G. André Ng

Predictors for permanent pacemaker requirement after transcatheter aortic valve implantation with the CoreValve bioprosthesis.

INTRODUCTION Changes in atrioventricular (AV) conduction and need for permanent pacemaker (PPM) are a recognized complication after open aortic valve replacement. We hypothesized that the need for PPM after CoreValve (Corevalve Inc, Irvine, CA) can be predicted with a combination of baseline variables. METHODS In patients undergoing transcatheter aortic valve implantation, potential clinical, electrocardiographic and echocardiographic predictors of permanent pacing requirement were studied. RESULTS Between January 2007 and March 2008, 34 patients with severe symptomatic aortic stenosis were recruited in a single center. Mean age was 84.4 years (SD 5.4, range 71-93). Of 34 cases paced at baseline, 3 (8.8%) were excluded from this analysis, as was the single periprocedural mortality. Of the remaining 30, 10 underwent permanent pacemaker implantation during the same admission (33.3%). PPM was for prolonged high-grade AV block in 4 cases, episodic high-grade AV block in 5, and sinus node disease in 1. Need for pacemaker was correlated to left axis deviation at baseline (P = .004, r = 0.508) and left bundle-branch block with left axis deviation (P = .002, r = 0.548). It was related to diastolic interventricular septal dimension on transthoracic echocardiography >17 mm (P = .045, r = 0.39) and the baseline thickness of the native noncoronary cusp (P = .002, r = 0.655). A susceptibility model was generated, and if at least one of (1) left bundle-branch block with left axis deviation, (2) interventricular septal dimension >17 mm, or (3) noncoronary cusp thickness >8 mm was present, the likelihood of PPM could be predicted with 75% sensitivity and 100% specificity and a receiver operating characteristic curve area of 0.93 +/- 0.055 (P < .001). CONCLUSIONS After transcatheter aortic valve implantation with CoreValve, permanent pacing was performed in around a third of patients and we present preliminary concepts towards a predictive model for this phenomenon.

Effects of Direct Sympathetic and Vagus Nerve Stimulation on the Physiology of the Whole Heart – A Novel Model of Isolated Langendorff Perfused Rabbit Heart with Intact Dual Autonomic Innervation

A novel isolated Langendorff perfused rabbit heart preparation with intact dual autonomic innervation is described. This preparation allows the study of the effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart. These hearts (n= 10) had baseline heart rates of 146 ± 2 beats min−1 which could be increased to 240 ±11 beats min−1 by sympathetic stimulation (15 Hz) and decreased to 74 ± 11 beats min−1 by stimulation of the vagus nerve (right vagus, 7 Hz). This model has the advantage of isolated preparations, with the absence of influence from circulating hormones and haemodynamic reflexes, and also that of in vivo preparations where direct nerve stimulation is possible without the need to use pharmacological agents. Data are presented characterising the preparation with respect to the effects of autonomic nerve stimulation on intrinsic heart rate and atrioventricular conduction at different stimulation frequencies. We show that stimulation of the right and left vagus nerve have differential effects on heart rate and atrioventricular conduction.

Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial

BACKGROUND Hypertension contributes to cardiovascular morbidity and mortality. We assessed the safety and efficacy of a central iliac arteriovenous anastomosis to alter the mechanical arterial properties and reduce blood pressure in patients with uncontrolled hypertension. METHODS We enrolled patients in this open-label, multicentre, prospective, randomised, controlled trial between October, 2012, and April, 2014. Eligible patients had baseline office systolic blood pressure of 140 mm Hg or higher and average daytime ambulatory blood pressure of 135 mm Hg or higher systolic and 85 mm Hg or higher diastolic despite antihypertensive treatment. Patients were randomly allocated in a 1:1 ratio to undergo implantation of an arteriovenous coupler device plus current pharmaceutical treatment or to maintain current treatment alone (control). The primary endpoint was mean change from baseline in office and 24 h ambulatory systolic blood pressure at 6 months. Analysis was by modified intention to treat (all patients remaining in follow-up at 6 months). This trial is registered with ClinicalTrials.gov, number NCT01642498. FINDINGS 83 (43%) of 195 patients screened were assigned arteriovenous coupler therapy (n=44) or normal care (n=39). Mean office systolic blood pressure reduced by 26·9 (SD 23·9) mm Hg in the arteriovenous coupler group (p<0·0001) and by 3·7 (21·2) mm Hg in the control group (p=0·31). Mean systolic 24 h ambulatory blood pressure reduced by 13·5 (18·8) mm Hg (p<0·0001) in arteriovenous coupler recipients and by 0·5 (15·8) mm Hg (p=0·86) in controls. Implantation of the arteriovenous coupler was associated with late ipsilateral venous stenosis in 12 (29%) of 42 patients and was treatable with venoplasty or stenting. INTERPRETATION Arteriovenous anastomosis was associated with significantly reduced blood pressure and hypertensive complications. This approach might be a useful adjunctive therapy for patients with uncontrolled hypertension. FUNDING ROX Medical.

Autonomic Nerve Stimulation Reverses Ventricular Repolarization Sequence in Rabbit Hearts

Sympathetic activity and spatial dispersion of repolarization (DOR) have been implicated as mechanisms that promote arrhythmia vulnerability; yet there are no direct measurements of the effects of autonomic nerve stimulation on DOR. Rabbit hearts were perfused in a Langendorff apparatus with full sympathetic and parasympathetic innervation and were optically mapped to measure action potential durations and DOR (apex–base) over the left ventricles. DOR was measured under sinus rhythm, during bilateral sympathetic nerve stimulation (SNS) and right and/or left vagus nerve stimulation and was compared with DOR during isoproterenol (100 nmol/L) or acetylcholine (1 &mgr;mol/L) infusion. In sinus rhythm, repolarization started at the apex and systematically progressed toward the base. SNS (10 to 15 Hz) increased DOR by 29% (from &Dgr;action potential duration=17±0.7 to −22±1.6 ms, n=6) and reversed DOR as the direction of repolarization from apex→base in sinus rhythm shifted to base→apex in 5 to 15 seconds after SNS. DOR flipped back to its sinus rhythm DOR pattern 115±15 seconds after the interruption of SNS. During right or left vagus nerve stimulation, there was no change in the direction of DOR, but bilateral vagus nerve stimulation increased and reversed DOR to base→apex direction. Infusion of isoproterenol or acetylcholine increased DOR but did not alter the direction of repolarization sequences. These findings demonstrate that bilateral autonomic activity (SNS or vagus nerve stimulation) cause reversible shifts of apex–base DOR and that the spatial heterogeneities of autonomic effects on the ventricles are most likely attributable to a greater innervation at the base than the apex of the heart.

Nitric oxide mediates the vagal protective effect on ventricular fibrillation via effects on action potential duration restitution in the rabbit heart

We have previously shown that direct vagus nerve stimulation (VNS) reduces the slope of action potential duration (APD) restitution while simultaneously protecting the heart against induction of ventricular fibrillation (VF) in the absence of any sympathetic activity or tone. In the current study we have examined the role of nitric oxide (NO) in the effect of VNS. Monophasic action potentials were recorded from a left ventricular epicardial site on innervated, isolated rabbit hearts (n= 7). Standard restitution, effective refractory period (ERP) and VF threshold (VFT) were measured at baseline and during VNS in the presence of the NO synthase inhibitor NG‐nitro‐l‐arginine (l‐NA, 200 μm) and during reversing NO blockade with l‐arginine (l‐Arg, 1 mm). Data represent the mean ±s.e.m. The restitution curve was shifted upwards and became less steep with VNS when compared to baseline. l‐NA blocked the effect of VNS whereas l‐Arg restored the effect of VNS. The maximum slope of restitution was reduced from 1.17 ± 0.14 to 0.60 ± 0.09 (50 ± 5%, P < 0.0001) during control, from 0.98 ± 0.14 to 0.93 ± 0.12 (2 ± 10%, P= NS) in the presence of l‐NA and from 1.16 ± 0.17 to 0.50 ± 0.10 (41 ± 9%, P= 0.003) with l‐Arg plus l‐NA. ERP was increased by VNS in control from 119 ± 6 ms to 130 ± 6 ms (10 ± 5%, P= 0.045) and this increase was not affected by l‐NA (120 ± 4 to 133 ± 4 ms, 11 ± 3%, P= 0.0019) or l‐Arg with l‐NA (114 ± 4 to 123 ± 4 ms, 8 ± 2%, P= 0.006). VFT was increased from 3.0 ± 0.3 to 5.8 ± 0.5 mA (98 ± 12%, P= 0.0017) in control, 3.4 ± 0.4 to 3.8 ± 0.5 mA (13 ± 12%, P= 0.6) during perfusion with l‐NA and 2.5 ± 0.4 to 6.0 ± 0.7 mA (175 ± 50%, P= 0.0017) during perfusion with l‐Arg plus l‐NA. Direct VNS increased VFT and flattened the slope of APD restitution curve in this isolated rabbit heart preparation with intact autonomic nerves. These effects were blocked using l‐NA and reversed by replenishing the substrate for NO production with l‐Arg. This is the first study to demonstrate that NO plays an important role in the anti‐fibrillatory effect of VNS on the rabbit ventricle, possibly via effects on APD restitution.

Vagus nerve stimulation protects against ventricular fibrillation independent of muscarinic receptor activation

AIMS The role of the vagus in the ventricle is controversial, although the vagus can protect against ventricular fibrillation (VF) via nitric oxide (NO). This study aims to determine whether the mechanisms involved are dependent on post-ganglionic release and muscarinic receptor activation. For this purpose, NO release and electrophysiological effects of vagus nerve stimulation (VNS) were evaluated in relation to acetylcholine and vasoactive intestinal peptide (VIP). In addition, the role of the coronary endothelium and afferent nerves was tested. METHODS AND RESULTS Using the isolated innervated rabbit heart, we measured ventricular NO release using 4,5-diaminofluorescein (DAF-2) fluorescence and ventricular fibrillation threshold (VFT) during VNS after muscarinic, ganglionic, and VIP inhibition [atropine, hexamethonium, and VIP (6-28), respectively] and after Triton-X endothelial functional dysfunction. The vagal-mediated increases in NO and VFT were not significantly affected (P> 0.05) during (i) atropine perfusion [increase in NO: 196.8 ± 35.2 mV (control) vs. 156.1 ± 20.3 mV (atropine) and VFT 3.1 ± 0.5 mA (control) vs. 2.7 ± 0.4 mA (atropine)], (ii) VIP inhibition-increase in NO: 243.0 ± 42.4 mV (control) vs. 203.9 ± 28.5 mV [VIP(6-28)] and VFT 3.3 ± 0.3 mA (control) vs. 3.9 ± 0.6 mA [VIP(6-28)], or (iii) after endothelial functional dysfunction [increase in NO: 127.7 ± 31.7 mV (control) vs. 172.1 ± 31.5 mV (Triton-X) and VFT 2.6 ± 0.4 mA (control) vs. 2.5 ± 0.5 mA (Triton-X)]. However, the vagal effects were inhibited during ganglionic blockade [increase in NO: 175.1 ± 38.1 mV (control) vs. 0.6 ± 25.3 mV (hexamethonium) and VFT 3.3 ± 0.5 mA (control) vs. -0.3 ± 0.3 mA (hexamethonium)]. CONCLUSIONS We show that the vagal anti-fibrillatory action in the rabbit ventricle occurs via post-ganglionic efferent nerve fibres, independent of muscarinic receptor activation, VIP, and the endothelium. Together with our previous publications, our data support the possibility of a novel ventricular nitrergic parasympathetic innervation and highlight potential for new therapeutic targets to treat ventricular dysrhythmias.

Treating patients with ventricular ectopic beats.

Ventricular ectopic beats (VEBs) are commonly seen in daily clinical practice. They are largely asymptomatic but can cause upsetting symptoms in some patients. In normal hearts, their occurrence is usually associated with no clinical significance. However, there are occasions where the presence of VEBs signifies a susceptibility towards more sinister arrhythmias, especially when heart disease is present. In some patients, VEBs are triggered by the same mechanism that gives rise to ventricular tachycardia which can be cured with catheter ablation. In addition, there are recent reports on the use of catheter ablation in cases where focal ventricular ectopics are found to trigger ventricular fibrillation. Appropriate clinical evaluation and investigations are important in assessing patients with VEBs so that effective treatment can be targeted when necessary. This article discusses the current knowledge and practice in this commonly encountered clinical cardiological problem. The first recorded description of intermittent perturbations interrupting the regular pulse, that could be consistent with VEBs, was from the early Chinese physician Pien Ts’Io, around 600 BC, who was the master in pulse palpation and diagnosis.1 He noted that these irregularities did not interfere with normal lifespan when they were occasional but an ominous prognosis was implied if they were frequent. This was shown to be so in more recent times where patients who have had a myocardial infarct were more prone to sudden death if they had frequent ventricular ectopics. Lown and colleagues2 proposed a classification and grading of ventricular ectopics based on their frequency and complexity. This triggered the widely accepted dogma that increasing “severity” of ventricular ectopic activity was directly related to the risk of malignant ventricular arrhythmias and considerable effort had been spent in developing and employing antiarrhythmic drugs to suppress ectopics in the 1960s and ’70s. This was set to change. VEBs …

Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations

BACKGROUND A longer heart-rate corrected QT interval (QTc) is associated with increased risk of ventricular arrhythmias. Women have longer resting QTc and are more likely than men to develop drug-induced QT prolongation. Recent studies have shown association between resting QTc and a common variant (rs10494366) of the NOS1 regulator, NOS1AP. We investigated the association between rs10494366 in NOS1AP and QTc, and assessed gender-specific NOS1AP associations with QTc during rest and after exercise. METHODS We investigated the SNP associations with resting QTc in 919 women and 918 men from 504 representative families in the UK GRAPHIC study, and with QTc at rest and at 3 min recovery after exercise in 699 women and 1225 men referred for exercise testing in the Finnish FINCAVAS study. RESULTS In the GRAPHIC study the minor allele (G) of the NOS1AP SNP rs10494366 prolonged QTc by 4.59 ms (95% CI 2.77-6.40; P = 7.63/10(7)) in women, but only by 1.62 ms (95% CI -0.15 to 3.38; P = 0.073) in men (gender-SNP interaction term P = 0.025). In the FINCAVAS study the G allele significantly prolonged QTc in both women (P = 0.0063) and men (P = 0.0043) at 3 min recovery after exercise, but at rest an association was only seen in women (P = 0.020 excluding outliers). CONCLUSIONS A common NOS1AP variant prolongs QTc with a difference between genders. Further studies should aim to confirm this finding and to assess whether NOS1AP genotype influences the risk of drug-induced QT prolongation and risk of consequent arrhythmias.

Direct evidence of nitric oxide release from neuronal nitric oxide synthase activation in the left ventricle as a result of cervical vagus nerve stimulation

Information regarding vagal innervation in the cardiac ventricle is limited and the direct effect of vagal stimulation on ventricular myocardial function is controversial. We have recently provided indirect evidence that the anti‐fibrillatory effect of vagus nerve stimulation on the ventricle is mediated by nitric oxide (NO). The aim of this study was to provide direct evidence for the release of nitric oxide in the cardiac ventricle during stimulation of the efferent parasympathetic fibres of the cervical vagus nerve. The isolated innervated rabbit heart was employed with the use of the NO fluorescent indicator 4,5‐diaminofluorescein diacetate (DAF‐2 DA) during stimulation of the cervical vagus nerves and acetylcholine perfusion in the absence and presence of the non‐specific NO synthase inhibitor NG‐nito‐l‐arginine (l‐NNA) and the neuronal NO synthase selective inhibitor 1‐(2‐trifluormethylphenyl)imidazole (TRIM). Using the novel fluorescence method in the beating heart, we have shown that NO‐dependent fluorescence is increased by 0.92 ± 0.26, 1.20 ± 0.30 and 1.91 ± 0.27% (during low, medium and high frequency, respectively) in the ventricle in a stimulation frequency‐dependent manner during vagus nerve stimulation, with comparable increases seen during separate stimulation of the left and right cervical vagus nerves. Background fluorescence is reduced during perfusion with l‐NNA and the increase in fluorescence during high frequency vagal stimulation is inhibited during perfusion with both l‐NNA (1.97 ± 0.35% increase before l‐NNA, 0.00 ± 0.02% during l‐NNA) and TRIM (1.78 ± 0.18% increase before TRIM, −0.11 ± 0.08% during TRIM). Perfusion with 0.1 μm acetylcholine increased NO fluorescence by 0.76 ± 0.09% which was blocked by l‐NNA (change of 0.00 ± 0.03%) but not TRIM (increase of 0.82 ± 0.21%). Activation of cardiac parasympathetic efferent nerve fibres by stimulation of the cervical vagus is associated with NO production and release in the ventricle of the rabbit, via the neuronal isoform of nitric oxide synthase.

Interaction between direct sympathetic and vagus nerve stimulation on heart rate in the isolated rabbit heart

The interaction between the effects of vagus nerve stimulation (VS) and sympathetic stimulation (SS) on intrinsic heart rate was studied in the novel innervated isolated rabbit heart preparation. The effects of background VS, at different frequencies – 2 Hz (low), 5 Hz (medium), 7 Hz (high) – on the chronotropic effects of different frequencies of SS – 2 Hz (low), 5 Hz (medium), 10 Hz (high) – were studied. The experiments were repeated in the reverse direction studying the effects of different levels of background SS on the chronotropic effects of different levels of VS. Background VS reduced the overall positive chronotropic effect of SS at steady state in a frequency dependent manner and the rate of increase in heart rate during low and medium SS (but not high SS) was slowed in the presence of background VS. These results suggest that pre‐ and postjunctional mechanisms may be involved in the sympatho–vagal interaction on heart rate. On the other hand, the chronotropic effect of VS was enhanced in the presence of background SS. Vagal stimulation appears to play a dominant role over sympathetic stimulation in chronotropic effects on the isolated heart. The innervated isolated heart preparation is a valuable model to study the complex mechanisms underlying the interaction between sympathetic and parasympathetic stimulation on cardiac function.