Initial experience of temperature-controlled irrigated radiofrequency ablation for ischaemic cardiomyopathy ventricular tachycardia ablation.

BACKGROUND: The DiamondTemp ablation (DTA) catheter system delivers high power, open-irrigated, temperature-controlled radiofrequency (RF) ablation. This novel ablation system has not been previously used for ventricular tachycardia (VT) ablation. OBJECTIVE: Feasibility of using the DTA catheter system for VT ablation in ischaemic cardiomyopathy (ICM) patients. METHOD: Ten ICM patients with optimal anti-arrhythmic drug therapy and implantable cardiac defibrillators (ICD) were recruited. VT inducibility testing was performed at the end of the procedure. ICD data for device detected VT episodes and device treated VT episodes were collected for 6-months pre- and post-ablation. RESULTS: Substrate analysis demonstrated reductions in the borderzone area of 4.4 cm2 (p = 0.026) and late potential area of 3.5 cm2 (p = 0.0449) post-ablation, with reductions in the mean bipolar and unipolar voltages of the ablation target areas (0.14 mV (p = 0.0007); 0.59 mV (p = 0.0072) respectively). Complete procedural success was achieved in 9 procedures. Post-ablation VT inducibility testing was not performed in 1 procedure due to a steam pop complication resulting in pericardial tamponade requiring drainage. Mean follow-up of 214 ± 33 days revealed an 88% reduction in total VT episodes (n = 266 median 16 [IQR 3-57] to n = 33 median 0; p = 0.0164) and 77% reduction in ICD therapies (n = 128 median 5 [IQR 2-15] to n = 30 median 0; p = 0.0181). CONCLUSION: The DTA system resulted in adequate lesion characteristics with effective substrate modification, acute procedural success and improved outcomes at intermediate-term follow-up. Randomised controlled trials are required to compare the performance of the DTA system against conventional ablation catheters.

Safety and outcome of nurse-led syncope clinics and implantable loop recorder implants.

BACKGROUND: Implantable loop recorders (ILRs) are effective in achieving symptom-rhythm correlation. Data on the diagnostic yield of ILRs, on nurse-led syncope clinics, and on nurse-led ILR implants are limited. OBJECTIVE: We evaluated the safety and efficacy of our nurse-led syncope clinic and nurse-led ILR implants. METHODS: A retrospective study of all consecutive patients undergoing nurse-led ILR implantations was performed between April 2016 and April 2018. Patients were referred from both nurse-led and physician-led clinics. Data were collected on baseline demographic characteristics, referral source, symptom-rhythm correlation, ILR findings, and subsequent changes to management. All ILRs were enrolled into remote monitoring with automatic arrhythmia detection, and all immediate (≤24 hours) ILR implant complications were recorded. Comparisons were made between nurse-led and physician-led clinics and subsequent outcomes. RESULTS: A total of 432 patients with an ILR were identified: 164 (38%) from nurse-led and 268 (62%) from physician-led clinics; 200 (46%) were women (mean age 66.5 ± 18.2 years; mean follow-up duration 28.9 ± 9.5 months). Primary ILR indications were syncope (n = 251 [58%]), presyncope (n = 33 [7%]), palpitation (n = 39 [9%]), cryptogenic stroke (n = 78 [18%]), and other reasons (n = 31 [7%]). No immediate ILR implant complications occurred. Overall, 156 patients (36%) had a change in management as a direct result of ILR findings, with no overall differences between nurse-led and physician-led clinics (35% vs 36%; P = .7). More patients had newly diagnosed atrial fibrillation in physician-led clinics (15% vs 7%; P = .01), and more patients had pacemaker implants for bradycardia in nurse-led clinics (23% vs 13%; P < .01). CONCLUSION: Nurse-led ILR implantation was safe and effective. Nurse-led syncope clinics achieved good symptom-rhythm correlation with resultant significant changes to management in comparison to physician-led clinics. Larger prospective studies are needed to evaluate their longer-term impact.

Safety and feasibility of trans-venous cardiac device extraction using conscious sedation alone-Implications for the post-COVID-19 era.

BACKGROUND: Transvenous lead extraction (TLE) for implantable cardiac-devices is traditionally performed under general anesthesia (GA). This can lead to greater risk of exposure to COVID-19, longer recovery-times and increased procedural-costs. We report the feasibility/safety of TLE using conscious-sedation alone with immediate GA/cardiac-surgery back-up if needed. METHODS: Retrospective case-series of consecutive TLEs performed using conscious-sedation alone between March 2016 and December 2019. All were performed in the electrophysiology-laboratory using intravenous Fentanyl, Midazolam/Diazepam with a stepwise approach using locking-stylets/cutting-sheaths, including mechanical-sheaths. Baseline patient-characteristics, procedural-details and TLE outcomes (including procedure-related complications/death) were recorded. RESULTS: A total of 130 leads were targeted in 54 patients, mean age ± SD 74.6 ± 11.8years, 47(87%) males; dual-chamber pacemakers (n = 26; 48%), cardiac resynchronization therapy-defibrillators (n = 17; 31%) and defibrillators (n = 8; 15%) were commonest extracted devices. Mean ± SD/median (range) lead-dwell times were 11.0 ± 8.8/8.3 (0.3-37) years, respectively. Extraction indications included systemic infection (n = 23; 43%) and lead/pulse-generator erosion (n = 27; 50%); mean 2.1 ± 2.0 leads were removed per procedure/mean procedure-time was 100 ± 54 min. Local anesthetic (LA) was used for all (mean-dose: 33 ± 8 ml 1% lidocaine), IV drug-doses used (mean ± SD) were: midazolam: 3.95 ± 2.44 mg, diazepam: 4.69 ± 0.89 mg and fentanyl: 57 ± 40 µg. Complete lead-extraction was achieved in 110 (85%) leads, partial lead-extraction (<4 cm-fragment remaining) in 5 (4%) leads. Sedation-related hypotension requiring IV fluids occurred in 2 (managed without adverse-consequences) and hypoxia requiring additional airway-management in none. No procedural deaths occurred, one patient required emergency cardiac surgery for localized ventricular perforation, nine had minor complications (transient hypotension/bradycardia/pericardial effusion not requiring intervention). CONCLUSION: TLE undertaken using LA/conscious-sedation was safe/feasible in our series and associated with good clinical outcome/low procedural complications. Reduced risk of aerosolization of COVID-19 and quicker patient recovery/reduced anesthetic risk are potential benefits that warrant further study.

Impact of a high-density grid catheter on long-term outcomes for structural heart disease ventricular tachycardia ablation.

BACKGROUND: Substrate mapping has highlighted the importance of targeting diastolic conduction channels and late potentials during ventricular tachycardia (VT) ablation. State-of-the-art multipolar mapping catheters have enhanced mapping capabilities. The purpose of this study was to investigate whether long-term outcomes were improved with the use of a HD Grid mapping catheter combining complementary mapping strategies in patients with structural heart disease VT. METHODS: Consecutive patients underwent VT ablation assigned to either HD Grid, Pentaray, Duodeca, or point-by-point (PbyP) RF mapping catheters. Clinical endpoints included recurrent anti-tachycardia pacing (ATP), appropriate shock, asymptomatic non-sustained VT, or all-cause death. RESULTS: Seventy-three procedures were performed (33 HD Grid, 22 Pentaray, 12 Duodeca, and 6 PbyP) with no significant difference in baseline characteristics. Substrate mapping was performed in 97% of cases. Activation maps were generated in 82% of HD Grid cases (Pentaray 64%; Duodeca 92%; PbyP 33% (p = 0.025)) with similar trends in entrainment and pace mapping. Elimination of all VTs occurred in 79% of HD Grid cases (Pentaray 55%; Duodeca 83%; PbyP 33% (p = 0.04)). With a mean follow-up of 372 ± 234 days, freedom from recurrent ATP and shock was 97% and 100% respectively in the HD Grid group (Pentaray 64%, 82%; Duodeca 58%, 83%; PbyP 33%, 33% (log rank p = 0.0042, p = 0.0002)). CONCLUSIONS: This study highlights a step-wise improvement in survival free from ICD therapies as the density of mapping capability increases. By using a high-density mapping catheter and combining complementary mapping strategies in a strict procedural workflow, long-term clinical outcomes are improved.

Real-world evaluation of followup strategies after ICD therapies in patients with VT (REFINE-VT).

Implantable cardiac defibrillators (ICDs) can prevent sudden cardiac death, but the risk of recurrent ventricular arrhythmia (VA) and ICD shocks persist. Strategies to minimise such risks include medication optimisation, device programming and ventricular tachycardia (VT) ablation. Whether the choice of these interventions at follow-up are influenced by factors such as the type of arrhythmia or ICD therapy remains unclear. To investigate this, we evaluated ICD follow-up strategies in a real-world population with primary and secondary prevention ICDs. REFINE-VT (Real-world Evaluation of Follow-up strategies after Implantable cardiac-defibrillator therapies in patients with Ventricular Tachycardia) is an observational study of 514 ICD recipients recruited between 2018 and 2019. We found that 77 patients (15%) suffered significant VA and/or ICD therapies, of whom 26% experienced a second event; 31% received no intervention. We observed an inconsistent approach to the choice of strategies across different types of arrhythmias and ICD therapies. Odds of intervening were significantly higher if ICD shock was detected compared with anti-tachycardia pacing (odds ratio [OR] 8.4, 95% confidence interval [CI] 1.7 to 39.6, p=0.007). Even in patients with two events, the rate of escalation of antiarrhythmics or referral for VT ablation were as low as patients with single events. This is the first contemporary study evaluating how strategies that reduce the risk of recurrent ICD events are executed in a real-world population. Significant inconsistencies in the choice of interventions exist, supporting the need for a multi-disciplinary approach to provide evidence-based care to this population.

Safety and cost-effectiveness of same-day complex left atrial ablation.

BACKGROUND: Catheter ablation for complex left-atrial arrhythmia is increasing worldwide with many centres admitting patients overnight. Same-day procedures using conscious sedation carry significant benefits to patients/healthcare providers but data are limited. We evaluated the safety and cost-effectiveness of same-day complex left-atrial arrhythmia ablation. METHOD: Multi-centre retrospective cohort study of all consecutive complex elective left-atrial ablation procedures performed between January 2011 and December 2019. Data were collected on planned same-day discharge versus overnight stay, baseline parameters, procedure details/success, ablation technology, post-operative complications, unplanned overnight admissions/outcomes at 4-months and mortality up to April 2020. A cost analysis of potential savings was also performed. RESULTS: A total of 967 consecutive patients underwent complex left-ablation using radiofrequency (point-by-point ablation aided by 3D-mapping or PVAC catheter ablation with fluoroscopic screening) or cryoballoon-ablation (mean age: 60.9 ± 11.6 years, range 23-83 yrs., 572 [59%] females). The majority of patients had isolation of pulmonary veins alone (n = 846, 87%) and most using conscious-sedation alone (n = 921, 95%). Of the total cohort, 414 (43%) had planned same-day procedure with 35 (8%) admitted overnight due to major (n = 5) or minor (n = 30) complications. Overall acute procedural success-rate was 96% (n = 932). Complications in planned overnight-stay/same-day cohorts were low. At 4-month follow-up there were 62 (6.4%) readmissions (femoral haematomas, palpitation, other reasons); there were 3 deaths at mean follow-up of 42.0 ± 27.6 months, none related to the procedure. Overnight stay costs £350; the same-day ablation policy over this period would have saved £310,450. CONCLUSIONS: Same-day complex left-atrial catheter ablation using conscious sedation is safe and cost-effective with significant benefits for patients and healthcare providers. This is especially important in the current financial climate and Covid-19 pandemic.

Enhanced ventricular tachycardia substrate resolution with a novel omnipolar high-density mapping catheter: the omnimapping study.

BACKGROUND: Defining diastolic slow-conduction channels within the borderzone (BZ) of scar-dependent re-entrant ventricular tachycardia (VT) is key for effective mapping and ablation strategies. Understanding wavefront propagation is driving advances in high-density (HD) mapping. The newly developed Advisor™ HD Grid Mapping Catheter (HD GRID) has equidistant spacing of 16, 1 mm electrodes in a 4 × 4 3 mm interspaced arrangement allowing bipolar recordings along and uniquely across the splines (orthogonal vector) to facilitate substrate mapping in a WAVE configuration (WAVE). The purpose of this study was to determine the relative importance of the WAVE configuration compared to the STANDARD linear-only bipolar configuration (STANDARD) in defining VT substrate. METHODS: Thirteen patients underwent VT ablation at our institution. In all cases, a substrate map was constructed with the HD GRID in the WAVE configuration (conWAVE) to guide ablation strategy. At the end of the procedure, the voltage map was remapped in the STANDARD configuration (conSTANDARD) using the turbo-map function. Detailed post-hoc analysis of the WAVE and STANDARD maps was performed blinded to the configuration. Quantification of total scar area, BZ and dense scar area with assessment of conduction channels (CC) was performed. RESULTS: The substrate maps conSTANDARD vs conWAVE showed statistically significant differences in the total scar area (56 ± 32 cm2 vs 51 ± 30 cm2; p = 0.035), dense scar area (36 ± 25 cm2 vs 29 ± 22 cm2; p = 0.002) and number of CC (3.3 ± 1.6 vs 4.8 ± 2.5; p = 0.026). conWAVE collected more points than the conSTANDARD settings (p = 0.001); however, it used fewer points in map construction (p = 0.023). CONCLUSIONS: The multipolar Advisor™ HD Grid Mapping Catheter in conWAVE provides more efficient point acquisition and greater VT substrate definition of the borderzone particularly at the low-voltage range compared to conSTANDARD. This greater resolution within the low-voltage range facilitated CC definition and quantification within the scar, which is essential in guiding the ablation strategy.

Long-term follow-up of normal and structural heart ventricular tachycardia catheter ablation: real-world experience from a UK tertiary centre.

Background: Ventricular tachycardia (VT) is associated with increased morbidity and mortality. There is growing evidence for the effectiveness of catheter ablation in improving outcomes in patients with recurrent VT. Consequently the threshold for referral for VT ablation has fallen over recent years, resulting in increased number of procedures. Objective: To evaluate the effectiveness and safety of VT ablation in a real-world tertiary centre setting. Methods: This is a prospective analysis of all VT ablation cases performed at University Hospital Coventry. Follow-up data were obtained from review of electronic medical records and patient interview. The primary endpoint for normal heart VT was death, cardiovascular hospitalisation and VT recurrence, and for structural heart VT was arrhythmic death, VT storm (>3 episodes within 24 hours) or appropriate shock. Results: Forty-seven patients underwent 53 procedures from January 2012 to January 2018. The mean age ±SD was 57±15 years, 68% were male, 81% were Caucasian and 66% were elective cases. The aetiology of VT included normal heart (49%), ischaemic cardiomyopathy (ICM, 36%), dilated cardiomyopathy (9%), hypertrophic cardiomyopathy (4%) and valvular heart disease (2%). Procedural success occurred in 83%, with six major complications. After a median follow-up of 231 days (lower quartile 133, upper quartile 631), the primary outcome occurred in 28% of patients. There were two non-arrhythmic deaths (4%). At a median follow-up of 193 days (129-468), the primary outcome occurred in 19% of patients with ICM, while VT storm/appropriate shocks occurred in three patients (17%). Conclusions: Our real-world registry confirms that VT ablation is safe, and is associated with high acute procedural success and long-term outcomes comparable with randomised controlled studies.

Long-Term Follow-Up of Isolated Epicardial Left Ventricular Lead Implant Using a Minithoracotomy Approach for Cardiac Resynchronization Therapy.

BACKGROUND: Transvenous left ventricular (LV) lead placement for cardiac resynchronization therapy is unsuccessful in 5-10% of reported cases. These patients may benefit from isolated surgical placement of an epicardial LV lead via minithoracotomy approach. AIM: To evaluate the success of this approach at long-term follow-up. METHODS: Retrospective evaluation of all consecutive patients undergoing isolated epicardial LV lead placement after failed transvenous attempt over a 6-year period. Data collected on baseline parameters, procedural details, and outcome at follow-up (hospital stay, complications, mortality, and clinical response). RESULTS: Forty-two patients underwent epicardial lead implant. Five died within 1 year (11.9%): two (4.8%) died within 30-days post op (one from intraoperative hemorrhage, the other from multiple organ failure); 39 (95.1%) were admitted to the high dependency unit and transferred to the ward <24 hours. Median hospital stay was 3.4 ± 1.9 days. The overall complication rate was 17.5% (n = 7): 15.0% (n = 6) short term and 2.5% (n = 1) long term; these included three (7.5%) LV noncapture events all treated with reprogramming. There were two (5.0%) wound infections requiring oral antibiotics and two (5.0%) device infections requiring intravenous antibiotics (one had device resiting, the other developed septic shock requiring intensive care admission). Assessment of clinical response was possible in 34 (81.0%) at follow-up: 21 (61.8%) were responders and 13 (28.2%) nonresponders with no significant differences between these groups; no clinical predictors of response were identified. CONCLUSION: Isolated epicardial LV lead implant using minithoracotomy is relatively safe and effective at successful LV pacing. Response rate and postoperative recovery at long-term follow-up are reasonable in these high-risk patients.

Same-day cardiac catheter ablation is safe and cost-effective: Experience from a UK tertiary center.

BACKGROUND: Catheter ablation is a curative intervention for common arrhythmias such as supraventricular tachycardia and atrial flutter. Many centers still admit patients overnight after this procedure. OBJECTIVE: This study was performed to evaluate the safety and cost-effectiveness of same-day standard catheter ablation. METHODS: We conducted a retrospective study of all consecutive elective same-day procedures performed between 2010 and 2014. Data were collected on baseline parameters, procedure details and success, postoperative complications, unplanned overnight hospital admissions, and clinical outcome (including mortality) at 4-month follow-up. A cost analysis of potential savings was also performed. RESULTS: A total of 1142 patients underwent planned same-day electrophysiological study with or without ablation. Radiofrequency ablation was performed in 897 of these patients (mean age ± standard error 56 ± 0.6 years, range 16-95 years, 467 males), with 921 arrhythmias ablated and with complete procedural success in 883 cases (96%). There were 92 unplanned admissions (10.3%): 50 for concealed pathways that required transseptal puncture, 19 for immediate complications (including 9 femoral bleeds and 5 pacemakers for heart block), 12 admitted at the operator's discretion, and 11 for other clinical reasons. All had transthoracic echocardiography after the procedure, and none had significant pericardial effusion. At 4-month follow-up, there were 16 readmissions (1 deep vein thrombosis, 3 pericarditic chest pain, 2 femoral hematomas, 7 palpitations, and 3 others) and 1 death (unrelated to ablation). An overnight stay at our center costs $450 (£300); same-day ablation over this period saved our institution $365,000 (£240,000). CONCLUSION: Same-day standard catheter ablation is safe and cost-effective, with significant benefits for patients and health care providers. This is particularly important given the current financial climate.

Multidetector CT assessment of partial anomalous pulmonary venous return in association with sinus venosus type atrial septal defect.

Sinus venosus defects account for 15% of all atrial septal defects. They are frequently associated with partial anomalous pulmonary venous drainage of the right superior pulmonary vein into the superior vena cava (SVC). These defects require surgical correction and accurate pre-operative imaging assessment is critical. We present a case of sinus venosus atrial septal defect in which multidetector computed tomography (MDCT) angiography identified separate sites of pulmonary venous return.

Combined metabolomic and proteomic analysis of human atrial fibrillation.

OBJECTIVES: We sought to decipher metabolic processes servicing the increased energy demand during persistent atrial fibrillation (AF) and to ascertain whether metabolic derangements might instigate this arrhythmia. BACKGROUND: Whereas electrical, structural, and contractile remodeling processes are well-recognized contributors to the self-perpetuating nature of AF, the impact of cardiac metabolism upon the persistence/initiation of this resilient arrhythmia has not been explored in detail. METHODS: Human atrial appendage tissues from matched cohorts in sinus rhythm (SR), from those who developed AF post-operatively, and from patients in persistent AF undergoing cardiac surgery were analyzed using a combined metabolomic and proteomic approach. RESULTS: High-resolution proton nuclear magnetic resonance (NMR) spectroscopy of cardiac tissue from patients in persistent AF revealed a rise in beta-hydroxybutyrate, the major substrate in ketone body metabolism, along with an increase in ketogenic amino acids and glycine. These metabolomic findings were substantiated by proteomic experiments demonstrating differential expression of 3-oxoacid transferase, the key enzyme for ketolytic energy production. Notably, compared with the SR cohort, the group susceptible to post-operative AF showed a discordant regulation of energy metabolites. Combined principal component and linear discriminant analyses of metabolic profiles from proton NMR spectroscopy correctly classified more than 80% of patients at risk of AF at the time of coronary artery bypass grafting. CONCLUSIONS: The present study characterized the metabolic adaptation to persistent AF, unraveling a potential role for ketone bodies, and demonstrated that discordant metabolic alterations are evident in individuals susceptible to post-operative AF.

The sinus tachycardias.

Sinus tachycardia, in the forms of four distinct rhythm disturbances, is frequently encountered in clinical practice but is often overlooked. The most common rhythm, normal sinus tachycardia, whether physiologic, pathologic or iatrogenic, is predominantly catecholamine driven, is virtually asymptomatic and is managed by identifying and treating the underlying cause. The other so-called primary sinus tachycardias, which include inappropriate sinus tachycardia, postural orthostatic tachycardia syndrome and sinus node re-entry tachycardia, have fundamentally different clinical features, basic underlying etiologic mechanisms and treatment strategies. Differentiation of these types from normal sinus tachycardia and from other atrial arrhythmias is crucial for successful management. Accurate diagnosis and appropriate therapy of the sinus tachycardias not only prevents multiple consultations but might also have important long-term prognostic implications.

Deciphering the sinus tachycardias.

Sinus tachycardia is the most common rhythm disturbance encountered in clinical practice. Primary sinus tachycardia without an underlying secondary cause, despite often being associated with troublesome symptoms, is often neglected leading to multiple consultations and frustration on part of both the practitioner and the patient. The fact that primary sinus tachycardias are a heterogeneous group of disorders is seldom appreciated; hence, a firm diagnosis is rarely reached and management is haphazard. Furthermore, there may be prognostic implications for prolonged or recurrent sinus tachycardia, making it imperative that this group of arrhythmias receive adequate and appropriate attention. Normal sinus tachycardia (i.e., secondary), inappropriate sinus tachycardia, postural orthostatic tachycardia syndrome (POTS) and sinus node reentry tachycardia make up this group of arrhythmias. Their definitions, clinical features, diagnostic criteria, pathophysiologic mechanisms, and optimum management are discussed in this review.

Quantification of mitochondrial sublimons in human fibrillating atria.

Supraventricular tachycardias, including AF (atrial fibrillation), and mtDNA (mitochondrial DNA) deletions may lead to dilated cardiomyopathy. It is unknown whether mtDNA function is impaired in the human atrium in AF. In the present study, we investigated the role of rearranged mtDNA 'sublimons' in the pathogenesis of AF. Right atrial biopsies were collected from 38 patients in AF and 35 patients with SR (sinus rhythm) undergoing elective cardiac surgery. Total DNA was extracted by standard methods. The break-point regions of the two most prevalent classes of sublimon were amplified by PCR using fluorescent oligonucleotides for the 3.75 kb partial duplication and the 2.83 kb deletion. Multiplex reactions included additional primers to amplify an internal genomic standard for semi-quantitative analysis. Reaction products were quantified as peak areas in the electrophoretogram and ratios computed of the sublimon abundance relative to the genomic standard. There was no difference in SCN (sublimon copy number) between AF and SR patients [19.09+/-28.29 compared with 10.25+/-24.68, the difference was 0.28 (95% confidence interval, -0.04 and +0.61; P =0.08)]. SCN did not increase with age ( P =0.207) and was unrelated to AF duration ( P =0.661), left atrial diameter ( P =0.560), post-operative AF ( P =0.52), underlying disease ( P =0.94), medication and gender (2.84+/-0.72 in females vs 2.97+/-0.67 in males; P =0.431). In conclusion, our findings do not indicate any role of mtDNA in the pathophysiology of AF.

Sinus tachyarrhythmias and the specific bradycardic agents: a marriage made in heaven?

A relatively novel group of drugs that inhibit the funny current in the sinus node pacemaker cells, the so-called specific bradycardic agents, are likely to play a significant role in the management of a wide range of cardiovascular disorders, including the sinus tachyarrhythmias. This comprehensive review initially provides an insight into these agents, their historical background, and their mechanism of action. It then discusses the differential diagnosis of the sinus tachyarrhythmias (normal sinus tachycardia, inappropriate sinus tachycardia, postural orthostatic tachycardia syndrome, and sinus node reentry tachycardia), elaborates on their pathophysiologic basis, and provides up-to-date evidence-based information on their optimum management. The specific bradycardic agents, by the very nature of their mode of action, may prove ideal therapies for the management of the sinus tachyarrhythmias, and this is explored at every stage.