Lee N. Graham

Sympathetic neural mechanisms in white-coat hypertension

OBJECTIVES This study planned to establish whether sympathetic hyperactivity exists in white-coat hypertension (WHT) in the clinical setting, relative to matched groups with normotension (NT) and untreated essential hypertension (EHT). BACKGROUND White-coat hypertension differs from EHT by the presence of normal ambulatory blood pressure. Sympathetic hyperactivity exists in patients with EHT in the clinical setting and is believed to contribute to the development of target organ damage. Similar organ damage has been reported in WHT, yet little is known about sympathetic neural activity in this condition. METHODS Using microneurography, we examined groups of 12 matched subjects with WHT, EHT and NT during the same clinical setting to quantify muscle sympathetic nerve activity as multiunit discharge (MSNA) and single units (s-MSNA). RESULTS The s-MSNA in WHT (54 +/- 4.2 impulses/100 beats) was greater (p < 0.05) than in NT (37 +/- 5.4 impulses/100 beats) despite similar age and body mass index (BMI). The EHT values of s-MSNA (73 +/- 5.2 impulses/100 beats) were significantly (p < 0.05) greater than in WHT despite similar age, BMI and blood pressure levels. The MSNA followed a similar trend. White-coat hypertension had a similar cardiac baroreceptor reflex sensitivity to NT, but this was impaired in EHT relative to both NT and WHT. CONCLUSIONS It was shown, in the clinical setting, that central sympathetic hyperactivity exists in WHT, albeit to a lesser degree than EHT. These findings suggest that WHT may not be entirely benign and that the observed sympathetic hyperactivity may be responsible for development of target organ damage in this group of 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.

Consensus best practice pathway of the UK Systemic Sclerosis Study group:management of cardiac disease in systemic sclerosis

Objective Cardiac disease in SSc can manifest in various ways and is associated with a poor prognosis. There is little evidence on how best to detect and manage cardiac disease in SSc. Our objective was to produce an expert consensus best practice pathway for the management of cardiac disease in SSc. Methods The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including cardiac disease. A multidisciplinary task force was convened. The guidelines were partly informed by a comprehensive literature review. Results A best practice pathway for cardiac disease (with a focus on primary cardiac disease) in SSc is presented, including approaches for early detection and standard pharmacological and device therapies. Due to the benefits, shared care and a multidisciplinary approach are recommended. A future research agenda has been formulated in response to the relative lack of understanding of the natural history of primary cardiac disease that was highlighted by the initiative. Conclusion The physician should be alert to the possibility of cardiac disease in SSc; it is best managed within a multidisciplinary team including both rheumatologists and cardiologists. This pathway provides a reference for all physicians managing patients with SSc.

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.

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

SAT0507 Implantable loop recorder can screen for incidental significant arrhythmias in scleroderma, with cardiac mri ecv and troponin biomarker, useful for risk stratification

Background Cardiac involvement and in particular conduction abnormalities represent a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). No studies assessed the value of implantable loop recorder (ILR) for early detection of arrhythmias in asymptomatic patients with SSc; or whether cardiac magnetic resonance (CMR) features associate with arrhythmias. Objectives To assess the prevalence of conduction abnormalities over a 3 year period using an ILR (REVEAL) and evaluate relationship with disease phenotype, cardiac biomarkers and CMR in SSc patients. Methods 20 patients(pts) with ACR/EULAR criteria for SSc, with no history of cardiovascular (CV) disease and ≤1 CV risk factor had 3T CMR with late gadolinium enhancement (LGE) and T1 mapping for ECV quantification. An ILR was then inserted, for 3 years follow-up. ILR data were downloaded every 3 months. Serum cardiac biomarkers were also measured at the initial visit. Results 19 pts had available ILR data; 12 (63%) females, median (SD) age 53(,12 6 (32%) diffuse SSc(dcSSc), 6 (32%) ACA+, 4 (21%) Scl70+, 8 (42%)history of interstitial lung disease (ILD) and 7 (36%) history of digital ulcers (DU). 14/19 had any ILR abnormalities, 8/14 significant arrhythmias: 1 complete heart block; 2 non-sustained ventricular tachycardia (NSVT), and 5 atrial arrhythmias (1 atrial flutter, 1 AF, 1 SVT, 1 AF and SVT and 1 AF followed by atrial flutter and SVT). Of these 8 pts, 4 had dcSSc, 2 Scl70+, 4 ACA+, 3 with ILD and 3 DU history. All 3 patients with severe arrhythmias (NSVT/CHB) were dcSSc, 2 Scl70+, 2 males. Management comprised 1 permanent pacemaker implantation, 3 antiarrhythmic treatment, 1 anticoagulation.15 pts had CMR. The 8 pts with significant arrhythmia appeared to have higher ECV, LV mass, and LVEF%(table 1). LGE was observed in 1(NSVT), of a total of 5/15 with LGE. HsTnI was considerably higher in those with significant arrhythmias[(mean diff.(95% CI)117 (-10, 245)].NTproBNP [(mean diff.(95% CI) 92 (-30, 214)] also appeared greater in those with significant arrhythmias. There was no difference in CK levels between the two groups. CMR baseline ILR significant arrhythmias, all yearsn=6Mean(SD) ILR no significant arrhythmiasn=9Mean(SD) Mean difference [95% CI] ECV% 32(,2 n=5 29(,4 n=9 2 [-2,6] LVEDV/BSA (ml/m2) 84(16 83(20 1 [-21, 22] LVEF% 62(4 59(5 2 [3–8] LV mass/BSA(g/m2) 46(7 44(14 2 [-10, 15] LVSV/BSA(ml/m2) 51(8 49(11 2 [-9, 13] LVESV/BSA(ml/m2) 33(9 34(10 −2[−13, 9] Distensibility(10–3mmHg-1) 5 (4) 4 (2) 0.4 [-3, 4] Torsion o 12(,6 n=5 14(,5 n=8 −2[−8, 5] LGE N 1/5 N 4/9 Conclusions This pilot study demonstrates the ability of ILR to detect life-threatening arrhythmia in asymptomatic SSc pt. The data suggest CMR ECV(but not LGE) and cardiac biomarkers, in particular hsTnI (indicating subclinical myocardial injury) may be able to identify at risk pts that would benefit from ILR screening. Future studies can inform a risk model, and provide insight into the pathogenesis of SSc associated arrhythmias. Disclosure of Interest None declared

OP0037 First Pilot Study of An Implantable Loop Recorder (ILR) in Systemic Sclerosis Detects Significant Cardiac Arrhythmias with CMR Abnormalities

Background SSc-cardiomyopathy associated conduction abnormalities carry a poor prognosis, but their pathogenesis is unclear. Early detection to prevent complications is essential. ILRs are well-established in cardiology practice. Objectives To determine the spectrum of cardiac conduction abnormalities (CCA) using the REVEAL® ILR & their association with CMR in patients (pts) with SSc with no known cardiac disease. Methods 20 pts with (ACR/EULAR criteria) SSc, with no diabetes &/or more than 1 cardiovascular (CV) risk factor, were assessed for SSc/CV profile & comprehensive CV assessment performed, inc. 3T delayed enhancement-CMR (reported by CMR-cardiologists) & ILR insertion. ILR data was downloaded 3 monthly +/− at pt request if indicated. One yr data is reported. CMR compared to 30 healthy controls. Results ILR data was available for 19 pts; 63% female, 84% Caucasian; mean (SD) age 53 (12)yrs, time from 1st non-RP symptom 9 (8)yrs; 32% dcSSc, 32% ACA+ve, 21% Scl70+ve, 54% palpitations hx, 42% known ILD, 11% DU hx, 0% pulmonary hypertension. Ten (52%) pts had ILR abnormalities; 4 with dcSSc, 3 ACA+ve, 3 Scl70+ve, 6 with palpitations hx, 4 known ILD, 3 DU hx. Subanalysis; 8 (42%) pts had supraventricular ectopics (SVE), 2 (11%) with ventricular ectopics (VE), 4 (21%) with arrhythmias of which 1 atrial flutter, 1 SVT, 1 VT & 1 complete heart block (CHB). Of the 4 pts with arrhythmias; 2 had dcSSc, 1 ACA+ve, 1 Scl70, 3 palpitations hx, 2 known ILD, 2 DU hx. Pt with CHB (dcSSc) had few SVE/VEs & 3 couplets on 24hr ECG 6 weeks previous. CMR data was available for 15 SSc pts (DE in 14; 1 pt claustrophobic, no IV access in 2, 1 CMR abandoned due to pacemaker insertion for CHB). Trend towards lower LVmass & distensibility (ie greater arterial stiffness) & higher extracellular volume (ECV, fibrosis marker) seen in pts with ILR abnormalities (p>0.05). Trend for higher ECV in those with SVE [unadj. mean difference (diff.) (95%CI) 1.1 (-2.5, 4.7)% p0.513], VE [0.7 (-4.9, 6.3)% p0.789] & arrhythmias [1.8 (-3.7, 7.3)% p0.486]. ECV was higher in SSc vs. controls; mean diff. 4.9 (3.2, 6.6)% p<0.001 R2 0.568, adj. for age/sex; with trend for lower LV mass & distensibility.Table 1. CMR measures in SSc pts with/without ILR abnormalities CMR variable ILR normal ILR abnormal Mean diff. Mean diff. n (%) = 7 (47) n (%) = 8 (53) [95% CI] [95% CI] p p adj. age/sex LVEF, % 58.7 (3.5) 61.3 (5.1) 2.6 0.3 [−2.4, 7.5] [−5.2, 5.8] 0.286 0.908 LVmass/BSA, g/m2 47.1 (13.7) 42.9 (7.0) −4.2 −6.1 [−17.2, 8.9] [−18.0, 5.7] 0.488 0.280 LV mass/EDV, g/ml 0.54 (0.07) 0.54 (0.08) −0.01 0.02 [−0.09, 0.08] [−0.11, 0.11] 0.895 0.974 Torsion, ° 12.4 (4.1) 13.5 (6.1) 1.1 −0.7 n=6 n=7 [−5.4, 7.6] [−8.9, 7.5] 0.714 0.849 Distensibility, 10–3mmHg–1 4.6 (3.0) 3.6 (2.6) −1.0 0.3 n=7 [−4.3, 2.3] [−3.5, 4.1] 0.510 0.863 ECV, % 29.1 (4.2) 31.1 (1.7) 2.0 1.7 n=7 [−2.0, 5.9] [−3.1, 6.5] 0.278 0.444 Late gad enhancement presence 3 (42.9)* 2 (28.6) n=7* p=1.00 p=0.784 Values = mean (SD) *n (%). Conclusions This first ILR in SSc study demonstrates its utility in the incidental detection of CCA, including serious cardiac arrhythmias & suggests associated CMR abnormalities. These data support the need for identification of pts at risk that would benefit from ILR & provide insights into the pathogenesis of SSc-cardiomyopathy Disclosure of Interest None declared