Andrew J. Hogarth

Ongoing requirement for pacing post-transcatheter aortic valve implantation and surgical aortic valve replacement

OBJECTIVES Transcatheter aortic valve implantation (TAVI) is an established intervention for aortic stenosis. While it is known that the requirement for permanent pacing is higher following CoreValve (Medtronic, Inc., Minneapolis, MN, USA) TAVI than after surgical aortic valve replacement (SAVR), it remains uncertain whether pacing is required in the medium-to-long term. We hypothesized that complete heart block following TAVI is more likely to resolve than that following SAVR. METHODS A retrospective analysis of prospectively collated data on 528 patients undergoing TAVI or SAVR from May 2008 to December 2010 at a cardiac tertiary referral hospital. Demographic data, timing and indication for pacing post-procedure plus follow-up were recorded. Paced patients were compared and analysed by existing initial indication for pacing. RESULTS In total, 31 (5.9%) patients received a pacemaker, and there were limited differences between not paced and paced patient characteristics by procedure type. Of these, a greater proportion were implanted post-TAVI compared with SAVR (17 vs 3.2%, P<0.001). The mean time to pacemaker follow-up for TAVI and SAVR was 234 and 188 days, P=0.32, respectively. Fewer patients compared with pacing indication remained in complete heart block at latest follow-up for TAVI (76.5 vs 33.3%, P=0.02) and SAVR (92.9 vs 58.3%, P=0.04). Although, there was a trend towards a greater magnitude of TAVI patients regaining atrioventricular nodal conduction, this did not differ significantly from that seen in SAVR patients. CONCLUSIONS In keeping with previous reports, this single-centre experience demonstrates that patients undergoing TAVI have higher rates of pacemaker implantation than those following SAVR. However, pacing indication in the short-to-medium term may not persist for all paced patients post-TAVI and -SAVR with the suggestion that a significant proportion recover atrioventricular conduction, which tended to be greatest in TAVI paced patients.

Genetics of congenital and drug-induced long QT syndromes: current evidence and future research perspectives

The long QT syndrome (LQTS) is a condition characterized by abnormal prolongation of the QT interval with an associated risk of ventricular arrhythmias and sudden cardiac death. Congenital forms of LQTS arise due to rare and highly penetrant mutations that segregate in a Mendelian fashion. Over the years, multiple mutations in genes encoding ion channels and ion channel binding proteins have been reported to underlie congenital LQTS. Drugs are by far the most common cause of acquired forms of LQTS. Emerging evidence suggests that drug-induced LQTS also has a significant heritable component. However, the genetic substrate underlying drug-induced LQTS is presently largely unknown. In recent years, advances in next-generation sequencing technology and molecular biology techniques have significantly enhanced our ability to identify genetic variants underlying both monogenic diseases and more complex traits. In this review, we discuss the genetic basis of congenital and drug-induced LQTS and focus on future avenues of research in the field. Ultimately, a detailed characterization of the genetic substrate underlying congenital and drug-induced LQTS will enhance risk stratification and potentially result in the development of tailored genotype-based therapies.

Gender differences in sympathetic neural activation following uncomplicated acute myocardial infarction

AIMS To determine whether the magnitude of post-acute myocardial infarction (AMI) sympathetic activation is greater in women (F-AMI) than men (M-AMI). METHODS AND RESULTS Both sympatho-humoral activation and female gender are associated with worse outcome in the early phase following AMI. However, women have lower sympathetic output than men. We therefore examined matched groups of F-AMI (18) and M-AMI (18) patients 2-4 days following uncomplicated AMI, then 3 monthly to 9 months; matched normal control (NC) groups comprised M-NC (18) and F-NC (18). Muscle sympathetic nerve activity (MSNA) was measured by microneurography. Muscle sympathetic nerve activity was lower in the F-NC than M-NC (at least P < 0.05) and greater in the two AMI groups than their corresponding NC groups (at least P < 0.001). Muscle sympathetic nerve activity was similar in the F-AMI and M-AMI groups indicating a post-AMI increase in women of about twice that in men (P < 0.0001). Both AMI groups returned to corresponding NC (lower in women) levels by 9 months. CONCLUSION Following uncomplicated AMI, women developed a relatively greater magnitude of sympathetic activation lasting until its resolution at 9 months. This is consistent with reports of their worse prognosis observed during this time period, with important potential clinical implications.

Sympathetic nerve hyperactivity and its effect in postmenopausal women.

Objectives Hypertension and its subsequent cardiovascular complications have been associated with sympathetic neural activation, and their prevalence in women increases after the menopause. However, there have been no data on the level of sympathetic activation and its relationship to vascular blood flow following the menopause. Therefore, we planned to find out whether the behavior of muscle sympathetic nerve activity (MSNA) and calf blood flow (CBF) in women with and without essential hypertension (EHT) is changed following the menopause. Methods Peroneal nerve activity was measured as mean frequency of single units and of multiunit bursts with simultaneously measured CBF in two matched groups of postmenopausal women with and without EHT in comparison with two matched groups of premenopausal women with and without EHT. Results As expected, nerve activity was greater in the hypertensive than in normotensive groups and in postmenopausal than in premenopausal normotensive groups. We found that single unit frequency in postmenopausal hypertensives (65 ± 3.9 impulses/100 cardiac beats) was not significantly different from that in postmenopausal normotensives (54 ± 2.2 impulses/100 cardiac beats) or in premenopausal hypertensives (57 ± 2.8 impulses/100 cardiac beats). Similar results were obtained for burst frequency. In addition, a statistically significant negative correlation between the frequency of nerve activity and CBF was found only in postmenopausal normotensive (at least r = −0.42, P < 0.04) and hypertensive women (at least r = −0.45, P < 0.03). Conclusion These findings suggest that sympathetic nerve hyperactivity in postmenopausal women may have greater vascular effects than in premenopausal women, and could have implications in the management of EHT in postmenopausal women.

Atrial Fibrillation reduces the Functional REServe of the Heart by a fifth: A pilot FRESH-AF study

The advent of catheter ablation has reignited the controversy about whether rhythm or rate control should be the preferred mode of therapy for atrial fibrillation (AF) [1]. It is well known that compared to sinus rhythm (SR), AF is associated with increased mortality and morbidity including stroke, heart failure, and impaired quality of life. Furthermore, patients may experience adverse effects from drug treatment that may negate thebeneficial effects ofmaintaining SR [2].What is still unknown is inwhatways and by howmuch overall cardiac function is impairedwhen the atrial “kick” in SR is lost after the onset of AF. To fill this gap in knowledge, it is essential to assess cardiac functionnot onlyat rest but also during maximal stress, and not merely piecemeal aspects of cardiac function. This can be achieved by conducting full cardiopulmonary exercise testing (CPX) in combination with non-invasive evaluation of central haemodynamics [3]. Thiswouldprovide a quantitative assessment of aerobic physical exercise capacity represented by peak O2 consumption (VO2max), together with peak cardiac power output (CPOmax) which measures the overall cardiac dysfunction [4], and is by far the strongest predictor of prognosis in heart failure patients [5]. As metabolic and circulatory demands increase during severe exercise, patients with AF have lower cardiovascular reserve. Previous studies have shown that VO2max improved by 5–13% after restoration of SR in patients with AF [6], buthowmuchcardiac functional gain is achieved thereby is still unknown. We therefore measured changes in CPOmax after successful DC cardioversion (DCCv) in patients with optimally rate-controlled AF. In so doing, we tested the hypothesis that the cardiac pumping capability of patients in AF is diminished by about a fifth. Twelve unselected ambulatory patients (10 males, age: 57.5 ± 13.7 (mean ± SD) years) with symptomatic persistent AF recruited from outpatient clinics underwent full CPX with measurements of non-invasive haemodynamics before and after successful DCCv. The aetiologies (including overlaps) of their AF were ischaemic heart disease (17%), hypertension (25%), LV dysfunction (42%), valve disease (25%), lone AF (25%), and obesity (BMI N 35, 25%). None of the patients had previous catheter ablation, or any contraindication to undergomaximal exercise, such as significant outflow obstruction, haemodynamically serious structural heart disease, uncontrolled ventricular tachyarrhythmia, uncontrolled hypertension, limiting symptoms of ischaemic heart disease, inability or deemed unsafe to exercise on treadmill, contraindications to electrical cardioversion or full anticoagulation, or inability to provide full informed consent. Standardexerciseparametersweremeasuredaspartof an incremental cardiopulmonary exercise test performed on a Trackmaster TMX425 treadmill (Full Vision, Kansas, USA) using the Bruce or modified Bruce protocol, as previously described [3]. Rates of oxygen consumption (VO2) and other gaseous exchanges were recorded breath-by-breath using the Medgraphics Ultima CardiO2 analytic system (Medgraphics, Minnesota, USA). Using the CO2-rebreathing technique (indirect Fick), cardiac output were measured at rest and during peak exercise. Mean arterial pressure was calculated from the equation, MAP=DBP+ 0.412 ∗ (SBP− DBP) [7]. CPOmax in watts is the product of peak cardiac output (COmax in l.min−1)multiplied by theMAP inmm Hg at peak exercisemultiplied by a conversion factor (2.22 × 10−3) [8]. A paired sample t-test was used to assess the change in cardiac reserve variables pre and post DCCv. This study was approved by the National Research Ethics Service Committee for Yorkshire & Humber in Leeds East. After successful cardioversion, subjectively all patients claimed to feel better and more energetic and, as shown in Table 1, objectively their treadmill exercise duration increased by 19.3% (P b 0.05), coupled with an improvement in peak O2 consumption by 16.5% (P b 0.01). Their resting ventricular rate decreased from 83.1 ±20.3 to 66.9 ± 20.5 min− 1 (P b 0.05), while peak exercise HR decreased from 163 ± 42 to 128 ± 18 min−1 to (P b 0.05). Secondarily, these negative chronotropic effects led to heightened stroke volume at peak exercise by 46% (P b 0.0001), thereby raising the peak cardiac output by 16.5% (P b 0.0001). Due to a concomitantly greater

Left atrial voltage, circulating biomarkers of fibrosis, and atrial fibrillation ablation. A prospective cohort study

Aims To test the ability of four circulating biomarkers of fibrosis, and of low left atrial voltage, to predict recurrence of atrial fibrillation after catheter ablation. Background Circulating biomarkers potentially may be used to improve patient selection for atrial fibrillation ablation. Low voltage areas in the left atrium predict arrhythmia recurrence when mapped in sinus rhythm. This study tested type III procollagen N terminal peptide (PIIINP), galectin-3 (gal-3), fibroblast growth factor 23 (FGF-23), and type I collagen C terminal telopeptide (ICTP), and whether low voltage areas in the left atrium predicted atrial fibrillation recurrence, irrespective of the rhythm during mapping. Methods 92 atrial fibrillation ablation patients were studied. Biomarker levels in peripheral and intra-cardiac blood were measured with enzyme-linked immunosorbent assay. Low voltage (<0.5mV) was expressed as a proportion of the mapped left atrial surface area. Follow-up was one year. The primary endpoint was recurrence of arrhythmia. The secondary endpoint was a composite of recurrence despite two procedures, or after one procedure if no second procedure was undertaken. Results The biomarkers were not predictive of either endpoint. After multivariate Cox regression analysis, high proportion of low voltage area in the left atrium was found to predict the primary endpoint in sinus rhythm mapping (hazard ratio 4.323, 95% confidence interval 1.337–13.982, p = 0.014) and atrial fibrillation mapping (hazard ratio 5.195, 95% confidence interval 1.032–26.141, p = 0.046). This effect was also apparent for the secondary endpoint. Conclusion The studied biomarkers do not predict arrhythmia recurrence after catheter ablation. Left atrial voltage is an independent predictor of recurrence, whether the left atrium is mapped in atrial fibrillation or sinus rhythm.

Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation

Aims Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. Methods and results We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012). Conclusions Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage.

Multichannel electrocardiogram diagnostics for the diagnosis of arrhythmogenic right ventricular dysplasia

Aims The identification of arrhythmogenic right ventricular dysplasia (ARVD) from 12-channel standard electrocardiogram (ECG) is challenging. High density ECG data may identify lead locations and criteria with a higher sensitivity. Methods and results Eighty-channel ECG recording from patients diagnosed with ARVD and controls were quantified by magnitude and integral measures of QRS and T waves and by a measure (the average silhouette width) of differences in the shapes of the normalized ECG cycles. The channels with the best separability between ARVD patients and controls were near the right ventricular wall, at the third intercostal space. These channels showed pronounced differences in P waves compared to controls as well as the expected differences in QRS and T waves. Conclusion Multichannel recordings, as in body surface mapping, add little to the reliability of diagnosing ARVD from ECGs. However, repositioning ECG electrodes to a high anterior position can improve the identification of ECG variations in ARVD. Additionally, increased P wave amplitude appears to be associated with ARVD.

Management strategies for atrial fibrillation.

Atrial fibrillation is the most prevalent cardiac arrhythmia, affecting 10% of those aged over 80 years. Despite multiple treatment options, it remains an independent prognostic marker of mortality due to its association with clinical sequelae, particularly cerebrovascular events. Management can be broadly divided into treatment of the arrhythmia, via rhythm or rate control, and stroke thromboprophylaxis via anticoagulation. Traditional options for pharmacotherapy include negatively chronotropic drugs such as β-blockers, and/or arrhythmia-modifying drugs such as amiodarone. More recently, catheter ablation has emerged as a suitable alternative for selected patients. Additionally, there has been extensive research to assess the role of novel oral anticoagulants as alternatives to warfarin therapy. There is mounting evidence to suggest that they provide comparable efficacy, while being associated with lower bleeding complications. While these findings are promising, recent controversies have arisen with the use of novel oral anticoagulants. Further research is warranted to fully elucidate mechanisms and establish antidotes so that treatment options can be appropriately directed.

Syncope: a rare manifestation of a common condition

A previously active, fi t, well 71-year-old man, presented to our cardiology department in January, 2011, with a recent history of syncope. This occurred suddenly on two separate occasions, with rapid recovery after a few seconds, but resulting in injury. There were no associated symptoms. Both events occurred after non-strenuous exertion, with one or two further episodes of pre-syncope while at rest. A working diagnosis of arrhythmic cardiogenic syncope was made. He had no exertional symptoms or additional risk factors for coronary disease. He took no medications. ECG corrected QT interval, echocardiography, and tilt table test were normal. A 24 h ambulatory ECG showed normal rhythm. Exercise treadmill testing was stopped at 7 min because of fatigue. There were no ECG changes and the target heart rate (220 minus age beats per min) was achieved. Nuclear myocardial perfusion scanning did not show any evidence of myocardial ischaemia. Since the most likely diagnosis was syncope caused by cardiac arrhythmia, arrangements were made for an implantable cardiac loop recording device (ILR) (Reveal, Medtronic, Minneapolis, USA). 1 month later our patient was urgently admitted to the cardiology department after experiencing an episode of pre-syncope. Interrogation of the loop recorder data (fi gure A) showed non sustained ventricular fi brillation preceded by ST segment depression. This fi nding raised the possibility of silent ischaemia triggering arrhythmia. Urgent coronary angiography showed clinically signifi cant stenosis in the left anterior descending (LAD) artery (fi gure B; see also appendix), and inpatient surgical revascularisation with a single vein graft to the LAD was undertaken without complication. 8 months after surgery the patient was well, taking aspirin, a β-blocker, and a