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.

Normal heart ventricular tachycardia associated with pregnancy: successful treatment with catheter ablation.

BACKGROUND: Normal heart ventricular arrhythmia occurring during pregnancy has been previously described. Whilst there are established reports of catheter ablation to treat supraventricular arrhythmia during pregnancy, there are no reports of ablation to treat ventricular tachycardia. CASE: We present the case of a 36 year old women, 31 weeks into an otherwise uncomplicated pregnancy, experiencing significant, troublesome and drug refractory tachycardia emanating from the right ventricular outflow tract. CONCLUSION: We describe a successful radio frequency ablation in the third trimester of pregnancy.

Left Atrial Appendage Occlusion: British Cardiovascular Intervention Society and British Heart Rhythm Society Position Statement.

Percutaneous left atrial appendage occlusion aims to reduce the risk of stroke in patients with AF, particularly those who are not good candidates for systemic anticoagulation. The procedure has been studied in large international randomised trials and registries and was approved by the National Institute for Health and Care Excellence in 2014 and by NHS England in 2018. This position statement summarises the evidence for left atrial appendage occlusion and presents the current indications. The options and consensus on best practice for pre-procedure planning, undertaking a safe and effective implant and appropriate post-procedure management and follow-up are described. Standards regarding procedure volume for implant centres and physicians, the role of multidisciplinary teams and audits are highlighted.

Left Atrial Appendage Occlusion: British Cardiovascular Intervention Society and British Heart Rhythm Society Position Statement.

Percutaneous left atrial appendage occlusion aims to reduce the risk of stroke in patients with AF, particularly those who are not good candidates for systemic anticoagulation. The procedure has been studied in large international randomised trials and registries and was approved by the National Institute for Health and Care Excellence in 2014 and by NHS England in 2018. This position statement summarises the evidence for left atrial appendage occlusion and presents the current indications. The options and consensus on best practice for pre-procedure planning, undertaking a safe and effective implant and appropriate post-procedure management and follow-up are described. Standards regarding procedure volume for implant centres and physicians, the role of multidisciplinary teams and audits are highlighted.

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.

Multicentre randomised trial comparing contact force with electrical coupling index in atrial flutter ablation (VERISMART trial).

INTRODUCTION: Electrical coupling index (ECI) and contact force (CF) have been developed to aid lesion formation during catheter ablation. ECI measures tissue impedance and capacitance whilst CF measures direct contact. The aim was to determine whether the presence of catheter / tissue interaction information, such as ECI and CF, reduce time to achieve bidirectional cavotricuspid isthmus block during atrial flutter (AFL) ablation. METHODS: Patients with paroxysmal or persistent AFL were randomised to CF visible (range 5-40g), CF not visible, ECI visible (change of 12%) or ECI not visible. Follow-up occurred at 3 and 6 months and included a 7 day ECG recording. The primary endpoint was time to bidirectional cavotricuspid isthmus block. RESULTS: 114 patients were randomised, 16 were excluded. Time to bidirectional block was significantly shorter when ECI was visible (median 30.0 mins (IQR 31) to median 10.5mins (IQR 12) p 0.023) versus ECI not visible. There was a trend towards a shorter time to bidirectional block when CF was visible. Higher force was applied when CF was visible (median 9.03g (IQR 7.4) vs. 11.3g (5.5) p 0.017). There was no difference in the acute recurrence of conduction between groups. The complication rate was 2%, AFL recurrence was 1.1% and at 6 month follow-up, 12% had atrial fibrillation. CONCLUSION: The use of tissue contact information during AFL ablation was associated with reduced time taken to achieve bidirectional block when ECI was visible. Contact force data improved contact when visible with a trend towards a reduction in the procedural endpoint. ClinicalTrials.gov trial identifier: NCT02490033.

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.

Time course of sympathetic neural hyperactivity after uncomplicated acute myocardial infarction.

BACKGROUND: Little information is available on sympathetic activity after acute myocardial infarction (AMI), despite the belief that sympathetic drive is important in relation to morbidity and mortality. Indirect indices such as plasma catecholamines are transiently elevated after uncomplicated AMI, whereas other prognostically important autonomic indices may be affected longer. We planned to quantify central sympathetic output to the periphery after uncomplicated AMI and to investigate its progress over time. METHODS AND RESULTS: After uncomplicated AMI, 13 patients had muscle sympathetic nerve activity (MSNA) assessed from multiunit discharges and from single units with defined vasoconstrictor properties (s-MSNA). Measurements were obtained 2 to 4 days after AMI and were repeated after 3 and 6 months. We also examined 3 matched control groups comprising normal subjects, patients with coronary artery disease, and hospitalized patients without AMI. MSNA and s-MSNA after AMI (84+/-4.6 bursts/100 beats and 95+/-5.8 impulses/100 beats) were unchanged at 3 months but decreased (P<0.01 and P<0.001) after 6 months (75+/-4.0 bursts/100 beats and 80+/-4.4 impulses/100 beats). These were still greater (at least P<0.01) than values in normal subjects, patients with coronary artery disease, and hospitalized patients without AMI (51+/-3.9 bursts/100 beats, 58+/-4.7 impulses/100 beats; 56+/-2.2 bursts/100 beats, 61+/-2.2 impulses/100 beats; and 55+/-3.6 bursts/100 beats, 61+/-3.3 impulses/100 beats, respectively). This sympathetic hyperactivity was inversely correlated to left ventricular ejection fraction but not to changes in blood pressure. CONCLUSIONS: A protracted state of sympathetic hyperactivity was shown to occur after uncomplicated AMI. It is suggested that this hyperactivity may explain delayed cardiovascular morbidity and mortality and that it arises because of an impairment of reflexes from cardiac receptors.

Sympathetic drive in anterior and inferior uncomplicated acute myocardial infarction.

BACKGROUND: The sympathetic activation that follows acute myocardial infarction (AMI) has been associated with increased morbidity and mortality. Because the prognosis after anterior AMI (ant-AMI) is worse than that after inferior AMI (inf-AMI), we planned to determine whether the magnitude of sympathetic hyperactivity differs between the two. METHODS AND RESULTS: Thirty-nine patients with uncomplicated AMI, comprising 2 matched groups of 17 patients with ant-AMI, and 22 patients with inf-AMI were examined. Measurements were obtained 2 to 4 days after AMI and compared with 20 normal subjects (NC) who were matched in terms of age and body weight to the AMI groups. Resting muscle sympathetic nerve activity was quantified from multiunit bursts (MSNA) and from single units (s-MSNA). Both groups of AMI patients were matched with regard to hemodynamic variables, left ventricular function, and infarct size. Both groups had greater (at least P<0.01) sympathetic nerve activity than NC (60+/-4.3 bursts/100 cardiac beats and 68+/-4.9 impulses/100 cardiac beats), but the magnitude of sympathetic nerve hyperactivity in ant-AMI (81+/-4.0 bursts/100 cardiac beats and 91+/-4.9 impulses/100 cardiac beats) was similar (P>0.05) to that in inf-AMI (80+/-3.2 bursts/100 cardiac beats and 90+/-4.0 impulses/100 cardiac beats) CONCLUSIONS: Both ant-AMI and inf-AMI resulted primarily in a similar magnitude of sympathetic nerve hyperactivity. These findings suggest that the worse prognosis after ant-AMI compared with after inf-AMI would not be related primarily to the degree of sympathetic hyperactivity.

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.

Relationship of neurovascular compression to central sympathetic discharge and essential hypertension.

OBJECTIVES: We planned to examine the relationship between neurovascular compression (NVC) of the rostral ventrolateral medulla (RVLM) and the magnitude of central sympathetic hyperactivity in normal subjects and in patients with untreated and uncomplicated essential hypertension (EHT). BACKGROUND: Previously it has not been possible to establish a definitive relationship between EHT and NVC of the RVLM, a location containing efferent sympathetic vasoconstrictor neurons. Furthermore, the relationship between NVC and magnitude of sympathetic nerve hyperactivity has not been adequately examined, despite the knowledge that hyperactivity varies according to EHT severity. METHODS: In 83 subjects, we used magnetic resonance imaging to detect NVC and, independently, peroneal microneurography to quantify muscle sympathetic nerve activity (MSNA), expressed as the mean frequency of multi-unit discharge (m-MSNA) and of single units (s-MSNA). Subjects were classified according to arterial pressure values into groups with normal (NT) (n = 24) or high-normal (HN) (n = 14) arterial pressure and mild (EHT-1) (n = 26) or severe (EHT-2/3) (n = 19) EHT. RESULTS: A significantly greater sympathetic activity was found in 23 subjects with NVC, compared with 60 subjects without NVC. The prevalence of NVC and the magnitude of sympathetic hyperactivity were greater in the EHT-1 group (p < 0.05) than in the other three groups. There was no significant difference in confounding variables between the groups. Although increased sympathetic activity was strongly predictive of NVC, this was not significantly related to baroreceptor sensitivity controlling the pulse interval (cardiac baroreceptor reflex sensitivity). CONCLUSIONS: Neurovascular compression of the RVLM may cause central sympathetic activation in normal and hypertensive populations and therefore has significant implications regarding the pathogenesis of EHT.

Relationship between central sympathetic activity and stages of human hypertension.

BACKGROUND: The magnitude of sympathetic hyperactivity in essential hypertension (EHT) varies with its severity and complications. There are no data on sympathetic nerve activity in borderline (BHT) or white-coat hypertension (WHT) relative to the various stages of EHT, despite suggestions that both lead to established EHT and organ damage through sympathetic mechanisms. We planned to determine the magnitude of sympathetic nerve activity in patients with BHT and WHT in relation to normality and various stages of sustained EHT. METHODS: We examined 90 untreated subjects comprising matched groups with BHT (n = 13), WHT (n = 12), Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure EHT stage 1 (EHT-1 n = 12), EHT stages 2 and 3 (EHT-2/3 n = 14), high-normal pressure (HN n = 14), and normal pressure (NT n = 13), as well as a group with EHT complicated by left ventricular hypertrophy (EHT+LVH n = 12). We quantified muscle sympathetic nerve activity as the mean frequency of multiunit discharge (MSNA) and that of single-units (s-MSNA). RESULTS: We found a greater (at least P <.01) mean central sympathetic frequency in BHT (75 +/- 5.8 impulses/100 beats), EHT-1 (76 +/- 4.0 impulses/100 beats), and EHT+LVH (79 +/- 4.3 impulses/100 beats) than in EHT-2/3 (57 +/- 3.1 impulses/100 beats), WHT (52 +/- 3.6 impulses/100 beats), HN (42 +/- 3.9 impulses/100 beats), and NT (33 +/- 3.6 impulses/100 beats). BHT hyperactivity was closer to that of EHT, whereas WHT was closer to NT. CONCLUSIONS: Central sympathetic activity was greatest in BHT, early stage, and complicated EHT, and as such is likely to play an integral role in the development of hypertension and its complications. Sympathetic hyperactivity occurs in WHT, but to a lesser extent than in BHT.

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.

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.

Sympathetic neural hyperactivity and its normalization following unstable angina and acute myocardial infarction.

Impaired autonomic function occurs after AMI (acute myocardial infarction) and UA (unstable angina), which may be important prognostically. However, the pattern of sympathetic nerve hyperactivity has been investigated only after AMI. We aimed to quantify central sympathetic output to the periphery in patients with UA, investigate its progress over time relative to that after uncomplicated AMI and to explore the mechanisms involved. Muscle sympathetic nerve activity (MSNA) assessed from multiunit discharges and from single units (s-MSNA) was obtained in matched patients with UA ( n =9), AMI ( n =14) and stable CAD (coronary artery disease, n =11), patients with chest pain in which AMI was excluded (NMI, n =9) and normal controls (NCs, n =14). Measurements were obtained 2-4 days after UA or AMI, and repeated at 3 monthly intervals until they returned to normal levels. The respective MSNA and s-MSNA early after UA (72+/-4.0 bursts/100 beats and 78+/-4.2 impulses/100 beats respectively) were less than those after AMI (83+/-4.4 bursts/100 beats and 93+/-5.5 impulses/100 beats respectively). Relative to the control groups of NCs (51+/-2.7 bursts/100 beats and 58+/-3.4 impulses/100 beats respectively) and patients with CAD (54+/-3.7 bursts/100 beats and 58+/-3.9 impulses/100 beats respectively) and NMI (52+/-4.5 bursts/100 beats and 59+/-4.9 impulses/100 beats respectively), values returned to normal after 6 months in UA (55+/-5.0 bursts/100 beats and 62+/-5.5 impulses/100 beats respectively) and 9 months after AMI (60+/-3.8 bursts/100 beats and 66+/-4.2 impulses/100 beats respectively). In conclusion, both UA and AMI result in sympathetic hyper-activity, although this is of smaller magnitude in UA and is less protracted than in AMI. It is suggested that this hyperactivity is related to the degree of left ventricular dysfunction and reflexes.