Phosphorylation of cardiac sodium channel at Ser571 anticipates manifestations of the aging myopathy.

Diastolic dysfunction and delayed ventricular repolarization are typically observed in the elderly, but whether these defects are intimately associated with the progressive manifestation of the aging myopathy remains to be determined. In this regard, aging in experimental animals is coupled with increased late Na+ current (INa,L) in cardiomyocytes, raising the possibility that INa,L conditions the modality of electrical recovery and myocardial relaxation of the aged heart. For this purpose, aging male and female wild-type (WT) C57Bl/6 mice were studied together with genetically engineered mice with phosphomimetic (gain of function, GoF) or ablated (loss of function, LoF) mutations of the sodium channel Nav1.5 at Ser571 associated with, respectively, increased and stabilized INa,L. At ∼18 mo of age, WT mice developed prolonged duration of the QT interval of the electrocardiogram and impaired diastolic left ventricular (LV) filling, defects that were reversed by INa,L inhibition. Prolonged repolarization and impaired LV filling occurred prematurely in adult (∼5 mo) GoF mutant mice, whereas these alterations were largely attenuated in aging LoF mutant animals. Ca2+ transient decay and kinetics of myocyte shortening/relengthening were delayed in aged (∼24 mo) WT myocytes, with respect to adult cells. In contrast, delayed Ca2+ transients and contractile dynamics occurred at adult stage in GoF myocytes and further deteriorated in old age. Conversely, myocyte mechanics were minimally affected in aging LoF cells. Collectively, these results document that Nav1.5 phosphorylation at Ser571 and the late Na+ current modulate the modality of myocyte relaxation, constituting the mechanism linking delayed ventricular repolarization and diastolic dysfunction.NEW & NOTEWORTHY We have investigated the impact of the late Na current (INa,L) on cardiac and myocyte function with aging by using genetically engineered animals with enhanced or stabilized INa,L, due to phosphomimetic or phosphoablated mutations of Nav1.5. Our findings support the notion that phosphorylation of Nav1.5 at Ser571 prolongs myocardial repolarization and impairs diastolic function, contributing to the manifestations of the aging myopathy.

Scn1b expression in the adult mouse heart modulates Na+ influx in myocytes and reveals a mechanistic link between Na+ entry and diastolic function.

Voltage-gated sodium channels (VGSCs) are macromolecular assemblies composed of a number of proteins regulating channel conductance and properties. VGSCs generate Na+ current (INa) in myocytes and play fundamental roles in excitability and impulse conduction in the heart. Moreover, VGSCs condition mechanical properties of the myocardium, a process that appears to involve the late component of INa. Variants in the gene SCN1B, encoding the VGSC ß1- and ß1B-subunits, result in inherited neurological disorders and cardiac arrhythmias. But the precise contributions of ß1/ß1B-subunits and VGSC integrity to the overall function of the adult heart remain to be clarified. For this purpose, adult mice with cardiac-restricted, inducible deletion of Scn1b (conditional knockout, cKO) were studied. Myocytes from cKO mice had increased densities of fast (+20%)- and slow (+140%)-inactivating components of INa, with respect to control cells. By echocardiography and invasive hemodynamics, systolic function was preserved in cKO mice, but diastolic properties and ventricular compliance were compromised, with respect to control animals. Importantly, inhibition of late INa with GS967 normalized left ventricular filling pattern and isovolumic relaxation time in cKO mice. At the cellular level, cKO myocytes presented delayed kinetics of Ca2+ transients and cell mechanics, defects that were corrected by inhibition of INa. Collectively, these results document that VGSC ß1/ß1B-subunits modulate electrical and mechanical function of the heart by regulating, at least in part, Na+ influx in cardiomyocytes.NEW & NOTEWORTHY We have investigated the consequences of deletion of Scn1b, the gene encoding voltage-gated sodium channel ß1-subunits, on myocyte and cardiac function. Our findings support the notion that Scn1b expression controls properties of Na+ influx and Ca2+ cycling in cardiomyocytes affecting the modality of cell contraction and relaxation. These effects at the cellular level condition electrical recovery and diastolic function in vivo, substantiating the multifunctional role of ß1-subunits in the physiology of the heart.

Unique technique to relieve left ventricular assist device electromagnetic interference with an implantable cardioverter defibrillator.

We introduced a simple technique to eliminate electromagnetic interference between a left ventricular assist device (LVAD) and an implantable cardioverter defibrillator (ICD). A 43-year-old male with heart failure and a reduced ejection fraction who had an ICD presented with decompensated heart failure and received an LVAD as a bridge to transplant. Remote monitoring showed persistent atrial fibrillation causing an inappropriate ICD shock leading to a decision to disable shock therapies. However, an in-office interrogation was unsuccessful due to electromagnetic interference. Patient was instructed to extend his arm above his head on the ipsilateral side of the ICD, thus increasing the distance between LVAD and ICD, eliminating the interaction to allow reprogramming of the device.

Rhythm dynamics of the aging heart: an experimental study using conscious, restrained mice.

Heart rate variability (HRV) is a measure of variation in time interval between heartbeats and reflects the influence of autonomic nervous system and circulating/locally released factors on sinoatrial node discharge. Here, we tested whether electrocardiograms (ECGs) obtained in conscious, restrained mice, a condition that affects sympathovagal balance, reveal alterations of heart rhythm dynamics with aging. Moreover, based on emergence of sodium channels as modulators of pacemaker activity, we addressed consequences of altered sodium channels on heart rhythm. C57Bl/6 mice and mice with enhanced late sodium current due to Nav1.5 mutation at Ser571 (S571E) at ~4 to ~24 mo of age, were studied. HRV was assessed using time- and frequency-domain and nonlinear parameters. For C57Bl/6 and S571E mice, standard deviation of RR intervals (SDRR), total power of RR interval variation, and nonlinear standard deviation 2 (SD2) were maximal at ~4 mo and decreased at ~18 and ~24 mo, together with attenuation of indexes of sympathovagal balance. Modulation of sympathetic and/or parasympathetic divisions revealed attenuation of autonomic tone at ~24 mo. At ~4 mo, S571E mice presented lower heart rate and higher SDRR, total power, and SD2 with respect to C57Bl/6, properties reversed by late sodium current inhibition. At ~24 mo, heart rate decreased in C57Bl/6 but increased in S571E, a condition preserved after autonomic blockade. Collectively, our data indicate that aging is associated with reduced HRV. Moreover, sodium channel function conditions heart rate and its age-related adaptations, but does not interfere with HRV decline occurring with age.NEW & NOTEWORTHY We have investigated age-associated alterations of heart rate properties in mice using conscious electrocardiographic recordings. Our findings support the notion that aging is coupled with altered sympathovagal balance with consequences on heart rate variability. Moreover, by using a genetically engineered mouse line, we provide evidence that sodium channels modulate heart rate and its age-related adaptations.

Notch signaling modulates the electrical behavior of cardiomyocytes.

Notch receptor signaling is active during cardiac development and silenced in myocytes after birth. Conversely, outward K+ Kv currents progressively appear in postnatal myocytes leading to shortening of the action potential (AP) and acquisition of the mature electrical phenotype. In the present study, we tested the possibility that Notch signaling modulates the electrical behavior of cardiomyocytes by interfering with Kv currents. For this purpose, the effects of Notch receptor activity on electrophysiological properties of myocytes were evaluated using transgenic mice with inducible expression of the Notch1 intracellular domain (NICD), the functional fragment of the activated Notch receptor, and in neonatal myocytes after inhibition of the Notch transduction pathway. By patch clamp, NICD-overexpressing cells presented prolonged AP duration and reduced upstroke amplitude, properties that were coupled with reduced rapidly activating Kv and fast Na+ currents, compared with cells obtained from wild-type mice. In cultured neonatal myocytes, inhibition of the proteolitic release of NICD with a γ-secretase antagonist increased transcript levels of the Kv channel-interacting proteins 2 (KChIP2) and enhanced the density of Kv currents. Collectively, these results indicate that Notch signaling represents an important regulator of the electrophysiological behavior of developing and adult myocytes by repressing, at least in part, repolarizing Kv currents. NEW & NOTEWORTHY We investigated the effects of Notch receptor signaling on the electrical properties of cardiomyocytes. Our results indicate that the Notch transduction pathway interferes with outward K+ Kv currents, critical determinants of the electrical repolarization of myocytes.

Hyperglycemia induces defective Ca2+ homeostasis in cardiomyocytes.

Diabetes and other metabolic conditions characterized by elevated blood glucose constitute important risk factors for cardiovascular disease. Hyperglycemia targets myocardial cells rendering ineffective mechanical properties of the heart, but cellular alterations dictating the progressive deterioration of cardiac function with metabolic disorders remain to be clarified. In the current study, we examined the effects of hyperglycemia on cardiac function and myocyte physiology by employing mice with high blood glucose induced by administration of streptozotocin, a compound toxic to insulin-producing ß-cells. We found that hyperglycemia initially delayed the electrical recovery of the heart, whereas cardiac function became defective only after ~2 mo with this condition and gradually worsened with time. Prolonged hyperglycemia was associated with increased chamber dilation, thinning of the left ventricle (LV), and myocyte loss. Cardiomyocytes from hyperglycemic mice exhibited defective Ca2+ transients before the appearance of LV systolic defects. Alterations in Ca2+ transients involved enhanced spontaneous Ca2+ releases from the sarcoplasmic reticulum (SR), reduced cytoplasmic Ca2+ clearance, and declined SR Ca2+ load. These defects have important consequences on myocyte contraction, relaxation, and mechanisms of rate adaptation. Collectively, our data indicate that hyperglycemia alters intracellular Ca2+ homeostasis in cardiomyocytes, hindering contractile activity and contributing to the manifestation of the diabetic cardiomyopathy. NEW & NOTEWORTHY: We have investigated the effects of hyperglycemia on cardiomyocyte physiology and ventricular function. Our results indicate that defective Ca2+ handling is a critical component of the progressive deterioration of cardiac performance of the diabetic heart.

Treatment of Ventricular Arrhythmias and Use of Implantable Cardioverter-Defibrillators to Improve Survival in Older Adult Patients with Cardiac Disease.

Ventricular arrhythmia (VA) and sudden cardiac death (SCD) are well-recognized problems in the overall heart failure population, but treatment decisions can be more complex and nuanced in older patients. Sustained VA does not always lead to SCD, but identifies a higher risk population and may cause significant symptoms. Antiarrhythmic drugs (AAD) and catheter ablation are the mainstays for prevention of VA, but have not been shown to improve mortality. The value of implantable cardiac defibrillators (ICDs) may be influenced by patient age. This article discusses long-term treatment of VA and the use of ICDs in the elderly.

Epicardial/endocardial sinus node ablation after failed endocardial ablation for the treatment of inappropriate sinus tachycardia.

INTRODUCTION: Success of endocardial sinus node (SN) ablation for refractory inappropriate sinus tachycardia (IST) is limited by the epicardial location of the SN and potential damage to the phrenic nerve (PN). An epicardial approach may overcome these limitations. METHODS AND RESULTS: IST patients who failed endocardial ablation underwent an epicardial approach. Percutaneous pericardial access was obtained with a double wire technique for PN protection (i.e., with a balloon catheter), if needed. Earliest sinus activation was mapped and ablated with remapping for changes in P-wave morphology or sinus rate. The endpoint was total SN ablation (patients with atrial pacing [AP]); otherwise the target was a >25% decrease in sinus rate and inversion of P-wave axis. Five patients (all female, age 36 ± 4 years) underwent ablation. Two had prior AP, and 1 elected to have SN ablation and pacemaker during the same procedure. Three had prior endocardial ablation limited by PN proximity. Baseline sinus rate was 119 ± 20 bpm. After 35.2 ± 21.3 lesions (22.4 ± 21.7 epicardial, 12.8 ± 21.3 endocardial), 4 were in junctional rhythm, 1 in atrial rhythm at 90 bpm. This latter patient had symptom recurrence and underwent combined minimally invasive surgical/catheter SN cryoablation. Atrial tachycardia subsequently occurred and was successfully ablated. The only significant complication was pericarditis (3 patients). At last follow-up (30.4 ± 18.4 months), all had symptom resolution. Two were AP >99%, 1 was AP 54%. Two remain in ectopic atrial rhythm with controlled rates. CONCLUSIONS: Combined epicardial/endocardial SN ablation is a viable approach for patients with severely symptomatic IST after a failed endocardial attempt.

Temporal stability in the spectral representation of complex fractionated atrial electrograms.

BACKGROUND: Although local electrograms during atrial fibrillation (AF) are often spectrally analyzed over 8-second (8s) intervals, changes may be common over intervals as short as 2s. We sought to determine whether averaged 2s measurements of electrogram spectral parameters were similar to 8s measurements, and whether the 2s intervals could provide an estimate of the temporal stability of the signal frequency content in paroxysmal versus persistent AF. METHODS: Complex fractionated atrial electrograms (CFAEs) were acquired outside the pulmonary vein ostia and from free wall sites in nine paroxysmal and 10 longstanding persistent AF patients. Using a 2s sliding calculation window, a frequency spectrum was computed every 100 ms over an interval of 8.4 seconds (82 spectra in total). The dominant frequency (DF), the dominant amplitude (DA), and the mean spectral profile (MP) were measured. The 2s measurements were compared to single 8.4-second interval measurements. Coefficients of variation (COV) were computed from the 82 spectra for each CFAE recording to determine temporal variability of parameters. RESULTS: Over the sliding 2s computation intervals, as for fixed 8.4-second computation intervals, mean DA and DF were significantly higher in longstanding persistent AF while MP was significantly higher in paroxysmal AF (P ≤ 0.001). The COV was significantly higher for the DF parameter in paroxysmal AF (P < 0.001) and significantly higher for the MP parameter in persistent AF (P < 0.02). CONCLUSIONS: For both paroxysmal and persistent AF data, the 2s sliding window averages provide similar results to single 8.4-second intervals, and information regarding temporal stability was additionally obtained in the process.

Elucidation of Complex Atrial Tachycardia Activation in a Patient with Tetralogy of Fallot Using Omnipolar Mapping Technology: A Case Report.

In this case report, omnipolar mapping, a unique technology, was used to analyze complex atrial arrhythmias in an adult with congenital heart disease. Our patient had surgically corrected tetralogy of Fallot and presented with highly symptomatic atrial arrhythmias. A successful ablation was performed with standard bipolar mapping techniques. However, due to the complex nature of the substrate and arrhythmias in this patient, bipolar arrhythmia maps were difficult to interpret, and ablation lesions were delivered based on inference and "educated guesses." An offline re-analysis with omnipolar technology (OT) research software, days after the procedure was performed, revealed details not seen with traditional mapping and explained why the delivered lesions were effective. The findings of this retrospective analysis are provocative, suggesting that OT may increase the accuracy and efficiency of mapping and ablation of complex arrhythmias. Further investigation using commercially released OT in real time is needed.

Heart Rate Variability Reveals Altered Autonomic Regulation in Response to Myocardial Infarction in Experimental Animals.

The analysis of beating rate provides information on the modulatory action of the autonomic nervous system on the heart, which mediates adjustments of cardiac function to meet hemodynamic requirements. In patients with myocardial infarction, alterations of heart rate variability (HRV) have been correlated to the occurrence of arrhythmic events and all-cause mortality. In the current study, we tested whether experimental rodent models of myocardial infarction recapitulate dynamics of heart rate variability observed in humans, and constitute valid platforms for understanding mechanisms linking autonomic function to the development and manifestation of cardiovascular conditions. For this purpose, HRV was evaluated in two engineered mouse lines using electrocardiograms collected in the conscious, restrained state, using a tunnel device. Measurements were obtained in naïve mice and animals at 3-∼28 days following myocardial infarction, induced by permanent coronary artery ligation. Two mouse lines with inbred and hybrid genetic background and, respectively, homozygous (Homo) and heterozygous (Het) for the MerCreMer transgene, were employed. In the naïve state, Het female and male mice presented prolonged RR interval duration (∼9%) and a ∼4-fold increased short- and long-term RR interval variability, with respect to sex-matched Homo mice. These differences were abrogated by pharmacological interventions inhibiting the sympathetic and parasympathetic axes. At 3-∼14 days after myocardial infarction, RR interval duration increased in Homo mice, but was not affected in Het animals. In contrast, Homo mice had minor modifications in HRV parameters, whereas substantial (> 50%) reduction of short- and long-term RR interval variation occurred in Het mice. Interestingly, ex vivo studies in isolated organs documented that intrinsic RR interval duration increased in infarcted vs. non-infarcted Homo and Het hearts, whereas RR interval variation was not affected. In conclusion, our study documents that, as observed in humans, myocardial infarction in rodents is associated with alterations in heart rhythm dynamics consistent with sympathoexcitation and parasympathetic withdrawal. Moreover, we report that mouse strain is an important variable when evaluating autonomic function via the analysis of HRV.

Tissue-specific variability in human epicardial impedance.

INTRODUCTION: Epicardial ablation can be employed to treat ventricular tachycardia. Voltage attenuation in regions of fat can mimic epicardial scar, limiting its specificity. Ablation over fat may not be as effective. Prior animal data have shown that infarcted myocardium has lower impedance than normal, and human bioimpedance studies suggest peripheral fat displays higher impedance. Therefore, we tested the hypothesis that human epicardial fat has higher impedance than myocardium when measured with standard ablation tools. METHODS: Patients undergoing elective surgery for coronary artery or valve disease were enrolled. A reference patch was placed on the patients' back between the scapulae and connected to a standard RF generator (Stockert, GmBH, Germany). Impedance was measured by passing a 1 µA, 50 kHz current from the catheter tip to the patch. After sternotomy but before initiation of cardiopulmonary bypass, an ablation catheter (Celsius, Biosense Webster, Diamond Bar, CA, USA) was placed onto the epicardial surface in ventricular regions visually identified as fat or myocardium. At each site, impedance was recorded from the generator. RESULTS: A total of 37 (7 patients) points were sampled. Impedance was significantly higher in regions of fat versus normal muscle (697 Ω vs. 301 Ω; P = 0.01). Moreover, normal sites from the LV had higher impedance than from the RV (381 Ω vs. 271 Ω; P = 0.01). CONCLUSIONS: Human epicardial fat has higher tissue impedance than normal muscle. Using epicardial impedance and voltage mapping in conjunction may improve differentiation of arrhythmia substrate from epicardial fat and improve the efficacy of epicardial ablation.

Assessing patients for catheter ablation during hospitalization for acute heart failure.

Heart rhythm problems are common among patients who are hospitalized with acute heart failure (HF). Although it is often difficult to determine whether a tachyarrhythmia is the major contributor to an acute HF decompensation or merely a consequence of the decompensation, both issues usually need to be addressed. There is also a subset of patients with HF who have a tachycardia-induced cardiomyopathy (TIC), where the sole cause of the ventricular dysfunction is the heart rhythm problem. In most cases, the management of a tachyarrhythmia in a patient with acute HF is not significantly different than the management of a heart rhythm problem in any patient, but there are several special clinical scenarios and important considerations. These considerations include the time urgency for an intervention, the usual need to be more aggressive and definitive, the need to stabilize a patient to allow for a heart rhythm intervention, such as catheter ablation to be performed safely, and the limitations of antiarrhythmic drugs in patients with ventricular dysfunction. Catheter ablation is a highly effective treatment option for many patients with supraventricular or ventricular tachycardias who are hospitalized with HF. This review will discuss the different types of tachyarrhythmias that can be associated with acute HF and are amenable to catheter ablation, and the assessment that needs to take place in potentially eligible patients to determine when catheter ablation is appropriate.

Improved detection of subendocardial hyperenhancement in myocardial infarction using dark blood-pool delayed enhancement MRI.

OBJECTIVE: Delayed enhancement MRI using fast segmented k-space inversion recovery (IR) gradient-echo imaging is a well established "bright-blood" technique for identifying myocardial infarction and is used as the reference standard sequence in this study. The purpose of this study was to validate a recently developed dark blood-pool delayed enhancement technique in a porcine animal model, evaluate its performance in human patients, and quantify its performance compared with the reference standard in both. SUBJECTS AND METHODS: In an animal study, the reference standard and dark blood-pool delayed enhancement were assessed in three pigs with induced myocardial infarction. In a human study, 26 patients, 31-81 years old (19 men and seven women), with a known history of myocardial infarction were imaged using the reference standard and dark blood-pool delayed enhancement. Contrast-to-noise ratio (CNR), signal intensity ratio, signal-to-noise ratio (SNR), and qualitative scores of hyperenhancement were recorded. Measurements were compared using paired samples t test and Wilcoxon's signed rank test. RESULTS: In the animal study, the mean CNR of infarct to blood pool was 11 times higher for dark blood-pool delayed enhancement than for the reference standard. The mean SNR was 4.4 times higher for the reference standard. In the human study, the mean CNR and signal intensity ratio of hyperenhancing myocardium to the blood pool were 1.9 (p = 0.04) and 5.5 (p < 0.01) times higher, respectively, for dark blood-pool delayed enhancement compared with reference standard. The mean CNR and signal intensity ratio of hyperenhancing myocardium to normal myocardium and SNR were 2.8 (p < 0.01), 1.3 (p = 0.07), and 2.8 (p < 0.01) higher, respectively, for the reference standard. Qualitative analysis identified seven extra segments with grade 1 scars using dark blood-pool delayed enhancement (p < 0.01). CONCLUSION: Dark blood-pool delayed enhancement is complementary to the reference standard. It can detect more subendocardial foci of hyperenhancement, thus potentially identifying more infarcts and changing patient management.

Brugada syndrome clinical update.

Brugada syndrome (BrS) was initially described in southeast Asians with a structurally normal heart presenting with polymorphic ventricular tachycardia and fibrillation. This condition is marked by J-point elevation ≥ 2 mm with coved-type ST segment elevation followed by negative T wave inversions in at least one precordial lead (V1 or V2) when other etiologies have been excluded. These changes on electrocardiogram (EKG) can either be spontaneous or manifest after sodium channel blockade. The worldwide prevalence of BrS is about 0.4%; however, it is higher in the Asian population at 0.9%. This article will review the current hypotheses regarding the pathophysiology, spectrum of clinical presentation, strategies for prevention of sudden cardiac death and the treatment for recurrent arrhythmias in BrS.

Survival of a Patient with an Esophagopericardial Fistula After Catheter Ablation for Atrial Fibrillation: A Case Report and Literature Review.

Esophageal injury leading to esophagopericardial fistula (EPF) or atrioesophageal fistula is a very rare and dreaded complication of catheter ablation for atrial fibrillation that carries a high mortality rate. We present a case of EPF following radiofrequency catheter ablation for atrial fibrillation and an extensive review of the literature regarding catheter ablation-related esophageal injury.

Arrhythmogenic Right Ventricular Cardiomyopathy Diagnosis.

Arrhythmogenic right ventricular cardiomyopathy, formerly called "arrhythmogenic right ventricular dysplasia," is an under-recognized clinical entity characterized by ventricular arrhythmias and a characteristic ventricular pathology. Diagnosis is often difficult due to the nonspecific nature of the disease and the broad spectrum of phenotypic variations. Therefore, consensus diagnostic criteria have been developed which combine electrocardiographic, echocardiographic, cardiac magnetic resonance imaging and histologic criteria. In 1994, an international task force first proposed the major and minor diagnostic criteria of arrhythmogenic right ventricular cardiomyopathy based on family history, arrhythmias, electrocardiographic abnormalities, tissue characterization, and structural and functional right ventricular abnormalities. In 2010, the task force criteria were revised to include quantitative abnormalities. These diagnostic modalities and the most recent task force criteria are discussed in this review.