Psychological stress, the central nervous system and arrhythmias.

This review highlights the links between psychological stress and the neurocircuitry of cardiac-brain interactions leading to arrhythmias. The role of efferent and afferent connections in the heart-brain axis is considered, with the mechanisms by which emotional responses promote arrhythmias illustrated by inherited cardiac conditions. Novel therapeutic targets for intervention in the autonomic nervous system are considered.

Outcome of ACHD patients with non-inducible versus inducible IART undergoing cavo-tricuspid isthmus ablation: the role of empiric ablation.

PURPOSE: Catheter ablation for supraventricular tachycardia (SVT) in adults with congenital heart disease (ACHD) is an important therapeutic option. Cavo-tricuspid isthmus (CTI)-dependent intraatrial re-entrant tachycardia (IART) is common. However, induction of sustained tachycardia at the time of ablation is not always possible. We hypothesised that performing an empiric CTI line in case of non-inducibility leads to good outcomes. Long-term outcomes of empiric versus entrained CTI ablation in ACHD patients were examined. METHODS: Retrospective, single-centre, case-control study over 7 years. Arrhythmia-free survival after empiric versus entrained CTI ablation was compared. RESULTS: Eighty-seven CTI ablations were performed in 85 ACHD patients between 2010 and 2017. The mean age of the cohort was 43 years and 48% were male. Underlying aetiology included ASD (31%), VSD (11.4%), AVSD (9.1%), AVR (4.8%), Fallot's (18.4%), Ebstein's (2.3%), Fontan's palliation (9.2%) and atrial switch (13.8%). CTI-dependent IART was entrained in 59 patients whereas it was non-inducible in 28. The latter had an empiric CTI ablation. Forty-three percent of procedures were performed under general anaesthesia. There were no reported procedural complications. There was no significant difference in the mean procedure or fluoroscopy times between the groups (empiric vs entrained CTI; 169.1 vs 183.3 and 28.1 vs 19.9 min). Arrhythmia-free survival was 64.3% versus 72.8% (p value 0.44) in the empiric and entrained groups at 21 months follow-up. CONCLUSIONS: Long-term outcomes after empiric and entrained CTI ablation for IART in ACHD patients are comparable. This is a safe and effective therapeutic option. In the case of non-inducibility of IART, an empiric CTI line should be considered in this cohort.

Left atrial scarring and conduction velocity dynamics: Rate dependent conduction slowing predicts sites of localized reentrant atrial tachycardias.

BACKGROUND: Low voltage zones (LVZs) are associated with conduction velocity (CV) slowing. Rate-dependent CV slowing may play a role in reentry mechanisms. METHODS: Patients undergoing catheter ablation for AT were enrolled. Aim was to assess the relationship between rate-dependent CV slowing and sites of localized reentrant atrial tachycardias (AT). On a bipolar voltage map regions were defined as non-LVZs [≥0.5 mV], LVZs [0.2-0.5 mV] and very-LVZs [<0.2 mV]. Unipolar electrograms were recorded with a 64-pole basket catheter during uninterrupted atrial pacing at four pacing intervals (PIs) during sinus rhythm. CVs were measured between pole pairs along the wavefront path. Sites of rate-dependent CV slowing were defined as exhibiting a reduction in CV between PI = 600 ms and 250 ms of ≥20% more than the mean CV reduction seen between these PIs for that voltage zone. Rate-dependent CV slowing sites were correlated to sites of localized reentrant ATs as confirmed with conventional mapping, entrainment and response to ablation. RESULTS: Eighteen patients were included (63 ±â€¯10 years). Mean CV at 600 ms was 1.53 ±â€¯0.19 m/s in non-LVZs, 1.14 ±â€¯0.15 m/s in LVZs, and 0.73 ±â€¯0.13 m/s in very-LVZs respectively (p < 0.001). Rate-dependent CV slowing sites were predominantly in LVZs [0.2-0.5 mV] (74.4 ±â€¯10.3%; p < 0.001). Localized reentrant ATs were mapped to these sites in 81.8% of cases (sensitivity 81.8%, 95% CI 48.2-97.9% and specificity 83.9%, 95% CI 81.8-86.0%). Macro-reentrant or focal ATs were not mapped to sites of rate-dependent CV slowing. CONCLUSIONS: Rate-dependent CV slowing sites are predominantly confined to LVZs [0.2-0.5 mV] and the resultant CV heterogeneity may promote reentry mechanisms. These may represent a novel adjunctive target for AT ablation.

Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype.

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is an inherited, frequently underdiagnosed disorder, which can predispose individuals to sudden cardiac death. Rare, recessive forms of AC can be associated with woolly hair and palmoplantar keratoderma, but most autosomal dominant AC forms have been reported to be cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP). OBJECTIVES: In this study, we systematically investigated the presence of a skin and hair phenotype in heterozygous DSP mutation carriers with AC. METHODS: Six AC pedigrees with 38 carriers of a dominant loss-of-function (nonsense or frameshift) mutation in DSP were evaluated by detailed clinical examination (cardiac, hair and skin) and molecular phenotyping. RESULTS: All carriers with mutations affecting both major DSP isoforms (DSPI and II) were observed to have curly or wavy hair in the pedigrees examined, except for members of Family 6, where the position of the mutation only affected the cardiac-specific isoform DSPI. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from nonlesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localization was comparable with control skin. CONCLUSIONS: This study identifies a highly recognizable cutaneous phenotype associated with dominant loss-of-function DSPI/II mutations underlying AC. Increased awareness of this phenotype among healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features.

Assessment of a conduction-repolarisation metric to predict Arrhythmogenesis in right ventricular disorders.

BACKGROUND: The re-entry vulnerability index (RVI) is a recently proposed activation-repolarization metric designed to quantify tissue susceptibility to re-entry. This study aimed to test feasibility of an RVI-based algorithm to predict the earliest endocardial activation site of ventricular tachycardia (VT) during electrophysiological studies and occurrence of haemodynamically significant ventricular arrhythmias in follow-up. METHODS: Patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (n = 11), Brugada Syndrome (BrS) (n = 13) and focal RV outflow tract VT (n = 9) underwent programmed stimulation with unipolar electrograms recorded from a non-contact array in the RV. RESULTS: Lowest values of RVI co-localised with VT earliest activation site in ARVC/BrS but not in focal VT. The distance between region of lowest RVI and site of VT earliest site (Dmin) was lower in ARVC/BrS than in focal VT (6.8 ±â€¯6.7 mm vs 26.9 ±â€¯13.3 mm, p = 0.005). ARVC/BrS patients with inducible VT had lower Global-RVI (RVIG) than those who were non-inducible (-54.9 ±â€¯13.0 ms vs -35.9 ±â€¯8.6 ms, p = 0.005) or those with focal VT (-30.6 ±â€¯11.5 ms, p = 0.001). Patients were followed up for 112 ±â€¯19 months. Those with clinical VT events had lower Global-RVI than both ARVC and BrS patients without VT (-54.5 ±â€¯13.5 ms vs -36.2 ±â€¯8.8 ms, p = 0.007) and focal VT patients (-30.6 ±â€¯11.5 ms, p = 0.002). CONCLUSIONS: RVI reliably identifies the earliest RV endocardial activation site of VT in BrS and ARVC but not focal ventricular arrhythmias and predicts the incidence of haemodynamically significant arrhythmias. Therefore, RVI may be of value in predicting VT exit sites and hence targeting of re-entrant arrhythmias.

Mechano-electrical feedback in the clinical setting: Current perspectives.

Mechano-electric feedback (MEF) is an established mechanism whereby myocardial deformation causes changes in cardiac electrophysiological parameters. Extensive animal, laboratory and theoretical investigation has demonstrated that abnormal patterns of cardiac strain can induce alteration of electrical excitation and recovery through MEF, which can potentially contribute to the establishment of dangerous arrhythmias. However, the clinical relevance of MEF in patients with heart disease remains to be established. This paper reviews up-to date experimental evidence describing the response to different types of mechanical stimuli in the intact human heart with the support of new data collected during cardiac surgery. It discusses modulatory effects of MEF that may contribute to increase the vulnerability to arrhythmia and describes MEF interaction with clinical conditions where mechanically induced changes in cardiac electrophysiology are likely to be more relevant. Finally, directions for future studies, including the need for in-vivo human data providing simultaneous assessment of the distribution of structural, functional and electrophysiological parameters at the regional level, are identified.

A propensity matched case-control study comparing efficacy, safety and costs of the subcutaneous vs. transvenous implantable cardioverter defibrillator.

BACKGROUND: Subcutaneous implantable cardioverter defibrillators (S-ICD) have become more widely available. However, comparisons with conventional transvenous ICDs (TV-ICD) are scarce. METHODS: We conducted a propensity matched case-control study including all patients that underwent S-ICD implantation over a five-year period in a single tertiary centre. Controls consisted of all TV-ICD implant patients over a contemporary time period excluding those with pacing indication, biventricular pacemakers and those with sustained monomorphic ventricular tachycardia requiring anti-tachycardia pacing. Data was collected on device-related complications and mortality rates. A cost efficacy analysis was performed. RESULTS: Sixty-nine S-ICD cases were propensity matched to 69 TV-ICD controls. During a mean follow-up of 31±19 (S-ICD) and 32±21months (TV-ICD; p=0.88) there was a higher rate of device-related complications in the TV-ICD group predominantly accounted for by lead failures (n=20, 29% vs. n=6, 9%; p=0.004). The total mean cost for each group, including the complication-related costs was £9967±4511 ($13,639±6173) and £12,601±1786 ($17,243±2444) in the TV-ICD and S-ICD groups respectively (p=0.0001). Even though more expensive S-ICD was associated with a relative risk reduction of device-related complication of 70% with a HR of 0.30 (95%CI 0.12-0.76; p=0.01) compared to TV-ICDs. CONCLUSIONS: TV-ICDs are associated with increased device-related complication rates compared to a propensity matched S-ICD group during a similar follow-up period. Despite the existing significant difference in unit cost of the S-ICD, overall S-ICD costs may be mitigated versus TV-ICDs over a longer follow-up period.

Management of atrial fibrillation: when are invasive approaches useful?

The management of atrial fibrillation extends from stroke prevention to rate or rhythm control strategies. The role of an invasive strategy is expanding and it remains important to identify suitable candidates early in the disease process.

Safety and efficacy of multipolar pulmonary vein ablation catheter vs. irrigated radiofrequency ablation for paroxysmal atrial fibrillation: a randomized multicentre trial.

AIMS: The current challenge in atrial fibrillation (AF) treatment is to develop effective, efficient, and safe ablation strategies. This randomized controlled trial assesses the medium-term efficacy of duty-cycled radiofrequency ablation via the circular pulmonary vein ablation catheter (PVAC) vs. conventional electro-anatomically guided wide-area circumferential ablation (WACA). METHODS AND RESULTS: One hundred and eighty-eight patients (mean age 62 ± 12 years, 116 M : 72 F) with paroxysmal AF were prospectively randomized to PVAC or WACA strategies and sequentially followed for 12 months. The primary endpoint was freedom from symptomatic or documented >30 s AF off medications for 7 days at 12 months post-procedure. One hundred and eighty-three patients completed 12 m follow-up. Ninety-four patients underwent PVAC PV isolation with 372 of 376 pulmonary veins (PVs) successfully isolated and all PVs isolated in 92 WACA patients. Three WACA and no PVAC patients developed tamponade. Fifty-six percent of WACA and 60% of PVAC patients were free of AF at 12 months post-procedure (P = ns) with a significant attrition rate from 77 to 78%, respectively, at 6 months. The mean procedure (140 ± 43 vs. 167 ± 42 min, P<0.0001), fluoroscopy (35 ± 16 vs. 42 ± 20 min, P<0.05) times were significantly shorter for PVAC than for WACA. Two patients developed strokes within 72 h of the procedure in the PVAC group, one possibly related directly to PVAC ablation in a high-risk patient and none in the WACA group (P = ns). Two of the 47 patients in the PVAC group who underwent repeat ablation had sub-clinical mild PV stenoses of 25-50% and 1 WACA patient developed delayed severe PV stenosis requiring venoplasty. CONCLUSION: The pulmonary vein ablation catheter is equivalent in efficacy to WACA with reduced procedural and fluoroscopy times. However, there is a risk of thrombo-embolic and pulmonary stenosis complications which needs to be addressed and prospectively monitored. CLINICALTRIALSGOV IDENTIFIER: NCT00678340.

Genetics and cardiovascular disease--causes and prevention of unexpected sudden adult death: the role of the SADS clinic.

Sudden arrhythmic death syndrome (SADS) accounts for approximately 500 deaths in England and Wales per year. Clinical screening of the surviving first-degree relatives can identify an inherited cardiovascular condition in up to half of families, permitting lifestyle modification and confirmed effective prophylactic therapies to prevent further sudden deaths. Mechanisms for molecular autopsy are available to improve the diagnostic yield but practical barriers to its successful implementation exist. This article reviews the clinical screening of the first-degree relatives of SADS patients, molecular autopsy of probands and the broader implications of national recommendations for the investigation of sudden cardiac death.

Heart-brain interactions in cardiac arrhythmia.

This review examines current knowledge of the effects of higher brain centres and autonomic control loops on the heart with particular relevance to arrhythmogenesis. There is now substantial evidence that higher brain function (cortex), the brain stem and autonomic nerves affect cardiac electrophysiology and arrhythmia, and that these may function as an interactive system. The roles of mental stress and emotion in arrhythmogenesis and sudden cardiac death are no longer confined to the realms of anecdote. Advances in molecular cardiology have identified cardiac cellular ion channel mutations conferring vulnerability to arrhythmic death at the myocardial level. Indeed, specific channelopathies such as long QT syndrome and Brugada syndrome are selectively sensitive to either sympathetic or vagal stimulation. There is increasing evidence that afferent feedback from the heart to the higher centres may affect efferent input to the heart and modulate the cardiac electrophysiology. The new era of functional neuroimaging has identified the central neural circuitry in this brain-heart axis. Since precipitants of sudden fatal arrhythmia are frequently environmental and behavioural, central pathways translating stress into autonomic effects on the heart might be considered as therapeutic targets. These brain-heart interactions help explain the apparent randomness of sudden cardiac events and provide new insights into future novel therapies to prevent sudden death.

High-density substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis.

BACKGROUND: Two principal mechanisms are thought to be responsible for Brugada syndrome (BS): (1) right ventricular (RV) conduction delay and (2) RV subepicardial action potential shortening. This in vivo high-density mapping study evaluated the conduction and repolarization properties of the RV in BS subjects. METHODS AND RESULTS: A noncontact mapping array was positioned in the RV of 18 BS patients and 20 controls. Using a standard S(1)-S(2) protocol, restitution curves of local activation time and activation recovery interval were constructed to determine local maximal restitution slopes. Significant regional conduction delays in the anterolateral free wall of the RV outflow tract of BS patients were identified. The mean increase in delay was 3-fold greater in this region than in control (P=0<0.001). Local activation gradient was also maximally reduced in this area: 0.33+/-0.1 (mean+/-SD) mm/ms in BS patients versus 0.51+/-0.15 mm/ms in controls (P<0.0005). The uniformity of wavefront propagation as measured by the square of the correlation coefficient, r(2), was greater in BS patients versus controls (0.94+/-0.04 versus 0.89+/-0.09 [mean+/-SD]; P<0.05). The odds ratio of BS hearts having any RV segment with maximal restitution slope >1 was 3.86 versus controls. Five episodes of provoked ventricular tachycardia arose from wave breaks originating from RV outflow tract slow-conduction zones in 5 BS patients. CONCLUSIONS: Marked regional endocardial conduction delay and heterogeneities in repolarization exist in BS. Wave break in areas of maximal conduction delay appears to be critical in the initiation and maintenance of ventricular tachycardia. These data indicate that further studies of mapping BS to identify slow-conduction zones should be considered to determine their role in spontaneous ventricular arrhythmias.

Myocardial gene and cell delivery.

Although we now have the tools to introduce vectors and stem cells into specific myocardial locations, these devices are yet to be matched by comparable advances in molecular virology, cell biology, and our understanding of the pathophysiology of ischaemic heart disease

Non-contact left ventricular endocardial mapping in cardiac resynchronisation therapy.

BACKGROUND: Up to 30% of patients with heart failure do not respond to cardiac resynchronisation therapy (CRT). This may reflect placement of the coronary sinus lead in regions of slow conduction despite optimal positioning on current criteria. OBJECTIVES: To characterise the effect of CRT on left ventricular activation using non-contact mapping and to examine the electrophysiological factors influencing optimal left ventricular lead placement. METHODS: and results: 10 patients implanted with biventricular pacemakers were studied. In six, the coronary sinus lead was found to be positioned in a region of slow conduction with an average conduction velocity of 0.4 m/s, v 1.8 m/s in normal regions (p < 0.02). Biventricular pacing with the left ventricle paced 32 ms before the right induced the optimal mean velocity time integral and timing for fusion of depolarisation wavefronts from the right and left ventricular pacing sites. Pacing outside regions of slow conduction decreased left ventricular activation time and increased cardiac output and dP/dt(max) significantly. CONCLUSIONS: In patients undergoing CRT for heart failure, non-contact mapping can identify regions of slow conduction. Significant haemodynamic improvements can occur when the site of left ventricular pacing is outside these slow conduction areas. Failure of CRT to produce clinical benefits may reflect left ventricular lead placement in regions of slow conduction which can be overcome by pacing in more normally activating regions.

Antiarrhythmic and anti-ischaemic effects of angina in patients with and without coronary collaterals.

OBJECTIVE: To determine whether the changes in the manifestations of myocardial ischaemia during sequential angina episodes caused by exercise or coronary artery occlusion are collateral dependent. METHODS: 40 patients awaiting percutaneous transluminal coronary angioplasty for an isolated left anterior descending artery stenosis underwent three sequential treadmill exercise tests, with the second exertion separated from the first by 15 minutes, and from the third by 90 minutes; 28 patients subsequently completed two (> 180 s) sequential intracoronary balloon inflations with measurement of collateral flow index from mean coronary artery wedge, aortic, and coronary sinus pressures. RESULTS: On second compared with first exercise, time to 0.1 mV ST depression (mean (SD): 340 (27) v 266 (25) s) and rate-pressure product at 0.1 mV ST depression (22 068 (725) v 19 586 (584) beats/min/mm Hg) were increased (all p < 0.005), while angina and ventricular ectopic beat frequency were diminished (p < 0.05). This advantage, which had waned by the third effort, was independent of collateral flow index. Similarly, at the end of the second compared with the first coronary occlusion, ventricular tachycardia (21% v 0%, p < 0.05), ST elevation (0.47 (0.07) v 0.33 (0.05) mV, p < 0.005), and angina severity (6.1 (0.7) v 4.6 (0.7) units, p < 0.005) were reduced despite similar collateral flow indices. CONCLUSIONS: In patients with coronary artery disease, ventricular arrhythmias, ST deviation, and angina are reduced during a second exertion or during a second coronary occlusion. This protective effect can occur independently of collateral recruitment. These characteristics, together with the breadth and temporal pattern of protection, are consistent with ischaemic preconditioning.