136 results found
Ardissino M, Slob E, Millar O, et al., 2022, Maternal hypertension increases risk of pre-eclampsia and low fetal birthweight: genetic evidence from a Mendelian randomization study, Hypertension, ISSN: 0194-911X
Background: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing pre-eclampsia or eclampsia, and low fetal birthweight.Methods: Uncorrelated single nucleotide polymorphisms associated systolic blood pressure, body mass index, type 2 diabetes mellitus, low-density lipoprotein with cholesterol, smoking, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate at genome-wide significance in studies of 298,957 to 1,201,909 European ancestry participants were selected as instrumental variables. A two-sample Mendelian randomization study was performed with primary outcome of pre-eclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight. Results: Higher genetically-predicted systolic blood pressure was associated increased risk of PET [odds ratio (OR) per 1-SD systolic blood pressure increase 1.90 (95% confidence interval (CI)1.45-2.49;p=3.23x10-6 and reduced birthweight (OR=0.83; 95%CI=0.79-0.86;p=3.96x10-18), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase=1.67 95%CI=1.44-1.94,;p=7.45x10-12; and OR per logOR increase type 2 diabetes=1.11 95%CI=1.04-1.19p;=1.19x10-3), but not with reduced birthweight. Conclusions: Our results provide evidence for causal effects of systolic blood pressure, body mass index and type 2 diabetes on PET, and identify that systolic blood pressure is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.
Ardissino M, Reddy RK, Slob EAW, et al., 2022, Sleep disordered breathing, obesity and atrial fibrillation: a mendelian randomisation study, Geneses, Vol: 13, Pages: 1-11, ISSN: 1155-3219
It remains unclear whether the association between obstructive sleep apnoea (OSA), a form of sleep-disordered breathing (SDB), and atrial fibrillation (AF) is causal or mediated by shared co-morbidities such as obesity. Existing observational studies are conflicting and limited by confounding and reverse causality. We performed Mendelian randomisation (MR) to investigate the causal relationships between SDB, body mass index (BMI) and AF. Single-nucleotide polymorphisms associated with SDB (n = 29) and BMI (n = 453) were selected as instrumental variables to investigate the effects of SDB and BMI on AF, using genetic association data on 55,114 AF cases and 482,295 controls. Primary analysis was conducted using inverse-variance weighted MR. Higher genetically predicted SDB and BMI were associated with increased risk of AF (OR per log OR increase in snoring liability 2.09 (95% CI 1.10–3.98), p = 0.03; OR per 1-SD increase in BMI 1.33 (95% CI 1.24–1.42), p < 0.001). The association between SDB and AF was not observed in sensitivity analyses, whilst associations between BMI and AF remained consistent. Similarly, in multivariable MR, SDB was not associated with AF after adjusting for BMI (OR 0.68 (95% CI 0.42–1.10), p = 0.12). Higher BMI remained associated with increased risk of AF after adjusting for OSA (OR 1.40 (95% CI 1.30–1.51), p < 0.001). Elevated BMI appears causal for AF, independent of SDB. Our data suggest that the association between SDB, in general, and AF is attributable to mediation or confounding from obesity, though we cannot exclude that more severe SDB phenotypes (i.e., OSA) are causal for AF.
Kim M-Y, Coyle C, Tomlinson DR, et al., 2021, Ectopy-triggering ganglionated plexus ablation to prevent atrial fibrillation: GANGLIA-AF study., Heart Rhythm, ISSN: 1547-5271
BACKGROUND: The ganglionated plexuses (GP) of the intrinsic cardiac autonomic system may play a role in atrial fibrillation (AF). OBJECTIVES: We hypothesized that ablating the ectopy-triggering GPs (ET-GP) prevents AF. METHODS: GANGLIA-AF (NCT02487654) was a prospective, randomized, controlled, 3-centre trial. ET-GP were mapped using high frequency stimulation (HFS), delivered within the atrial refractory period and ablated until non-functional. If triggered AF became incessant, atrioventricular dissociating GPs (AVD-GP) were ablated. We compared GP ablation (GPA) without pulmonary vein isolation (PVI) against PVI, in patients with paroxysmal AF. Follow-up was for 12 months including 3-monthly 48hr Holter monitors. The primary endpoint was documented ≥30s atrial arrhythmia after a 3-month blanking period. RESULTS: 102 randomized patients were analysed on a per-protocol basis after GPA (n=52) or PVI (n=50). GPA patients had 89±26 HFS sites tested, identifying median 18.5 (IQR 16; 21%) GPs. RF ablation time in GPA was 22.9±9.8mins and 38±14.4mins in PVI (p<0.0001). The freedom from ≥30s atrial arrhythmia at 12-month follow-up with GPA was 50% (26/52) vs 64% (32/50) with PVI (log rank p=0.09). ET-GP ablation without AVD-GP ablation achieved 58% (22/38) freedom from the primary endpoint. There was a significantly higher reduction in AAD usage post-ablation after GPA vs PVI (55.5% vs 36%; p=0.05). Patients were referred for redo ablations in 31% (16/52) after GPA and 24% (12/50) after PVI (p=0.53). CONCLUSIONS: GPA did not prevent atrial arrhythmias more than PVI. However, less RF ablation was delivered to achieve a higher reduction in AAD usage with GPA than PVI.
Patel K, Hwang T, Se Liebers C, et al., 2021, Epicardial adipose tissue as a mediator of cardiac arrhythmias, American Journal of Physiology: Heart and Circulatory Physiology, Vol: 322, ISSN: 0363-6135
Obesity is associated with higher risks of cardiac arrhythmias. Although this may be partly explained by concurrent cardiometabolic ill-health, growing evidence suggests that increasing adiposity independently confers risk for arrhythmias. Amongst fat depots, epicardial adipose tissue (EAT) exhibits a proinflammatory secretome, and given the lack of fascial separation, has been implicated as a transducer of inflammation to the underlying myocardium. The present review explores the mechanisms underpinning adverse electrophysiological remodelling as a consequence of EAT accumulation and the consequent inflammation. We first describe the physiological and pathophysiological function of EAT and its unique secretome, and subsequently discuss the evidence for ionic channel and connexin expression modulation as well as fibrotic remodelling induced by cytokines and free fatty acids that are secreted by EAT. Finally, we highlight how weight reduction and regression of EAT volume may cause reverse remodelling to ameliorate arrhythmic risk.
Chow J-J, Leong KMW, Yazdani M, et al., 2021, A Multicenter External Validation of a Score Model to Predict Risk of Events in Patients With Brugada Syndrome, AMERICAN JOURNAL OF CARDIOLOGY, Vol: 160, Pages: 53-59, ISSN: 0002-9149
Patel K, Li X, Sun L, et al., 2021, Neural networks applied to 12-lead electrocardiograms predict body mass index, visceral adiposity and concurrent cardiometabolic ill-health, Cardiovascular Digital Health Journal, Vol: 2, Pages: S1-S10, ISSN: 2666-6936
BackgroundObesity is associated with electrophysiological remodeling, which manifests as detectable changes on the surface electrocardiogram (ECG).ObjectiveTo develop neural networks (NN) to predict body mass index (BMI) from ECGs and test the hypothesis that discrepancies between NN-predicted BMI and measured BMI are indicative of underlying adiposity and/or concurrent cardiometabolic ill-health.MethodsNN models were developed using 36,856 12-lead resting ECGs from the UK Biobank. Two architectures were developed for continuous and categorical BMI estimation (normal weight [BMI <25 kg/m2] vs overweight/obese [BMI ≥25 kg/m2]). Models for male and female participants were trained and tested separately. For each sex, data were randomly divided into 4 folds, and models were evaluated in a leave-1-fold-out manner.ResultsECGs were available for 17,807 male and 19,049 female participants (mean ages: 61 ± 7 and 63 ± 8 years; mean BMI 26 ± 5 kg/m2 and 27 ± 4 kg/m2, respectively). NN models detected overweight/obese individuals with average accuracies of 75% and 73% for male and female subjects, respectively. The magnitudes of difference between NN-predicted BMI and actual BMI were significantly correlated with visceral adipose tissue volumes. Concurrent hypertension, diabetes, dyslipidemia, and/or coronary heart disease explained false-positive classifications (ie, calculated BMI <25 kg/m2 misclassified as ≥25 kg/m2 by NN model, P < .001).ConclusionNN models applied to 12-lead ECGs predict BMI with a reasonable degree of accuracy. Discrepancies between NN-predicted and calculated BMI may be indicative of underlying visceral adiposity and concomitant cardiometabolic perturbation, which could be used to identify individuals at risk of cardiometabolic disease.
Hartley A, Shalhoub J, Ng F, et al., 2021, Size matters in atrial fibrillation: the underestimated importance of reduction of contiguous electrical mass underlying the effectiveness of catheter ablation, Europace, Vol: 23, Pages: 1698-1707, ISSN: 1099-5129
Evidence has accumulated over the last century of the importance of a critical electrical mass in sustaining atrial fibrillation (AF). AF ablation certainly reduces electrically contiguous atrial mass, but this is not widely accepted to be an important part of its mechanism of action. In this article, we review data showing that atrial size is correlated in many settings with AF propensity. Larger mammals are more likely to exhibit AF. This is seen both in the natural world and in animal models, where it is much easier to create a goat model than a mouse model of AF, for example. This also extends to humans—athletes, taller people, and obese individuals all have large atria and are more likely to exhibit AF. Within an individual, risk factors such as hypertension, valvular disease and ischaemia can enlarge the atrium and increase the risk of AF. With respect to AF ablation, we explore how variations in ablation strategy and the relative effectiveness of these strategies may suggest that a reduction in electrical atrial mass is an important mechanism of action. We counter this with examples in which there is no doubt that mass reduction is less important than competing theories such as ganglionated plexus ablation. We conclude that, when considering future strategies for the ablative therapy of AF, it is important not to discount the possibility that contiguous electrical mass reduction is the most important mechanism despite the disappointing consequence being that enhancing success rates in AF ablation may involve greater tissue destruction.
Li X, Shi X, Handa BS, et al., 2021, Classification of fibrillation organisation using electrocardiograms to guide mechanism-directed treatments, Frontiers in Physiology, Vol: 12, Pages: 1-14, ISSN: 1664-042X
Background: Atrial fibrillation (AF) and ventricular fibrillation (VF) are complex heart rhythm disorders and may be sustained by distinct electrophysiological mechanisms. Disorganised self-perpetuating multiple-wavelets and organised rotational drivers (RDs) localising to specific areas are both possible mechanisms by which fibrillation is sustained. Determining the underlying mechanisms of fibrillation may be helpful in tailoring treatment strategies. We investigated whether global fibrillation organisation, a surrogate for fibrillation mechanism, can be determined from electrocardiograms (ECGs) using band-power (BP) feature analysis and machine learning.Methods: In this study, we proposed a novel ECG classification framework to differentiate fibrillation organisation levels. BP features were derived from surface ECGs and fed to a linear discriminant analysis classifier to predict fibrillation organisation level. Two datasets, single-channel ECGs of rat VF (n = 9) and 12-lead ECGs of human AF (n = 17), were used for model evaluation in a leave-one-out (LOO) manner.Results: The proposed method correctly predicted the organisation level from rat VF ECG with the sensitivity of 75%, specificity of 80%, and accuracy of 78%, and from clinical AF ECG with the sensitivity of 80%, specificity of 92%, and accuracy of 88%.Conclusion: Our proposed method can distinguish between AF/VF of different global organisation levels non-invasively from the ECG alone. This may aid in patient selection and guiding mechanism-directed tailored treatment strategies.
Katritsis G, Luther V, Jamil-Copley S, et al., 2021, Postinfarct ventricular tachycardia substrate: Characterization and ablation of conduction channels using ripple mapping, HEART RHYTHM, Vol: 18, Pages: 1682-1690, ISSN: 1547-5271
Arnold AD, Shun-Shin MJ, Ali N, et al., 2021, Left ventricular activation time and pattern are preserved with both selective and non-selective his bundle pacing, Heart Rhythm O2, Vol: 2, Pages: 439-445, ISSN: 2666-5018
BackgroundHis bundle pacing (HBP) can be achieved in two ways: selective HBP (S-HBP), where the His bundle is captured alone, and non-selective HBP (NS-HBP), where local myocardium is also captured resulting a pre-excited ECG appearance.ObjectiveWe assessed the impact of this ventricular pre-excitation on left and right ventricular dys-synchrony.MethodsWe recruited patients who displayed both S-HBP and NS-HBP. We performed non-invasive epicardial electrical mapping for left and right ventricular activation time (LVAT and RVAT) and pattern.Results20 patients were recruited. In the primary analysis, the mean within-patient change in LVAT from S-HBP to NS-HBP was -5.5ms (95% confidence interval: -0.6 to -10.4, non-inferiority p<0.0001). NS-HBP did not prolong RVAT (4.3ms, -4.0 to 12.8, p=0.296) but did prolong QRS duration (QRSd, 22.1ms, 11.8 to 32.4, p = 0.0003). In patients with narrow intrinsic QRS (n=6), NS-HBP preserved LVAT (-2.9ms, -9.7 to 4.0, p=0.331) but prolonged QRS duration (31.4ms, 22.0 to 40.7, p=0.0003) and mean RVAT (16.8ms, -5.3 to 38.9, p=0.108) compared to S-HBP. Activation pattern of the left ventricular surface was unchanged between S-HBP and NS-HBP but NS-HBP produced early basal right ventricular activation that was not seen in S-HBP.ConclusionCompared to S-HBP, local myocardial capture during NS-HBP produces pre-excitation of the basal right ventricle resulting in QRS duration prolongation. However, NS-HBP preserves the left ventricular activation time and pattern of S-HBP. Left ventricular dys-synchrony is not an important factor when choosing between S-HBP and NS-HBP in most patients.
Kim M-Y, Coyle C, Sohaib DT-SA, et al., 2021, GANGLIONATED PLEXUS ABLATION TO PREVENT ATRIAL FIBRILLATION (GANGLIA-AF TRIAL), HEART RHYTHM, Vol: 18, Pages: 1632-1632, ISSN: 1547-5271
Nagy SZ, Kasi P, Afonso VX, et al., 2021, Cycle length evaluation in persistent atrial fibrillation using kernel density estimation to identify transient and stable rapid atrial activity, Cardiovascular Engineering and Technology, Pages: 1-15, ISSN: 1869-408X
PurposeLeft atrial (LA) rapid AF activity has been shown to co-localise with areas of successful atrial fibrillation termination by catheter ablation. We describe a technique that identifies rapid and regular activity.MethodsEight-second AF electrograms were recorded from LA regions during ablation for psAF. Local activation was annotated manually on bipolar signals and where these were of poor quality, we inspected unipolar signals. Dominant cycle length (DCL) was calculated from annotation pairs representing a single activation interval, using a probability density function (PDF) with kernel density estimation. Cumulative annotation duration compared to total segment length defined electrogram quality. DCL results were compared to dominant frequency (DF) and averaging.ResultsIn total 507 8 s AF segments were analysed from 7 patients. Spearman’s correlation coefficient was 0.758 between independent annotators (P < 0.001), 0.837–0.94 between 8 s and ≥ 4 s segments (P < 0.001), 0.541 between DCL and DF (P < 0.001), and 0.79 between DCL and averaging (P < 0.001). Poorer segment organization gave greater errors between DCL and DF.ConclusionDCL identifies rapid atrial activity that may represent psAF drivers. This study uses DCL as a tool to evaluate the dynamic, patient specific properties of psAF by identifying rapid and regular activity. If automated, this technique could rapidly identify areas for ablation in psAF.
Arnold AD, Shun-Shin MJ, Ali N, et al., 2021, Left ventricular activation time and pattern are preserved with both selective and nonselective His bundle pacing, Heart rhythm O2, Vol: 2, Pages: 439-445, ISSN: 2666-5018
<h4>Background</h4> His bundle pacing (HBP) can be achieved in 2 ways: selective HBP (S-HBP), where the His bundle is captured alone, and nonselective HBP (NS-HBP), where local myocardium is also captured, resulting a pre-excited electrocardiogram appearance. <h4>Objective</h4> We assessed the impact of this ventricular pre-excitation on left and right ventricular dyssynchrony. <h4>Methods</h4> We recruited patients who displayed both S-HBP and NS-HBP. We performed noninvasive epicardial electrical mapping for left and right ventricular activation time (LVAT and RVAT) and pattern. <h4>Results</h4> Twenty patients were recruited. In the primary analysis, the mean within-patient change in LVAT from S-HBP to NS-HBP was -5.5 ms (95% confidence interval: -0.6 to -10.4, noninferiority P < .0001). NS-HBP did not prolong RVAT (4.3 ms, -4.0 to 12.8, P = .296) but did prolong QRS duration (QRSd, 22.1 ms, 11.8 to 32.4, P = .0003). In patients with narrow intrinsic QRS (n = 6), NS-HBP preserved LVAT (-2.9 ms, -9.7 to 4.0, P = .331) but prolonged QRS duration (31.4 ms, 22.0 to 40.7, P = .0003) and mean RVAT (16.8 ms, -5.3 to 38.9, P = .108) compared to S-HBP. Activation pattern of the left ventricular surface was unchanged between S-HBP and NS-HBP, but NS-HBP produced early basal right ventricular activation that was not seen in S-HBP. <h4>Conclusion</h4> Compared to S-HBP, local myocardial capture during NS-HBP produces pre-excitation of the basal right ventricle resulting in QRS duration prolongation. However, NS-HBP preserves the left ventricular activation time and pattern of S-HBP. Left ventricular dyssynchrony is not an important factor when choosing between S-HBP and NS-HBP in most patients. Graphical abstract
Jabbour R, Owen T, Pandey P, et al., 2021, In vivo grafting of large engineered heart tissue patches for cardiac repair, JCI Insight, Vol: 6, Pages: 1-13, ISSN: 2379-3708
Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be anovel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more dataare needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.5 cm × 1.5 cm × 1.5mm) consisting of up to 20 million human induced pluripotent stem cell–derived cardiomyocytes(hPSC-CMs) embedded in a fibrin-based hydrogel was developed. A rabbit myocardial infarctionmodel was then established to test for feasibility and efficacy. Our data showed that hPSC-CMs inEHTs became more aligned over 28 days and had improved contraction kinetics and faster calciumtransients. Blinded echocardiographic analysis revealed a significant improvement in function ininfarcted hearts that received EHTs, along with reduction in infarct scar size by 35%. Vascularizationfrom the host to the patch was observed at week 1 and stable to week 4, but electrical couplingbetween patch and host heart was not observed. In vivo telemetry recordings and ex vivoarrhythmia provocation protocols showed that the patch was not pro-arrhythmic. In summary, EHTsimproved function and reduced scar size without causing arrhythmia, which may be due to the lackof electrical coupling between patch and host heart.
Ng FS, Toman O, Petru J, et al., 2021, Novel low-voltage multiPulse therapy to terminate atrial fibrillation., JACC: Clinical Electrophysiology, Vol: 7, Pages: 988-999, ISSN: 2405-5018
OBJECTIVES: This first-in-human feasibility study was undertaken to translate the novel low-voltage MultiPulse Therapy (MPT) (Cardialen, Inc., Minneapolis, Minnesota), which was previously been shown to be effective in preclinical studies in terminating atrial fibrillation (AF), into clinical use. BACKGROUND: Current treatment options for AF, the most common arrhythmia in clinical practice, have limited success. Previous attempts at treating AF by using implantable devices have been limited by the painful nature of high-voltage shocks. METHODS: Forty-two patients undergoing AF ablation were recruited at 6 investigational centers worldwide. Before ablation, electrode catheters were placed in the coronary sinus, right and/or left atrium, for recording and stimulation. After the induction of AF, MPT, which consists of up to a 3-stage sequence of far- and near-field stimulation pulses of varied amplitude, duration, and interpulse timing, was delivered via temporary intracardiac leads. MPT parameters and delivery methods were iteratively optimized. RESULTS: In the 14 patients from the efficacy phase, MPT terminated 37 of 52 (71%) of AF episodes, with the lowest median energy of 0.36 J (interquartile range [IQR]: 0.14 to 1.21 J) and voltage of 42.5 V (IQR: 25 to 75 V). Overall, 38% of AF terminations occurred within 2 seconds of MPT delivery (p < 0.0001). Shorter time between AF induction and MPT predicted success of MPT in terminating AF (p < 0.001). CONCLUSIONS: MPT effectively terminated AF at voltages and energies known to be well tolerated or painless in some patients. Our results support further studies of the concept of implanted devices for early AF conversion to reduce AF burden, symptoms, and progression.
Patel K, Li X, Quint J, et al., 2021, Increasing adiposity and the presence of cardiometabolic morbidity is associated with increased Covid-19-related mortality: results from the UK Biobank, BMC Endocrine Disorders, Vol: 21, Pages: 1-6, ISSN: 1472-6823
Background: Although obesity, defined by body mass index (BMI), has been associated with a higher risk of hospitalisation and more severe course of illness in Covid-19 positive patients amongst the British population, it is unclear if this translates into increased mortality. Furthermore, given that BMI is an insensitive indicator of adiposity, the effect of adipose volume on Covid-19 outcomes is also unknown. Methods: We used the UK Biobank repository, which contains clinical and anthropometric data, and is linked to Public Health England Covid-19 healthcare records, to address our research question. We performed age- and sex- adjusted logistic regression and Chi-squared test to compute the odds for Covid-19-related mortality as a consequence of increasing BMI, other more sensitive indices of adiposity such as waist:hip ratio (WHR) and percent body fat, as well as concomitant cardiometabolic illness.Results: 13502 participants were tested for Covid-19 (mean age 70+8 years, 48.9% male). 1,582 tested positive (mean age 68+9 years, 52.8% male), of which 305 died (mean age 75+6 years, 65.5% male). Increasing adiposity was associated with higher odds for Covid-19-related mortality. For every unit increase in BMI, WHR and percent body fat, the odds of death amongst the Covid19-positive participants increased by 1.04 (95% CI 1.01-1.07), 10.71 (95% CI 1.57-73.06) and 1.03 (95% CI 1.01-1.05), respectively (all p<0.05). Referenced to Covid-19 positive participants with a normal weight (BMI 18.5-25kg/m2), Covid-19 positive participants with BMI>35kg/m2 had significantly higher odds of Covid-19-related death (OR 1.70, 95% CI 1.06-2.74, p<0.05). Covid-19-positive participants with metabolic (diabetes, hypertension, dyslipidaemia) or cardiovascular morbidity (atrial fibrillation, angina) also had higher odds of death.Conclusions: Anthropometric indices that are more sensitive to adipose volume and its distribution than BMI, as well as concurrent cardiometabolic illnes
Mann I, Linton NWF, Coyle C, et al., 2021, RETRO-MAPPING A New Approach to Activation Mapping in Persistent Atrial Fibrillation Reveals Evidence of Spatiotemporal Stability, CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY, Vol: 14, ISSN: 1941-3149
Sekelj S, Sandler B, Johnston E, et al., 2021, Detecting undiagnosed atrial fibrillation in UK primary care: Validation of a machine learning prediction algorithm in a retrospective cohort study, European Journal of Preventive Cardiology, Vol: 28, Pages: 598-605, ISSN: 2047-4873
AimsTo evaluate the ability of a machine learning algorithm to identify patients at high risk of atrial fibrillation in primary care.MethodsA retrospective cohort study was undertaken using the DISCOVER registry to validate an algorithm developed using a Clinical Practice Research Datalink (CPRD) dataset. The validation dataset included primary care patients in London, England aged ≥30 years from 1 January 2006 to 31 December 2013, without a diagnosis of atrial fibrillation in the prior 5 years. Algorithm performance metrics were sensitivity, specificity, positive predictive value, negative predictive value (NPV) and number needed to screen (NNS). Subgroup analysis of patients aged ≥65 years was also performed.ResultsOf 2,542,732 patients in DISCOVER, the algorithm identified 604,135 patients suitable for risk assessment. Of these, 3.0% (17,880 patients) had a diagnosis of atrial fibrillation recorded before study end. The area under the curve of the receiver operating characteristic was 0.87, compared with 0.83 in algorithm development. The NNS was nine patients, matching the CPRD cohort. In patients aged ≥30 years, the algorithm correctly identified 99.1% of patients who did not have atrial fibrillation (NPV) and 75.0% of true atrial fibrillation cases (sensitivity). Among patients aged ≥65 years (n = 117,965), the NPV was 96.7% with 91.8% sensitivity.ConclusionsThis atrial fibrillation risk prediction algorithm, based on machine learning methods, identified patients at highest risk of atrial fibrillation. It performed comparably in a large, real-world population-based cohort and the developmental registry cohort. If implemented in primary care, the algorithm could be an effective tool for narrowing the population who would benefit from atrial fibrillation screening in the United Kingdom.
Sekelj S, Sandler B, Johnston E, et al., 2021, Detecting undiagnosed atrial fibrillation in UK primary care: Validation of a machine learning prediction algorithm in a retrospective cohort study., Eur J Prev Cardiol, Vol: 28, Pages: 598-605
AIMS: To evaluate the ability of a machine learning algorithm to identify patients at high risk of atrial fibrillation in primary care. METHODS: A retrospective cohort study was undertaken using the DISCOVER registry to validate an algorithm developed using a Clinical Practice Research Datalink (CPRD) dataset. The validation dataset included primary care patients in London, England aged ≥30 years from 1 January 2006 to 31 December 2013, without a diagnosis of atrial fibrillation in the prior 5 years. Algorithm performance metrics were sensitivity, specificity, positive predictive value, negative predictive value (NPV) and number needed to screen (NNS). Subgroup analysis of patients aged ≥65 years was also performed. RESULTS: Of 2,542,732 patients in DISCOVER, the algorithm identified 604,135 patients suitable for risk assessment. Of these, 3.0% (17,880 patients) had a diagnosis of atrial fibrillation recorded before study end. The area under the curve of the receiver operating characteristic was 0.87, compared with 0.83 in algorithm development. The NNS was nine patients, matching the CPRD cohort. In patients aged ≥30 years, the algorithm correctly identified 99.1% of patients who did not have atrial fibrillation (NPV) and 75.0% of true atrial fibrillation cases (sensitivity). Among patients aged ≥65 years (n = 117,965), the NPV was 96.7% with 91.8% sensitivity. CONCLUSIONS: This atrial fibrillation risk prediction algorithm, based on machine learning methods, identified patients at highest risk of atrial fibrillation. It performed comparably in a large, real-world population-based cohort and the developmental registry cohort. If implemented in primary care, the algorithm could be an effective tool for narrowing the population who would benefit from atrial fibrillation screening in the United Kingdom.
Chowdhury R, Debney M, Protti A, et al., 2021, Rotigaptide Infusion for the First 7 Days After Myocardial Infarction–Reperfusion Reduced Late Complexity of Myocardial Architecture of the Healing Border-Zone and Arrhythmia Inducibility, Journal of the American Heart Association, Vol: 10, Pages: 1-18, ISSN: 2047-9980
BackgroundSurvivors of myocardial infarction are at increased risk of late ventricular arrhythmias, with infarct size and scar heterogeneity being key determinants of arrhythmic risk. Gap junctions facilitate the passage of small ions and morphogenic cell signaling between myocytes. We hypothesized that gap junctions enhancement during infarction–reperfusion modulates structural and electrophysiological remodeling and reduces late arrhythmogenesis.Methods and ResultsInfarction–reperfusion surgery was carried out in male Sprague‐Dawley rats followed by 7 days of rotigaptide or saline administration. The in vivo and ex vivo arrhythmogenicity was characterized by programmed electrical stimulation 3 weeks later, followed by diffusion‐weighted magnetic resonance imaging and Masson's trichrome histology. Three weeks after 7‐day postinfarction administration of rotigaptide, ventricular tachycardia/ventricular fibrillation was induced on programmed electrical stimulation in 20% and 53% of rats, respectively (rotigaptide versus control), resulting in reduction of arrhythmia score (3.2 versus 1.4, P=0.018), associated with the reduced magnetic resonance imaging parameters fractional anisotropy (fractional anisotropy: −5% versus −15%; P=0.062) and mean diffusivity (mean diffusivity: 2% versus 6%, P=0.042), and remodeling of the 3‐dimensional laminar structure of the infarct border zone with reduction of the mean (16° versus 19°, P=0.013) and the dispersion (9° versus 12°, P=0.015) of the myofiber transverse angle. There was no change in ECG features, spontaneous arrhythmias, or mortality.ConclusionsEnhancement of gap junctions function by rotigaptide administered during the early healing phase in reperfused infarction reduces later complexity of infarct scar morphology and programmed electrical stimulation–induced arrhythmias, and merits further exploration as a feasible and practicable intervention in the acute myocardial infarcti
Katritsis G, Luther V, Cortez-Dias N, et al., 2021, Electroanatomic characterization and ablation of scar-related isthmus sites supporting perimitral flutter, JACC: Clinical Electrophysiology, Vol: 7, Pages: 578-590, ISSN: 2405-5018
ObjectivesThe authors reviewed 3-dimensional electroanatomic maps of perimitral flutter to identify scar-related isthmuses and determine their effectiveness as ablation sites.BackgroundPerimitral flutter is usually treated by linear ablation between the left lower pulmonary vein and mitral annulus. Conduction block can be difficult to achieve, and recurrences are common.MethodsPatients undergoing atrial tachycardia ablation using CARTO3 (Biosense Webster Inc., Irvine, California) were screened from 4 centers. Patients with confirmed perimitral flutter were reviewed for the presence of scar-related isthmuses by using CARTO3 with the ConfiDense and Ripple Mapping modules.ResultsConfirmed perimitral flutter was identified in 28 patients (age 65.2 ± 8.1 years), of whom 26 patients had prior atrial fibrillation ablation. Scar-related isthmus ablation was performed in 12 of 28 patients. Perimitral flutter was terminated in all following correct identification of a scar-related isthmus using ripple mapping. The mean scar voltage threshold was 0.11 ± 0.05 mV. The mean width of scar-related isthmuses was 8.9 ± 3.5 mm with a conduction speed of 31.8 ± 5.5 cm/s compared to that of normal left atrium of 71.2 ± 21.5 cm/s (p < 0.0001). Empirical, anatomic ablation was performed in 16 of 28, with termination in 10 of 16 (63%; p = 0.027). Significantly less ablation was required for critical isthmus ablation compared to empirical linear lesions (11.4 ± 5.3 min vs. 26.2 ± 17.1 min; p = 0.0004). All 16 cases of anatomic ablation were reviewed with ripple mapping, and 63% had scar-related isthmus.ConclusionsPerimitral flutter is usually easy to diagnose but can be difficult to ablate. Ripple mapping is highly effective at locating the critical isthmus maintaining the tachycardia and avoiding anatomic ablation lines. This approach has a higher termination rate with less radiofrequency ablation required.
Handa B, Li X, Baxan N, et al., 2021, Ventricular fibrillation mechanism and global fibrillatory organisation are determined by gap junction coupling and fibrosis pattern, Cardiovascular Research, Vol: 117, Pages: 1078-1090, ISSN: 0008-6363
AimsConflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganised multiple-wavelet activation to organised rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism.Methods and ResultsOptical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact (CF), diffuse (DiF) and patchy (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum.Enhanced GJ coupling with rotigaptide (n = 10) progressively organised fibrillation in a concentration-dependent manner; increasing FDI (0nM: 0.53±0.04, 80nM: 0.78±0.03, p < 0.001), increasing RA sustained VF time (0nM:44±6%, 80nM: 94±2%, p < 0.001) and stabilised RAs (maximum rotations for a RA; 0nM:5.4±0.5, 80nM: 48.2±12.3, p < 0.001). GJ uncoupling with carbenoxolone progressively disorganised VF; the FDI decreased (0µM: 0.60±0.05, 50µM: 0.17±0.03, p < 0.001) and RA-sustained VF time decreased (0µM: 61±9%, 50µM: 3±2%, p < 0.001).In CF, VF activity was disorganised and the RA-sustained VF time was the lowest (CF: 27±7% versus PF: 75±5%, p < 0.001). Global fibrillatory organisation measured by FDI was highest in PF (PF: 0.67±0.05 versus CF: 0.33±0.03, p < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411&plusm
Leong KMW, Ng FS, Shun-Shin MJ, et al., 2021, Non-invasive detection of exercise-induced cardiac conduction abnormalities in sudden cardiac death survivors in the inherited cardiac conditions, EUROPACE, Vol: 23, Pages: 305-312, ISSN: 1099-5129
Moscoso Costa F, Ng FS, 2021, Oxidative stress and atrial fibrillation - association or causation?, Revista Portuguesa de Cardiología, Vol: 40, Pages: 11-12, ISSN: 0870-2551
Forte E, Panahi M, Baxan N, et al., 2021, Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart, Journal of Cellular and Molecular Medicine, Vol: 25, Pages: 229-243, ISSN: 1582-1838
Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.
Forte E, Perkins B, Sintou A, et al., 2020, Cross-priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart, Circulation, Vol: 143, Pages: 821-836, ISSN: 0009-7322
Background: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of HF. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4+ helperand CD8+ cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross priming DC in post-MI myocardial impairment through presentation of self-antigen fromnecrotic cardiomyocytes to cytotoxic CD8+ T cells.Methods: We induced type-2 myocardial infarction (MI)-like ischemic injury in the heart by treatment with a single high dose of the beta-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long term cardiac immunopathology and functional decline in wild type and Clec9a-depleted mice lacking DC cross-priming function.Results: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a -/- mice deficient in DC cross-priming are protected from long-term immune-mediated myocardial damage and decline of cardiac function, likely dueto dampened activation of cytotoxic CD8+ T cells.Conclusion: Activation of cytotoxic CD8+ T cells by cross-priming DC contributes to exacerbation of post-ischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent immune-mediated worsening of post-ischemic HF.
Pollock KG, Sekelj S, Johnston E, et al., 2020, Application of a machine learning algorithm for detection of atrial fibrillation in secondary care, IJC HEART & VASCULATURE, Vol: 31
Kim M-Y, Sandler B, Sikkel MB, et al., 2020, The ectopy-triggering ganglionated plexuses in atrial fibrillation, Autonomic Neuroscience, Vol: 228, ISSN: 1566-0702
BackgroundEpicardial ganglionated plexus (GP) have an important role in the pathogenesis of atrial fibrillation (AF). The relationship between anatomical, histological and functional effects of GP is not well known. We previously described atrioventricular (AV) dissociating GP (AVD-GP) locations. In this study, we hypothesised that “ET-GP” are upstream triggers of atrial ectopy/AF and have different anatomical distribution to AVD-GP.ObjectivesWe mapped and characterised ET-GP to understand their neural mechanism in AF and anatomical distribution in the left atrium (LA).Methods26 patients with paroxysmal AF were recruited. All were paced in the LA with an ablation catheter. HFS (80 ms) was synchronised to each paced stimulus (after 20 ms delay) for delivery within the local atrial refractory period. HFS responses were tagged onto CARTO™ 3D LA geometry. All geometries were transformed onto one reference LA shell. A probability distribution atlas of ET-GP was created. This identified high/low ET-GP probability regions.Results2302 sites were tested with HFS, identifying 579 (25%) ET-GP. 464 ET-GP were characterised, where 74 (16%) triggered ≥30s AF/AT. Median 97 (IQR 55) sites were tested, identifying 19 (20%) ET-GP per patient. >30% of ET-GP were in the roof, mid-anterior wall, around all PV ostia except in the right inferior PV (RIPV) in the posterior wall.ConclusionET-GP can be identified by endocardial stimulation and their anatomical distribution, in contrast to AVD-GP, would be more likely to be affected by wide antral circumferential ablation. This may contribute to AF ablation outcomes.
Keene D, Shun-Shin MJ, Arnold AD, et al., 2020, Within-patient comparison of His-bundle pacing, right ventricular pacing, and right ventricular pacing avoidance algorithms in patients with PR prolongation: Acute hemodynamic study, Journal of Cardiovascular Electrophysiology, Vol: 31, Pages: 2964-2974, ISSN: 1045-3873
AimsA prolonged PR interval may adversely affect ventricular filling and, therefore, cardiac function. AV delay can be corrected using right ventricular pacing (RVP), but this induces ventricular dyssynchrony, itself harmful. Therefore, in intermittent heart block, pacing avoidance algorithms are often implemented. We tested His‐bundle pacing (HBP) as an alternative.MethodsOutpatients with a long PR interval (>200 ms) and intermittent need for ventricular pacing were recruited. We measured within‐patient differences in high‐precision hemodynamics between AV‐optimized RVP and HBP, as well as a pacing avoidance algorithm (Managed Ventricular Pacing [MVP]).ResultsWe recruited 18 patients. Mean left ventricular ejection fraction was 44.3 ± 9%. Mean intrinsic PR interval was 266 ± 42 ms and QRS duration was 123 ± 29 ms. RVP lengthened QRS duration (+54 ms, 95% CI 42–67 ms, p < .0001) while HBP delivered a shorter QRS duration than RVP (−56 ms, 95% CI −67 to −46 ms, p < .0001). HBP did not increase QRS duration (−2 ms, 95% CI −8 to 13 ms, p = .6). HBP improved acute systolic blood pressure by mean of 5.0 mmHg (95% CI 2.8–7.1 mmHg, p < .0001) compared to RVP and by 3.5 mmHg (95% CI 1.9–5.0 mmHg, p = .0002) compared to the pacing avoidance algorithm. There was no significant difference in hemodynamics between RVP and ventricular pacing avoidance (p = .055).ConclusionsHBP provides better acute cardiac function than pacing avoidance algorithms and RVP, in patients with prolonged PR intervals. HBP allows normalization of prolonged AV delays (unlike pacing avoidance) and does not cause ventricular dyssynchrony (unlike RVP). Clinical trials may be justified to assess whether these acute
Brook J, Kim M-Y, Koutsoftidis S, et al., 2020, Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling, Pflügers Archiv European Journal of Physiology, Vol: 472, Pages: 1435-1446, ISSN: 0031-6768
We describe a human and large animal Langendorff experimental apparatus for live electrophysiological studies and measure the electrophysiological changes due to gap-junction uncoupling in human and porcine hearts. The resultant ex vivo intact human and porcine model can bridge the translational gap between smaller simple laboratory models and clinical research. In particular, electrophysiological models would benefit from the greater myocardial mass of a large heart due to its effects on far field signal, electrode contact issues and motion artefacts, consequently more closely mimicking the clinical setting Porcine (n=9) and human (n=4) donor hearts were perfused on a custom-designed Langendorff apparatus. Epicardial electrograms were collected at 16 sites across the left atrium and left ventricle. 1mM of carbenoxolone was administered at 5ml/min to induce cellular uncoupling, and then recordings were repeated at the same sites. Changes in electrogram characteristics were analysed.We demonstrate the viability of a controlled ex vivo model of intact porcine and human hearts for electrophysiology with pharmacological modulation. Carbenoxolone reduces cellular coupling and changes contact electrogram features. The time from stimulus artefact to (-dV/dt)max increased between baseline and carbenoxolone (47.9±4.1ms to 67.2±2.7ms) indicating conduction slowing. The features with the largest percentage change between baseline to Carbenoxolone were Fractionation +185.3%, Endpoint amplitude -106.9%, S-Endpoint Gradient +54.9%, S Point, -39.4%, RS Ratio +38.6% and (-dV/dt)max -20.9%.The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically-induced proarrhythmic substrates.
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