Emergency out-of-hours catheter ablation for ventricular arrhythmia storm: a UK and Australian experience.

AIMS: There are limited data on emergency catheter ablation (CA) for ventricular arrhythmia (VA) storm. We describe the feasibility and safety of performing emergency CA in an out-of-hours setting for VA storm refractory to medical therapy at 2 tertiary hospitals. METHODS AND RESULTS: Twenty-five consecutive patients underwent out-of-hours (5pm-8am [weekday] or Friday 5pm-Monday 8am [weekend]) CA for VA storm refractory to anti-arrhythmic drugs and sedation. Baseline and procedural characteristics along with outcomes were compared to 91 consecutive patients undergoing weekday daytime-hours (8am-5pm) CA for VA storm. More patients undergoing out-of-hours CA had a left ventricular ejection fraction ≤35% (68% vs. 42%, P = 0.022), chronic kidney disease (60% vs. 20%, P < 0.001), and presented following a resuscitated out-of-hospital cardiac arrest (56% vs. 5%, P < 0.001), compared to the daytime-hours group. During median follow-up (377 [interquartile range 138-826] days), both groups experienced similar survival free from recurrent VA and VA storm. Survival free from cardiac transplant and/or mortality was lower in the out-of-hours group (44% vs. 81%, P = 0.007), but out-of-hours CA was not independently associated with increased cardiac transplant and/or mortality (hazard ratio 1.34, 95% confidence interval 0.61-2.96, P = 0.47). Of the 11 patients in the out-of-hours group who survived follow-up, VA-free survival was 91% and VA storm-free survival was 100% at 1-year after CA. CONCLUSION: Out-of-hours CA may occasionally be required to control VA storm and can be safe and efficacious in this scenario. During follow-up, cardiac transplant and/or mortality is common but undergoing out-of-hours CA was not predictive of this composite endpoint.

Convergent approach to persistent atrial fibrillation ablation: long-term single-centre safety and efficacy.

Background: Efforts to maintain sinus rhythm in patients with persistent atrial fibrillation (PsAF) remain challenging, with suboptimal long-term outcomes. Methods: All patients undergoing convergent PsAF ablation at our centre were retrospectively analysed. The Atricure Epi-Sense® system was used to perform surgical radiofrequency ablation of the LA posterior wall followed by endocardial ablation. Results: A total of 24 patients underwent convergent PsAF ablation, and 21 (84%) of them were male with a median age of 63. Twelve (50%) patients were obese. In total, 71% of patients had a severely dilated left atrium, and the majority (63%) had preserved left ventricular function. All were longstanding persistent. Eighteen (75%) patients had an AF duration of >2 years. There were no endocardial procedure complications. At 36 months, all patients were alive with no new stroke/transient ischaemic attack (TIA). Freedom from documented AF at 3, 6, 12, 18, 24, and 36 months was 83%, 78%, 74%, 74%, 74%, and 61%, respectively. There were no major surgical complications, with five minor complications recorded comprising minor wound infection, pericarditic pain, and hernia. Conclusions: Our data suggest that convergent AF ablation is effective with excellent immediate and long-term safety outcomes in a real-world cohort of patients with a significant duration of AF and evidence of established atrial remodelling. Convergent AF ablation appears to offer a safe and effective option for those who are unlikely to benefit from existing therapeutic strategies for maintaining sinus rhythm, and further evaluation of this exciting technique is warranted. Our cohort is unique within the published literature both in terms of length of follow-up and very low rate of adverse events.

Entirely subcutaneous defibrillator and complex congenital heart disease: Data on long-term clinical follow-up.

AIM: To describe the long-term follow-up of patients with complex congenital heart disease who underwent subcutaneous implantable cardiac defibrillator (S-ICD), focusing on local complications, appropriate and inappropriate shocks. METHODS: Patients with complex congenital heart disease underwent S-ICD implant in two centers with the conventional technique. Data at follow-up were retrieved from clinical notes and institutional database. RESULTS: Eight patients were implanted in two centres between 2010 and 2016. Median age at implant was 37.5 years (range 13-57). All patients who were deemed suitable for S-ICD implant passed the pre-procedural screening. Three patients were previously implanted with a anti-bradycardia device, one of whom with CRT. In one patient the device was explanted due to local infection. During the total median follow-up of 874 d, one patient had an appropriate and one inappropriate shock triggered by fast atrial tachycardia. None of the patients had inappropriate shocks secondary to T wave oversensing or electrical interference with anti- bradycardia devices. CONCLUSION: S-ICD appears to be effective and safe in patients with complex congenital heart disease.

Nickel inhibits ß-1 adrenoceptor mediated activation of cardiac CFTR chloride channels.

Cardiac ventricular myocytes exhibit a protein kinase A-dependent Cl(-) current (ICl.PKA) mediated by the cystic fibrosis transmembrane conductance regulator (CFTR). There is conflicting evidence regarding the ability of the divalent cation nickel (Ni(2+)), which has been used widely in vitro in the study of other cardiac ionic conductances, to inhibit ICl.PKA. Here the action of Ni(2+) on ICl.PKA activated by ß-adrenergic stimulation has been elucidated. Whole-cell patch-clamp recordings were made from rabbit isolated ventricular myocytes. Externally applied Ni(2+) blocked ICl.PKA activated by 1 µM isoprenaline with a log IC50 (M) of -4.107 ± 0.075 (IC50=78.1 µM) at +100 mV and -4.322 ± 0.107 (IC50=47.6 µM) at -100 mV. Thus, the block of ICl.PKA by Ni(2+) was not strongly voltage dependent. Ni(2+) applied internally via the patch-pipette was ineffective at inhibiting isoprenaline-activated ICl,PKA, but in the same experiments the current was suppressed by external Ni(2+) application, indicative of an external site of Ni(2+) action. In the presence of 1 µM atenolol isoprenaline was ineffective at activating ICl.PKA, but in the presence of the ß2-adrenoceptor inhibitor ICI 118,551 isoprenaline still activated Ni(2+)-sensitive ICl.PKA. Collectively, these data demonstrate that Ni(2+) ions produce marked inhibition of ß1-adrenoceptor activated ventricular ICl.PKA at submillimolar [Ni(2+)]: an action that is likely to involve an interaction between Ni(2+) and ß1-adrenoceptors. The concentration-dependence for ICl.PKA inhibition seen here indicates the potential for confounding effects on ICl,PKA to occur even at comparatively low Ni(2+) concentrations, when Ni(2+) is used to study other cardiac ionic currents under conditions of ß-adrenergic agonism.

Atrial remodeling and the substrate for atrial fibrillation in rat hearts with elevated afterload.

BACKGROUND: Although arterial hypertension and left ventricular hypertrophy are considered good epidemiological indicators of the risk of atrial fibrillation (AF) in patients, the link between elevated afterload and AF remains unclear. We investigated atrial remodeling and the substrate for arrhythmia in a surgical model of elevated afterload in rats. METHODS AND RESULTS: Male Wistar rats (aged 3-4 weeks) were anesthetized and subjected to either partial stenosis of the ascending aorta (AoB) or sham operation (Sham). Experiments were performed on excised hearts 8, 14, and 20 weeks after surgery. Unipolar electrograms were recorded from the left atrial epicardial surface of perfused hearts using a 5×5 electrode array. Cryosections of left atrial tissue were retained for histological and immunocytochemical analyses. Compared to Sham, AoB hearts showed marked left atrial hypertrophy and fibrosis at 14 and 20 weeks postsurgery. The incidence and duration of pacing-induced AF was increased in hearts from AoB rats at 20 weeks postsurgery. The substrate for arrhythmia was associated with reduced vectorial conduction velocity and greater inhomogeneity in conduction but without changes in effective refractory period. Left atrial expression of the gap junction protein, connexin43, was markedly reduced in AoB compared with Sham hearts. CONCLUSIONS: Using a small-animal model, we demonstrate that elevated afterload in the absence of systemic hypertension results in increased inducibility of AF and left atrial remodeling involving fibrosis, altered atrial connexin43 expression, and marked conduction abnormalities.

ß-Adrenoceptor/PKA-stimulation, Na(+)-Ca(2+) exchange and PKA-activated Cl(-) currents in rabbit cardiomyocytes: a conundrum.

Investigations into the functional modulation of the cardiac Na(+)-Ca(2+) exchanger (NCX) by acute ß-adrenoceptor/PKA stimulation have produced conflicting results. Here, we investigated (i) whether or not ß-adrenoceptor activation/PKA stimulation activates current in rabbit cardiac myocytes under NCX-'selective' conditions and (ii) if so, whether a PKA-activated Cl(-)-current may contribute to the apparent modulation of NCX current (I(NCX)). Whole-cell voltage-clamp experiments were conducted at 37°C on rabbit ventricular and atrial myocytes. The ß-adrenoceptor-activated currents both in NCX-'selective' and Cl(-)-selective recording conditions were found to be sensitive to 10mM Ni(2+). In contrast, the PKA-activated Cl(-) current was not sensitive to Ni(2+), when it was activated downstream to the ß-adrenoceptors using 10µM forskolin (an adenylyl cyclase activator). When 10µM forskolin was applied under NCX-selective recording conditions, the Ni(2+)-sensitive current did not differ between control and forskolin. These findings suggest that in rabbit myocytes: (a) a PKA-activated Cl(-) current contributes to the Ni(2+)-sensitive current activated via ß-adrenoceptor stimulation under recording conditions previously considered selective for I(NCX); (b) downstream activation of PKA does not augment Ni(2+)-sensitive I(NCX), when this is measured under conditions where the Ni(2+)-sensitive PKA-activated Cl(-) current is not present.

Cardiac ion channel current modulation by the CFTR inhibitor GlyH-101.

The role in the heart of the cardiac isoform of the cystic fibrosis transmembrane conductance regulator (CFTR), which underlies a protein kinase A-dependent Cl(-) current (I(Cl.PKA)) in cardiomyocytes, remains unclear. The identification of a CFTR-selective inhibitor would provide an important tool for the investigation of the contribution of CFTR to cardiac electrophysiology. GlyH-101 is a glycine hydrazide that has recently been shown to block CFTR channels but its effects on cardiomyocytes are unknown. Here the action of GlyH-101 on cardiac I(Cl.PKA) and on other ion currents has been established. Whole-cell patch-clamp recordings were made from rabbit isolated ventricular myocytes. GlyH-101 blocked I(Cl.PKA) in a concentration- and voltage-dependent fashion (IC(50) at +100 mV=0.3 ± 1.5 µM and at -100 mV=5.1 ± 1.3 µM). Woodhull analysis suggested that GlyH-101 blocks the open pore of cardiac CFTR channels at an electrical distance of 0.15 ± 0.03 from the external membrane surface. A concentration of GlyH-101 maximally effective against I(Cl.PKA) (30 µM) was tested on other cardiac ion currents. Inward current at -120 mV, comprised predominantly of the inward-rectifier background K(+) current, I(K1), was reduced by ∼43% (n=5). Under selective recording conditions, the Na(+) current (I(Na)) was markedly inhibited by GlyH-101 over the entire voltage range (with a fractional block at -40 mV of ∼82%; n=8). GlyH-101 also produced a voltage-dependent inhibition of L-type Ca(2+) channel current (I(Ca,L)); fractional block at +10 mV of ∼49% and of ∼28% at -10 mV; n=11, with a ∼-3 mV shift in the voltage-dependence of I(Ca,L) activation. Thus, this study demonstrates for the first time that GlyH-101 blocks cardiac I(Cl.PKA) channels in a similar fashion to that reported for recombinant CFTR. However, inhibition of other cardiac conductances may limit its use as a CFTR-selective blocker in the heart.