14-1.81; p = 0.002, 10-year HR = 1.35; 95%CI 1.19-1.53; p ≤ 0.001). Other consistent predictors of mortality at both 1- and 10-year follow-up include age, renal failure, and advanced HF. CONCLUSIONS: Being unmarried is independently associated with worse short- and long-term outcomes, particularly among women. Thus, attempts to intensify secondary preventive measures should focus mainly on unmarried patients and mainly women.

Incorrectly corrected? QT interval analysis in rats and mice.

QT interval, a surrogate measure for ventricular action potential duration (APD) in the surface ECG, is widely used to identify cardiac abnormalities and drug safety. In humans, cardiac APD and QT interval are prominently affected by heart rate (HR), leading to widely accepted formulas to correct the QT interval for HR changes (QT corrected - QTc). While QTc is widely used in the clinic, the proper way to correct the QT interval in small mammals such as rats and mice is not clear. Over the years, empiric correction formulas were developed for rats and mice, which are widely used in the literature. Recent experimental findings obtained from pharmacological and direct pacing experiments in unanesthetized rodents show that the rate-adaptation properties are markedly different from those in humans and the use of existing QTc formulae can lead to major errors in data interpretation. In the present review, these experimental findings are summarized and discussed.

Recapitulation of dyssynchrony-associated contractile impairment in asymmetrically paced engineered heart tissue.

BACKGROUND: One third of heart failure patients exhibit dyssynchronized electromechanical activity of the heart (evidenced by a broad QRS-complex). Cardiac resynchronization therapy (CRT) in the form of biventricular pacing improves cardiac output and clinical outcome of responding patients. Technically demanding and laborious large animal models have been developed to better predict responders of CRT and to investigate molecular mechanisms of dyssynchrony and CRT. The aim of this study was to establish a first humanized in vitro model of dyssynchrony and CRT. METHODS: Cardiomyocytes were differentiated from human induced pluripotent stem cells and cast into a fibrin matrix to produce engineered heart tissue (EHT). EHTs were either field stimulated in their entirety (symmetrically) or excited locally from one end (asymmetrically) or they were allowed to beat spontaneously. RESULTS: Asymmetrical pacing led to a depolarization wave from one end to the other end, which was visualized in human EHT transduced with a fast genetic Ca2+-sensor (GCaMP6f) arguing for dyssynchronous excitation. Symmetrical pacing in contrast led to an instantaneous (synchronized) Ca2+-signal throughout the EHT. To investigate acute and long-term functional effects, spontaneously beating human EHTs (0.5-0.8 Hz) were divided into a non-paced control group, a symmetrically and an asymmetrically paced group, each stimulated at 1 Hz. Symmetrical pacing was clearly superior to asymmetrical pacing or no pacing regarding contractile force both acutely and even more pronounced after weeks of continuous stimulation. Contractile dysfunction that can be evoked by an increased afterload was aggravated in the asymmetrically paced group. Consistent with reports from paced dogs, p38MAPK and CaMKII-abundance was higher under asymmetrical than under symmetrical pacing while pAKT was considerably lower. CONCLUSIONS: This model allows for long-term pacing experiments mimicking electrical dyssynchrony vs. synchrony in vitro. Combined with force measurement and afterload stimulus manipulation, it provides a robust new tool to gain insight into the biology of dyssynchrony and CRT.

A new implantable tool for repeated assessment of supraventricular electrophysiology and atrial fibrillation susceptibility in freely moving rats.

The complex pathophysiology of atrial fibrillation (AF) is governed by multiple risk factors in ways that are still elusive. Basic electrophysiological properties, including atrial effective refractory period (AERP) and conduction velocity, are major factors determining the susceptibility of the atrial myocardium to AF. Although there is a great need for affordable animal models in this field of research, in vivo rodent studies are limited by technical challenges. Recently, we introduced an implantable system for long-term assessment of AF susceptibility in ambulatory rats. However, technical considerations did not allow us to perform concomitant supraventricular electrophysiology measurements. Here, we designed a novel quadripolar electrode specifically adapted for comprehensive atrial studies in ambulatory rats. Electrodes were fabricated from medical-grade silicone, four platinum-iridium poles, and stainless-steel fixating pins. Initial quality validation was performed ex vivo, followed by implantation in adult rats and repeated electrophysiological studies 1, 4, and 8 wk postimplantation. Capture threshold was stable. Baseline AERP values (38.1 ± 2.3 and 39.5 ± 2.0 using 70-ms and 120-ms S1-S1 cycle lengths, respectively) confirmed the expected absence of rate adaptation in the unanesthetized state and validated our prediction that markedly higher values reported under anesthesia are nonphysiological. Evaluation of AF substrate in parallel with electrophysiological parameters validated our recent finding of a gradual increase in AF susceptibility over time and demonstrated that this phenomenon is associated with an electrical remodeling process characterized by AERP shortening. Our findings indicate that the miniature quadripolar electrode is a potent new tool, which opens a window of opportunities for better utilization of rats in AF research.NEW & NOTEWORTHY Rodents are increasingly used in AF research. However, technical challenges restrict long-term supraventricular electrophysiology studies in these species. Here, we developed an implantable electrode adapted for such studies in the rat. Our findings indicate that this new tool is effective for long-term follow-up of critical parameters such as atrial refractoriness. Obtained data shed light on the normal electrophysiology and on the increased AF susceptibility that develops in rats with implanted atrial electrodes over time.

Female gender is associated with a worse prognosis amongst patients hospitalised for de-novo acute heart failure.

BACKGROUND: Recent evidence showed that new-onset (de-novo) acute heart failure (AHF) is a distinct type of AHF. However, the prognostic implication of gender on these patients remains unclear. AIMS: We aimed to investigate the impact of gender on both short and long-term mortality outcomes after hospitalisation for de-novo AHF. METHODS: We analysed the data of 721 patients with de-novo AHF, who were enrolled in the HF survey in Israel between March and April 2003 and were followed until December 2014. RESULTS: Fifty-four percent (N = 387) of the patients were men. In comparison to women, men patients were more likely to be younger, smokers, and with ischemic HF aetiology. At 30 days, mortality rates were higher in women (12% vs 7%, P = .013). Survival analysis showed that at 1 and 10 years the all-cause mortality rates were significantly higher in women (28% vs 17%, and 78% vs 67%, 1 and 10 years, P < .001, respectively). Consistently, multivariable analysis showed that women had an independently 82% and 24% higher mortality risk at 1 and 10 years, respectively, (1-year hazard ratio = 1.82; 95% confidence interval = 1.07 to 3.11, P = .03; 10-year hazard ratio = 1.24; 95% confidence interval = 1.03 to 1.48, P = .02). CONCLUSIONS: Amongst patients with de-novo AHF, women had higher mortality rates compared with men. The observed gender-related differences in de-novo AHF patients highlight the need for further and deeper research in this field.

Sex Differences in Clinical Characteristics and 1- and 10-Year Mortality Among Patients Hospitalized With Acute Heart Failure.

BACKGROUND: The impact of sex on mortality in patients with acute heart failure (AHF) is unresolved. We aimed to investigate the impact of sex on both short- and long-term mortality outcomes after hospitalization for AHF. METHODS: We analyzed data of 2,328 patients with AHF who were enrolled in the multicenter national survey in Israel between March and April 2003 and followed up until December 2014. RESULTS: Women comprised 45% of the study population. In comparison with men, women were older, had higher rates of heart failure with preserved ejection fraction as well as hypertensive heart disease and had a lower rate of coronary artery disease (all P < 0.001). Survival analysis showed that at 1 year the rate of all-cause mortality was 31% among women compared to 28% among men (P = 0.19). At 10-year follow-up mortality rates were significantly higher among women compared to men (87% vs. 83%, P = 0.048). However, this sex association disappeared once multivariable analysis was carried out, (hazard ratio [HR] = 0.93; CI = 0.79-1.09, P = 0.36). Renal dysfunction, older age and severe heart failure were consistent independent predictors of mortality among men and women. Hyponatremia was a prognostic predictor only among men, whereas digoxin use predicted mortality only among women. CONCLUSIONS: There are important differences in the clinical characteristics between women and men hospitalized with AHF. There were no significant differences in both short- and long-term mortality following multivariable analysis. Although, most independent predictors of mortality were consistent among both sexes, few sex-based differences in prognostic predictors were identified.

Sex-Based Differences in Characteristics and In-Hospital Outcomes among Patients With Diagnosed Acute Myocarditis.

Data are scarce regarding sex differences among patients with acute myocarditis (AM). Our aim was to define the sex differences in clinical characteristics as well as in-hospital outcomes in a cohort of consecutive patients hospitalized due to AM. We analyzed data of 322 consecutive patients from January 2005 to December 2017 who were hospitalized with the diagnosis of AM. Eighty-four percent (N = 272) of the patients were males. When compared to females, male patients were younger (36 ± 14 vs 45 ± 17 years, p <0.001), more likely to present with ST segment elevation (75% vs 44%. p <0.001) as well as PR depression upon ECG, and have higher admission troponin levels (7.6 ± 11 vs 2.3 ± 4 µg/L, p <0.001). Moreover, males were more likely to have late gadolinium enhancement upon cardiac magnetic resonance. While male patients were more likely to have ventricular arrhythmias during hospitalization (7% vs 0%, p = 0.05), there were no differences in the incidence of in-hospital mortality or the need for escalation therapy during hospitalization between both groups. There were no episodes of mortality upon all patients among a follow-up of 1 year. In conclusion, male patients, which constitute the majority of patients admitted with AM were younger, more likely to present with ST elevation, had higher troponin levels at admission, and had a higher rate of ventricular arrhythmias compared to females. There were no differences in post-discharge mortality rates between males and females.

An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions.

Atrial fibrillation (AF) is a progressive arrhythmia with underlying mechanisms that are not fully elucidated, partially due to lack of reliable and affordable animal models. Here, we introduce a system for long-term assessment of AF susceptibility (substrate) in ambulatory rats implanted with miniature electrodes on the atrium. Rats were subjected to excessive aldosterone (Aldo) or solvent only (Sham). An additional group was exposed to myocardial infarction (MI). AF substrate was tested two- and four-weeks post implantation and was also compared with implanted rats early post-implantation (Base). Aldo and MI increased the AF substrate and atrial fibrosis. In the MI group only, AF duration was correlated with the level of atrial fibrosis and was inversely correlated with systolic function. Unexpectedly, Shams also developed progressive AF substrate relative to Base individuals. Further studies indicated that serum inflammatory markers (IL-6, TNF-alpha) were not elevated in the shams. In addition, we excluded anxiety\depression due to social-isolation as an AF promoting factor. Finally, enhanced biocompatibility of the atrial electrode did not inhibit the gradual development of AF substrate over a testing period of up to 8 weeks. Overall, we successfully validated the first system for long-term AF substrate testing in ambulatory rats.

Epidemiology Characteristics and Outcome of Patients With Clinically Diagnosed Acute Myocarditis.

BACKGROUND: There are controversial data regarding the outcome and management of patients hospitalized with clinically diagnosed acute myocarditis. METHODS: We retrospectively evaluated data of 322 consecutive patients admitted to the Sheba Medical Center with clinically suspected acute myocarditis from January 2005 to December 2017. Patients were subdivided into 2 groups based on their left ventricular ejection fraction (LVEF) at presentation: 1) patients with an LVEF <50% (n = 60) and 2) patients with an LVEF ≥50% (n = 260). We aimed to evaluate the clinical characteristics, management, and in-hospital outcome as well as short-term and 1-year outcome of patients admitted with acute myocarditis. RESULTS: The mean age of the study population was 37 ± 14 years, most of them (84%) males. Although chest pain was the main complaint in 89% of the patients at presentation, only 35% had typical pericardial pain. Patients with a LVEF <50% were more likely to demonstrate ST depression or T wave inversion on their electrocardiogram (ECG) at presentation (33% vs 18%, P = 0.007), and have higher levels of admission and peak troponin compared to those with LVEF ≥50%,(12.7 µ/L ± 15 µ/L vs 5.5 µ/L ± 9.2 µ/L, P = 0.001 for admission troponin, 18.8 µ/L ± 19.9 µ/L vs 8.4 µ/L ± 11.6 µ/L, P <0.001, for peak troponin). Univariate analysis showed that patients with an LVEF <50% were more likely to suffer from adverse cardiovascular events, defined as a composite of the following: 1) acute decompensated congestive heart failure; 2) ventricular arrhythmias; and 3) in-hospital mortality, compared to those with an LVEF ≥50% (15 [25%] vs10 [4%], P <0.001). Consistently, multivariable analysis showed that patients with an LVEF <50% had a 4-fold increased risk of adverse cardiovascular events compared to those patients with an LVEF ≥50% (heart rate [HR] = 4.30; 95% confidence interval [CI] 1.59-11.49; P <0.001). CONCLUSIONS: Patients with clinical acute myocarditis seem to have an overall good prognosis. Although patients with an LVEF <50% are at a higher risk of in-hospital adverse events compared to those with an LVEF ≥50%, this propensity is not reflected during 1-year of follow-up.

Rapid Atrial Pacing Promotes Atrial Fibrillation Substrate in Unanesthetized Instrumented Rats.

AIM: The self-perpetuating nature of atrial fibrillation (AF) has been a subject of intense research in large mammalian models exposed to rapid atrial pacing (RAP). Recently, rodents are increasingly used to gain insight into the pathophysiology of AF. However, little is known regarding the effects of RAP on the atria of rats and mice. Using an implantable device for electrophysiological studies in rodents, we examined on a daily basis, the effects of continuous RAP on the developed AF substrate of unanesthetized rats and mice. METHODS AND RESULTS: Aggressive burst pacing did not induce AF at baseline in the large majority of rodents, but repeatedly induced AF episodes in rats exposed to RAP for more than 2 days. A microarray study of left atrial tissue from rats exposed to RAP for 2 days vs. control pacing identified 304 differentially expressed genes. Enrichment analysis and comparison with a dataset of atrial tissue from AF patients revealed indications of increased carbohydrate metabolism and changes in pathways that are thought to play critical roles in human AF, including TGF-beta and IL-6 signaling. Among 19 commonly affected genes in comparison with human AF, downregulation of FOXP1 and upregulation of the KCNK2 gene encoding the Kir2.1 potassium channel were conspicuous findings, suggesting NFAT activation. Further results included reduced expression of MIR-26 and MIR-101, which is in line with NFAT activation. CONCLUSION: Our results demonstrate electrophysiological evidence for AF promoting effects of RAP in rats and several molecular similarities between the effects of RAP in large and small mammalian models.

Differences in Mortality of New-Onset (De-Novo) Acute Heart Failure Versus Acute Decompensated Chronic Heart Failure.

Minimal attention has been paid to understanding the implications of the chronicity of heart failure (HF) diagnosis on prognosis of hospitalized patients with acute HF (AHF). We aimed to assess the differences in outcomes between hospitalized patients with AHF that are new-onset (de-novo) AHF and acutely decompensated chronic HF (ADCHF). We analyzed data of 2,328 patients with AHF, who were enrolled in the HF survey in Israel. Patients were classified into de-novo AHF and ADCHF. A total of 721 (31%) patients were classified as de-novo AHF and 1,607 (69%) patients were classified as ADCHF. Patients with de-novo AHF were more likely to be younger, with fewer co-morbidities represented by lower Charlson index, and less likely to have past myocardial infarction as well as coronary revascularization. At 30 days mortality rates were similar in both groups (9% vs 8% in de-novo AHF and ADCHF, respectively). Survival analysis showed that at 1 and 10 years the all-cause mortality rates were significantly higher in patients with ADCHF (33% vs 22% and 90% vs 72%, 1 and 10 years, log-rank p < 0.001, respectively). Consistently, multivariable analysis showed that patients with ADCHF had an independently 58% and 48%, higher mortality risk at 1 and 10 years, respectively, (1-year hazard ratio = 1.58; 95% confidence interval 1.05 to 2.38, p = 0.03; 10-year hazard ratio = 1.48; 95% confidence interval = 1.23 to 2.77; p < 0.001). In conclusion, previous history of HF is an independent predictor of 1-year and 10-year mortality after hospitalization for AHF. Distinction between de-novo AHF and ADCHF may improve our understanding and risk stratification of patients with AHF.

Nocturnal Atrial Fibrillation Caused by Mutation in KCND2, Encoding Pore-Forming (α) Subunit of the Cardiac Kv4.2 Potassium Channel.

BACKGROUND: Paroxysmal atrial fibrillation (AF) can be caused by gain-of-function mutations in genes, encoding the cardiac potassium channel subunits KCNJ2, KCNE1, and KCNH2 that mediate the repolarizing potassium currents Ik1, Iks, and Ikr, respectively. METHODS: Linkage analysis, whole-exome sequencing, and Xenopus oocyte electrophysiology studies were used in this study. RESULTS: Through genetic studies, we showed that autosomal dominant early-onset nocturnal paroxysmal AF is caused by p.S447R mutation in KCND2, encoding the pore-forming (α) subunit of the Kv4.2 cardiac potassium channel. Kv4.2, along with Kv4.3, contributes to the cardiac fast transient outward K+ current, Ito. Ito underlies the early phase of repolarization in the cardiac action potential, thereby setting the initial potential of the plateau phase and governing its duration and amplitude. In Xenopus oocytes, the mutation increased the channel's inactivation time constant and affected its regulation: p.S447 resides in a protein kinase C (PKC) phosphorylation site, which normally allows attenuation of Kv4.2 membrane expression. The mutant Kv4.2 exhibited impaired response to PKC; hence, Kv4.2 membrane expression was augmented, enhancing potassium currents. Coexpression of mutant and wild-type channels (recapitulating heterozygosity in affected individuals) showed results similar to the mutant channel alone. Finally, in a hybrid channel composed of Kv4.3 and Kv4.2, simulating the mature endogenous heterotetrameric channel underlying Ito, the p.S447R Kv4.2 mutation exerted a gain-of-function effect on Kv4.3. CONCLUSIONS: The mutation alters Kv4.2's kinetic properties, impairs its inhibitory regulation, and exerts gain-of-function effect on both Kv4.2 homotetramers and Kv4.2-Kv4.3 heterotetramers. These effects presumably increase the repolarizing potassium current Ito, thereby abbreviating action potential duration, creating arrhythmogenic substrate for nocturnal AF. Interestingly, Kv4.2 expression was previously shown to demonstrate circadian variation, with peak expression at daytime in murine hearts (human nighttime), with possible relevance to the nocturnal onset of paroxysmal AF symptoms in our patients. The atrial-specific phenotype suggests that targeting Kv4.2 might be effective in the treatment of nocturnal paroxysmal AF, avoiding adverse ventricular effects.

Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length.

Aim: The cardiac electrophysiology of mice and rats has been analyzed extensively, often in the context of pathological manipulations. However, the effects of beating rate on the basic electrical properties of the rodent heart remain unclear. Due to technical challenges, reported electrophysiological studies in rodents are mainly from ex vivo preparations or under deep anesthesia, conditions that might be quite far from the normal physiological state. The aim of the current study was to characterize the ventricular rate-adaptation properties of unanesthetized rats and mice. Methods: An implanted device was chronically implanted in rodents for atrial or ventricular pacing studies. Following recovery from surgery, QT interval was evaluated in rodents exposed to atrial pacing at various frequencies. In addition, the frequency dependence of ventricular refractoriness was tested by conventional ventricular programmed stimulation protocols. Results: Our findings indicate total absence of conventional rate-adaptation properties for both QT interval and ventricular refractoriness. Using monophasic action potential recordings in isolated mice hearts we could confirm the previously reported shortening of the action potential duration at fast pacing rates. However, we found that this mild shortening did not result in similar decrease of ventricular refractory period. Conclusion: Our findings indicate that unanesthetized rodents exhibit flat QT interval and ventricular refractory period rate-dependence. This data argue against empirical use of QT interval correction methods in rodent studies. Our new methodology allowing atrial and ventricular pacing of unanesthetized freely moving rodents may facilitate more appropriate utility of these important animal models in the context of cardiac electrophysiology studies.

Prominent differences in left ventricular performance and myocardial properties between right ventricular and left ventricular-based pacing modes in rats.

Biventricular pacing is an important modality to improve left ventricular (LV) synchronization and long-term function. However, the biological effects of this treatment are far from being elucidated and existing animal models are limited and demanding. Recently, we introduced an implanted device for double-site epicardial pacing in rats and echocardiographically demonstrated favorable effects of LV and biventricular (LV-based) pacing modes typically observed in humans. Here, this new animal model was further characterized. Electrodes were implanted either on the right atria (RA) and right ventricle (RV) or on the RV and LV. Following recovery, rats were either used for invasive hemodynamic measurements (pressure-volume analysis) or exposed to sustained RV vs. biventricular tachypacing for 3 days. RV pacing compromised, while LV-based pacing modes markedly enhanced cardiac performance. Changes in LV performance were associated with prominent compensatory changes in arterial resistance. Sustained RV tachypacing increased the electrocardiogram QTc interval by 7.9 ± 3.1 ms (n = 6, p < 0.05), dispersed refractoriness between the right and left pacing sites and induced important molecular changes mainly in the early-activated septal tissue. These effects were not observed during biventricular tachypacing (n = 6). Our results demonstrate that the rat is an attractive new model to study the biological consequences of LV dyssynchrony and resynchronization.

Speckle-tracking echocardiography elucidates the effect of pacing site on left ventricular synchronization in the normal and infarcted rat myocardium.

BACKGROUND: Right ventricular (RV) pacing generates regional disparities in electrical activation and mechanical function (ventricular dyssynchrony). In contrast, left ventricular (LV) or biventricular (BIV) pacing can improve cardiac efficiency in the setting of ventricular dyssynchrony, constituting the rationale for cardiac resynchronization therapy (CRT). Animal models of ventricular dyssynchrony and CRT currently relay on large mammals which are expensive and not readily available to most researchers. We developed a methodology for double-site epicardial pacing in conscious rats. Here, following post-operative recovery, we compared the effects of various pacing modes on LV dyssynchrony in normal rats and in rats with ischemic cardiomyopathy. METHODS: Two bipolar electrodes were implanted in rats as follows: Group A (n = 6) right atrial (RA) and RV sites; Group B (n = 7) RV and LV sites; Group C (n = 8) as in group B in combination with left coronary artery ligation. Electrodes were exteriorized through the back. Following post-operative recovery, two-dimensional transthoracic echocardiography was performed during pacing through the different electrodes. Segmental systolic circumferential strain (Ecc) was used to evaluate LV dyssynchrony. RESULTS: In normal rats, RV pacing induced marked LV dyssynchrony compared to RA pacing or sinus rhythm, as measured by the standard deviation (SD) of segmental time to peak Ecc, SD of peak Ecc, and the average delay between opposing ventricular segments. LV pacing and, to a greater extend BIV pacing diminished the LV dyssynchrony compared to RV pacing. In rats with extensive MI, the effects of LV and BIV pacing were markedly attenuated, and the response of individual animals was variable. CONCLUSIONS: Rodent cardiac pacing mimics important features seen in humans. This model may be developed as a simple new tool to study the pathophysiology of ventricular dyssynchrony and CRT.