The Spatial Ventricular Gradient is Associated with Inducibility of Ventricular Arrhythmias During Electrophysiology Study.

BACKGROUND: Myocardial electrical heterogeneity is critical for normal cardiac electromechanical function, but abnormal/excessive electrical heterogeneity is proarrhythmic. The spatial ventricular gradient (SVG), a vectorcardiographic measure of electrical heterogeneity, has been associated with arrhythmic events over long-term follow-up, but its relationship with short-term inducibility of ventricular arrhythmias (VAs) is unclear. OBJECTIVE: Determine associations between SVG and inducible VAs during electrophysiology study (EPS). METHODS: Retrospective study of adults without prior sustained VA, cardiac arrest, or implantable cardioverter-defibrillator (ICD), who underwent ventricular stimulation for evaluation of syncope, non-sustained VT, and/or risk-stratification prior to primary prevention ICD implantation. 12-lead ECGs were converted into vectorcardiograms and SVG magnitude (SVGmag) and direction (azimuth and elevation) were calculated. Odds of inducible VA were regressed using logistic models. RESULTS: Among 143 patients (median age 66, 80% male, median LVEF 47%, 52% myocardial infarction), 34 (23.8%) had inducible VAs. Inducible patients had lower median LVEF (38 vs 50%, p<0.0001), smaller SVGmag (29.5 vs 39.4mV*ms, p=0.0099), and smaller cosine SVG azimuth (cosSVGaz) (0.64 vs 0.89, p=0.0007). When LVEF, SVGmag, and cosSVGaz were dichotomized at their medians, there was a 39-fold increase in adjusted odds (p=0.002) between patients with all low LVEF, SVGmag, and cosSVGaz (65% inducible), compared to patients with all high LVEF, SVGmag, and cosSVGaz (4% [n=1] inducible). After multivariable adjustment, SVGmag, cosSVGaz, and sex, but not LVEF or other characteristics, remained associated with inducible VAs. CONCLUSION: Assessment of electrical heterogeneity via SVG, which reflects abnormal electrophysiological substrate, adds to LVEF and identifies patients at high and low risk of inducible VA at EPS.

Noninvasive Techniques for Tracking Biological Aging of the Cardiovascular System: JACC Family Series.

Population aging is one of the most important demographic transformations of our time. Increasing the "health span"-the proportion of life spent in good health-is a global priority. Biological aging comprises molecular and cellular modifications over many years, which culminate in gradual physiological decline across multiple organ systems and predispose to age-related illnesses. Cardiovascular disease is a major cause of ill health and premature death in older people. The rate at which biological aging occurs varies across individuals of the same age and is influenced by a wide range of genetic and environmental exposures. The authors review the hallmarks of biological cardiovascular aging and their capture using imaging and other noninvasive techniques and examine how this information may be used to understand aging trajectories, with the aim of guiding individual- and population-level interventions to promote healthy aging.

Therapeutic potential of conduction system pacing as a method for improving cardiac output during ventricular tachycardia.

BACKGROUND: Ventricular tachycardia (VT) reduces cardiac output through high heart rates, loss of atrioventricular synchrony, and loss of ventricular synchrony. We studied the contribution of each mechanism and explored the potential therapeutic utility of His bundle pacing to improve cardiac output during VT. METHODS: Study 1 aimed to improve the understanding of mechanisms of harm during VT (using pacing simulated VT). In 23 patients with left ventricular impairment, we recorded continuous ECG and beat-by-beat blood pressure measurements. We assessed the hemodynamic impact of heart rate and restoration of atrial and biventricular synchrony. Study 2 investigated novel pacing interventions during clinical VT by evaluating the hemodynamic effects of His bundle pacing at 5 bpm above the VT rate in 10 patients. RESULTS: In Study 1, at progressively higher rates of simulated VT, systolic blood pressure declined: at rates of 125, 160, and 190 bpm, -22.2%, -42.0%, and -58.7%, respectively (ANOVA p < 0.0001). Restoring atrial synchrony alone had only a modest beneficial effect on systolic blood pressure (+ 3.6% at 160 bpm, p = 0.2117), restoring biventricular synchrony alone had a greater effect (+ 9.1% at 160 bpm, p = 0.242), and simultaneously restoring both significantly increased systolic blood pressure (+ 31.6% at 160 bpm, p = 0.0003). In Study 2, the mean rate of clinical VT was 143 ± 21 bpm. His bundle pacing increased systolic blood pressure by + 14.2% (p = 0.0023). In 6 of 10 patients, VT terminated with His bundle pacing. CONCLUSIONS: Restoring atrial and biventricular synchrony improved hemodynamic function in simulated and clinical VT. Conduction system pacing could improve VT tolerability and treatment.

Machine learning-derived cycle length variability metrics predict spontaneously terminating ventricular tachycardia in implantable cardioverter defibrillator recipients.

Aims: Implantable cardioverter defibrillator (ICD) therapies have been associated with increased mortality and should be minimized when safe to do so. We hypothesized that machine learning-derived ventricular tachycardia (VT) cycle length (CL) variability metrics could be used to discriminate between sustained and spontaneously terminating VT. Methods and results: In this single-centre retrospective study, we analysed data from 69 VT episodes stored on ICDs from 27 patients (36 spontaneously terminating VT, 33 sustained VT). Several VT CL parameters including heart rate variability metrics were calculated. Additionally, a first order auto-regression model was fitted using the first 10 CLs. Using features derived from the first 10 CLs, a random forest classifier was used to predict VT termination. Sustained VT episodes had more stable CLs. Using data from the first 10 CLs only, there was greater CL variability in the spontaneously terminating episodes (mean of standard deviation of first 10 CLs: 20.1 ± 8.9 vs. 11.5 ± 7.8 ms, P < 0.0001). The auto-regression coefficient was significantly greater in spontaneously terminating episodes (mean auto-regression coefficient 0.39 ± 0.32 vs. 0.14 ± 0.39, P < 0.005). A random forest classifier with six features yielded an accuracy of 0.77 (95% confidence interval 0.67 to 0.87) for prediction of VT termination. Conclusion: Ventricular tachycardia CL variability and instability are associated with spontaneously terminating VT and can be used to predict spontaneous VT termination. Given the harmful effects of unnecessary ICD shocks, this machine learning model could be incorporated into ICD algorithms to defer therapies for episodes of VT that are likely to self-terminate.

Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations.

AIMS: Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations. METHODS AND RESULTS: Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations. CONCLUSION: These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy.

Using genetic techniques to mimic the effects of PCSK9-inhibitors, a group of lipid-lowering medications, this study provides evidence to support recommendations to avoid the use of these medications in pregnancy due to potential risk of multiple malformations in the newborn. This study provides genetic evidence to support potential associations of PCSK9-inhibitor medications with newborn malformations affecting multiple organ systems, the skin, and a cluster of structural defects simultaneously affecting the spine, anus/rectum, heart, throat, kidneys, arms and legs.There was also weaker evidence of an association of PCSK9-inhibitor medications with newborn malformations resulting in blockages of the kidneys and urine system, though the evidence was less certain for these than for the other malformations.

Characterization of conduction system activation in the postinfarct ventricle using ripple mapping.

BACKGROUND: Three-dimensional (3D) mapping of the ventricular conduction system is challenging. OBJECTIVE: The purpose of this study was to use ripple mapping to distinguish conduction system activation to that of adjacent myocardium in order to characterize the conduction system in the postinfarct left ventricle (LV). METHODS: High-density mapping (PentaRay, CARTO) was performed during normal rhythm in patients undergoing ventricular tachycardia ablation. Ripple maps were viewed from the end of the P wave to QRS onset in 1-ms increments. Clusters of >3 ripple bars were interrogated for the presence of Purkinje potentials, which were tagged on the 3D geometry. Repeating this process allowed conduction system delineation. RESULTS: Maps were reviewed in 24 patients (mean 3112 ± 613 points). There were 150.9 ± 24.5 Purkinje potentials per map, at the left posterior fascicle (LPF) in 22 patients (92%) and at the left anterior fascicle (LAF) in 15 patients (63%). The LAF was shorter (41.4 vs 68.8 mm; P = .0005) and activated for a shorter duration (40.6 vs 64.9 ms; P = .002) than the LPF. Fourteen of 24 patients had left bundle branch block (LBBB), with 11 of 14 (78%) having Purkinje potential-associated breakout. There were fewer breakouts from the conduction system during LBBB (1.8 vs 3.4; 1.6 ± 0.6; P = .039) and an inverse correlation between breakout sites and QRS duration (P = .0035). CONCLUSION: We applied ripple mapping to present a detailed electroanatomic characterization of the conduction system in the postinfarct LV. Patients with broader QRS had fewer LV breakout sites from the conduction system. However, there was 3D mapping evidence of LV breakout from an intact conduction system in the majority of patients with LBBB.

Birth weight influences cardiac structure, function, and disease risk: evidence of a causal association.

BACKGROUND AND AIMS: Low birth weight is a common pregnancy complication, which has been associated with higher risk of cardiometabolic disease in later life. Prior Mendelian randomization (MR) studies exploring this question do not distinguish the mechanistic contributions of variants that directly influence birth weight through the foetal genome (direct foetal effects), vs. variants influencing birth weight indirectly by causing an adverse intrauterine environment (indirect maternal effects). In this study, MR was used to assess whether birth weight, independent of intrauterine influences, is associated with cardiovascular disease risk and measures of adverse cardiac structure and function. METHODS: Uncorrelated (r2 < .001), genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms were extracted from genome-wide association studies summary statistics for birth weight overall, and after isolating direct foetal effects only. Inverse-variance weighted MR was utilized for analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 16 measures of cardiac structure and function. Multiple comparisons were accounted for by Benjamini-Hochberg correction. RESULTS: Lower genetically-predicted birth weight, isolating direct foetal effects only, was associated with an increased risk of coronary artery disease (odds ratio 1.21, 95% confidence interval 1.06-1.37; P = .031), smaller chamber volumes, and lower stroke volume, but higher contractility. CONCLUSIONS: The results of this study support a causal role of low birth weight in cardiovascular disease, even after accounting for the influence of the intrauterine environment. This suggests that individuals with a low birth weight may benefit from early targeted cardiovascular disease prevention strategies, independent of whether this was linked to an adverse intrauterine environment during gestation.

Left bundle branch pacing with and without anodal capture: impact on ventricular activation pattern and acute haemodynamics.

AIMS: Left bundle branch pacing (LBBP) can deliver physiological left ventricular activation, but typically at the cost of delayed right ventricular (RV) activation. Right ventricular activation can be advanced through anodal capture, but there is uncertainty regarding the mechanism by which this is achieved, and it is not known whether this produces haemodynamic benefit. METHODS AND RESULTS: We recruited patients with LBBP leads in whom anodal capture eliminated the terminal R-wave in lead V1. Ventricular activation pattern, timing, and high-precision acute haemodynamic response were studied during LBBP with and without anodal capture. We recruited 21 patients with a mean age of 67 years, of whom 14 were males. We measured electrocardiogram timings and haemodynamics in all patients, and in 16, we also performed non-invasive mapping. Ventricular epicardial propagation maps demonstrated that RV septal myocardial capture, rather than right bundle capture, was the mechanism for earlier RV activation. With anodal capture, QRS duration and total ventricular activation times were shorter (116 ± 12 vs. 129 ± 14 ms, P < 0.01 and 83 ± 18 vs. 90 ± 15 ms, P = 0.01). This required higher outputs (3.6 ± 1.9 vs. 0.6 ± 0.2 V, P < 0.01) but without additional haemodynamic benefit (mean difference -0.2 ± 3.8 mmHg compared with pacing without anodal capture, P = 0.2). CONCLUSION: Left bundle branch pacing with anodal capture advances RV activation by stimulating the RV septal myocardium. However, this requires higher outputs and does not improve acute haemodynamics. Aiming for anodal capture may therefore not be necessary.

Information theory-based direct causality measure to assess cardiac fibrillation dynamics.

Understanding the mechanism sustaining cardiac fibrillation can facilitate the personalization of treatment. Granger causality analysis can be used to determine the existence of a hierarchical fibrillation mechanism that is more amenable to ablation treatment in cardiac time-series data. Conventional Granger causality based on linear predictability may fail if the assumption is not met or given sparsely sampled, high-dimensional data. More recently developed information theory-based causality measures could potentially provide a more accurate estimate of the nonlinear coupling. However, despite their successful application to linear and nonlinear physical systems, their use is not known in the clinical field. Partial mutual information from mixed embedding (PMIME) was implemented to identify the direct coupling of cardiac electrophysiology signals. We show that PMIME requires less data and is more robust to extrinsic confounding factors. The algorithms were then extended for efficient characterization of fibrillation organization and hierarchy using clinical high-dimensional data. We show that PMIME network measures correlate well with the spatio-temporal organization of fibrillation and demonstrated that hierarchical type of fibrillation and drivers could be identified in a subset of ventricular fibrillation patients, such that regions of high hierarchy are associated with high dominant frequency.

Genetically predicted androgenic profiles and adverse cardiac markers: a sex-specific Mendelian randomization study.

AIMS: Observational evidence suggests associations between sex hormone levels and heart failure (HF). We used sex-specific genetic variants associated with androgenic sex hormone profiles to investigate the causal relevance of androgenic sex hormone profiles on cardiac structure and function and HF using Mendelian randomization (MR). METHODS AND RESULTS: Sex-specific uncorrelated genome-wide significant (P < 5 × 10-8 ) variants predicting sex hormone-binding globulin (SHBG), total testosterone, and bioavailable testosterone were extracted from summary statistics of genome-wide association study (GWAS) on 425 097 participants in the UK Biobank. Sex-specific gene-outcome association estimates were computed for left ventricular ejection fraction (LVEF), left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV, respectively), left ventricular stroke volume (LVSV), cardiac index, and cardiac output in 11 528 female and 14 356 male UK Biobank Imaging Study participants and for incident or prevalent HF in an external cohort of 47 309 cases and 930 014 controls. Inverse-variance weighted MR was the primary analysis method. In females, higher genetically predicted bioavailable testosterone was associated with lower LVEDV [ß per nmol/L = -0.11 (-0.19 to -0.03), P = 0.006], lower LVESV [ß = -0.09 (-0.17 to -0.01), P = 0.022], lower LVSV [ß = -0.11 (-0.18 to -0.03), P = 0.005], lower cardiac output [ß = -0.08 (-0.16 to 0.00), P = 0.046], and lower cardiac index [ß = -0.08 (-0.16 to -0.01), P = 0.034] and a higher risk of HF [odds ratio 1.10 (1.01-1.19), P = 0.026] on external validation analysis in larger scale, sex-adjusted GWAS data. Higher genetically predicted SHBG was associated with higher LVEDV [ß per nmol/L = 0.17 (0.08-0.25), P = 2 × 10-4 ], higher LVESV [ß = 0.13 (0.05-0.22), P = 0.003], and higher LVSV [ß = 0.18 (0.08-0.28), P = 2 × 10-4 ]. In males, higher genetically predicted total and bioavailable testosterone was associated with lower LVESV [ß = -0.07 (-0.12 to -0.02), P = 0.007] and LVEF [ß = -0.11 (-0.18 to -0.04), P = 0.003], respectively. CONCLUSIONS: This study supports a causal effect of pro-androgenic sex hormone profiles in females on adverse markers of left ventricular structure and function typically associated with HF with preserved ejection fraction and with HF. There was weaker evidence of association in males.

Nanopore sequencing of DNA-barcoded probes for highly multiplexed detection of microRNA, proteins and small biomarkers.

There is an unmet need to develop low-cost, rapid and highly multiplexed diagnostic technology platforms for quantitatively detecting blood biomarkers to advance clinical diagnostics beyond the single biomarker model. Here we perform nanopore sequencing of DNA-barcoded molecular probes engineered to recognize a panel of analytes. This allows for highly multiplexed and simultaneous quantitative detection of at least 40 targets, such as microRNAs, proteins and neurotransmitters, on the basis of the translocation dynamics of each probe as it passes through a nanopore. Our workflow is built around a commercially available MinION sequencing device, offering a one-hour turnaround time from sample preparation to results. We also demonstrate that the strategy can directly detect cardiovascular disease-associated microRNA from human serum without extraction or amplification. Due to the modularity of barcoded probes, the number and type of targets detected can be significantly expanded.

Limits of the spatial ventricular gradient and QRST angles in patients with normal electrocardiograms and no known cardiovascular disease stratified by age, sex, and race.

INTRODUCTION: Measurement of the spatial ventricular gradient (SVG), spatial QRST angles, and other vectorcardiographic measures of myocardial electrical heterogeneity have emerged as novel risk stratification methods for sudden cardiac death and other adverse cardiovascular events. Prior studies of normal limits of these measurements included primarily young, healthy, White volunteers, but normal limits in older patients are unknown. The influence of race and body mass index (BMI) on these measurements is also unclear. METHODS: Normal 12-lead electrocardiograms (ECGs) from a single center were identified. Patients with abnormal cardiovascular, pulmonary, or renal history (assessed by International Classification of Disease [ICD-9/ICD-10] codes) or abnormal cardiovascular imaging were excluded. The SVG and QRST angles were measured and stratified by age, sex, and race. Multivariable linear regression was used to assess the influence of age, BMI, and heart rate (HR) on these measurements. RESULTS: Among 3292 patients, observed ranges of SVG and QRST angles (peak and mean) differed significantly based on sex, age, and race. Sex differences attenuated with increasing age. Men tended to have larger SVG magnitude (60.4 [46.1-77.8] vs. 52.5 [41.3-65.8] mv*ms, p < .0001) and elevation, and more anterior/negative SVG azimuth (-14.8 [-25.1 to -4.3] vs. 1.3 [-9.8 to 10.5] deg, p < .0001) compared to women. Men also had wider QRST angles. Observed ranges varied significantly with BMI and HR. SVG and QRST angle measurements were robust to different filtering bandwidths and moderate fiducial point annotation errors, but were heavily affected by changes in baseline correction. CONCLUSIONS: Age, sex, race, BMI, and HR significantly affect the range of SVG and QRST angles in patients with normal ECGs and no known cardiovascular disease, and should be accounted for in future studies. An online calculator for prediction of these "normal limits" given demographics is provided at https://bivectors.github.io/gehcalc/.

Temporal Trends and Lesion Sets for Persistent Atrial Fibrillation Ablation: A Meta-Analysis With Trial Sequential Analysis and Meta-Regression.

BACKGROUND: Ablation for persistent atrial fibrillation (PsAF) has been performed for over 20 years, although success rates have remained modest. Several adjunctive lesion sets have been studied but none have become standard of practice. We sought to describe how the efficacy of ablation for PsAF has evolved in this time period with a focus on the effect of adjunctive ablation strategies. METHODS: Databases were searched for prospective studies of PsAF ablation. We performed meta-regression and trial sequential analysis. RESULTS: A total of 99 studies (15 424 patients) were included. Ablation for PsAF achieved the primary outcome (freedom of atrial fibrillation/atrial tachycardia rate at 12 months follow-up) in 48.2% (5% CI, 44.0-52.3). Meta-regression showed freedom from atrial arrhythmia at 12 months has improved over time, while procedure time and fluoroscopy time have significantly reduced. Through the use of cumulative meta-analyses and trial sequential analysis, we show that some ablation strategies may initially seem promising, but after several randomized controlled trials may be found to be ineffective. Trial sequential analysis showed that complex fractionated atrial electrogram ablation is ineffective and further study of this treatment would be futile, while posterior wall isolation currently does not have sufficient evidence for routine use in PsAF ablation. CONCLUSIONS: Overall success rates from PsAF ablation and procedure/fluoroscopy times have improved over time. However, no adjunctive lesion set, in addition to pulmonary vein isolation, has been conclusively demonstrated to be beneficial. Through the use of trial sequential analysis, we highlight the importance of adequately powered randomized controlled trials, to avoid reaching premature conclusions, before widespread adoption of novel therapies.

Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization.

Background Observational associations between type 2 diabetes (T2D) and atrial fibrillation (AF) have been established, but causality remains undetermined. We performed Mendelian randomization (MR) to study causal effects of genetically predicted T2D on AF risk, independent of cardiometabolic risk factors. Methods and Results Instrumental variables included 182 uncorrelated single nucleotide polymorphisms associated with T2D at genome-wide significance (P <5×10-8). Genetic association estimates for cardiometabolic exposures were obtained from genome-wide association studies including 188 577 individuals for low-density lipoprotein-C, 694 649 individuals for body mass index, and 757 601 for systolic blood pressure. Two-sample, inverse-variance weighted MR formed the primary analyses. The MR-TRYX approach was used to dissect potential pleiotropic pathways, with multivariable MR performed to investigate cardiometabolic mediation. Genetically predicted T2D associated with increased AF liability in univariable MR (odds ratio [OR], 1.08 [95% CI, 1.02-1.13], P=0.003). Sensitivity analyses indicated potential pleiotropy, with radial MR identifying 4 outlier single nucleotide polymorphisms that were likely contributors. Phenomic scanning on MR-base and subsequent least absolute shrinkage and selection operator regression allowed prioritization of 7 candidate traits. The outlier-adjusted effect estimate remained consistent with the original inverse-variance weighted estimate (OR, 1.07 [95% CI, 1.02-1.12], P=0.008). On multivariable MR, T2D remained associated with increased AF liability after adjustment for low-density lipoprotein-C and body mass index. Following adjustment for systolic blood pressure, the relationship between T2D and AF became nonsignificant (OR, 1.04 [95% CI, 0.95-1.13], P=0.40). Conclusions These data provide novel genetic evidence that while T2D likely causally associates with AF, mediation via systolic blood pressure exists. Endeavoring to lower systolic blood pressure alongside achieving normoglycemia may provide particular benefit on AF risk in patients with T2D.

Multiple anthropometric measures and proarrhythmic 12-lead ECG indices: A mendelian randomization study.

BACKGROUND: Observational studies suggest that electrocardiogram (ECG) indices might be influenced by obesity and other anthropometric measures, though it is difficult to infer causal relationships based on observational data due to risk of residual confounding. We utilized mendelian randomization (MR) to explore causal relevance of multiple anthropometric measures on P-wave duration (PWD), PR interval, QRS duration, and corrected QT interval (QTc). METHODS AND FINDINGS: Uncorrelated (r2 < 0.001) genome-wide significant (p < 5 × 10-8) single nucleotide polymorphisms (SNPs) were extracted from genome-wide association studies (GWAS) on body mass index (BMI, n = 806,834), waist:hip ratio adjusted for BMI (aWHR, n = 697,734), height (n = 709,594), weight (n = 360,116), fat mass (n = 354,224), and fat-free mass (n = 354,808). Genetic association estimates for the outcomes were extracted from GWAS on PR interval and QRS duration (n = 180,574), PWD (n = 44,456), and QTc (n = 84,630). Data source GWAS studies were performed between 2018 and 2022 in predominantly European ancestry individuals. Inverse-variance weighted MR was used for primary analysis; weighted median MR and MR-Egger were used as sensitivity analyses. Higher genetically predicted BMI was associated with longer PWD (ß 5.58; 95%CI [3.66,7.50]; p = < 0.001), as was higher fat mass (ß 6.62; 95%CI [4.63,8.62]; p < 0.001), fat-free mass (ß 9.16; 95%CI [6.85,11.47]; p < 0.001) height (ß 4.23; 95%CI [3.16, 5.31]; p < 0.001), and weight (ß 8.08; 95%CI [6.19,9.96]; p < 0.001). Finally, genetically predicted BMI was associated with longer QTc (ß 3.53; 95%CI [2.63,4.43]; p < 0.001), driven by both fat mass (ß 3.65; 95%CI [2.73,4.57]; p < 0.001) and fat-free mass (ß 2.08; 95%CI [0.85,3.31]; p = 0.001). Additionally, genetically predicted height (ß 0.98; 95%CI [0.46,1.50]; p < 0.001), weight (ß 3.45; 95%CI [2.54,4.36]; p < 0.001), and aWHR (ß 1.92; 95%CI [0.87,2.97]; p = < 0.001) were all associated with longer QTc. The key limitation is that due to insufficient power, we were not able to explore whether a single anthropometric measure is the primary driver of the associations observed. CONCLUSIONS: The results of this study support a causal role of BMI on multiple ECG indices that have previously been associated with atrial and ventricular arrhythmic risk. Importantly, the results identify a role of both fat mass, fat-free mass, and height in this association.

Septal scar as a barrier to left bundle branch area pacing.

BACKGROUND: The use of left bundle branch area pacing (LBBAP) for bradycardia pacing and cardiac resynchronization is increasing, but implants are not always successful. We prospectively studied consecutive patients to determine whether septal scar contributes to implant failure. METHODS: Patients scheduled for bradycardia pacing or cardiac resynchronization therapy were prospectively enrolled. Recruited patients underwent preprocedural scar assessment by cardiac MRI with late gadolinium enhancement imaging. LBBAP was attempted using a lumenless lead (Medtronic 3830) via a transeptal approach. RESULTS: Thirty-five patients were recruited: 29 male, mean age 68 years, 10 ischemic, and 16 non-ischemic cardiomyopathy. Pacing indication was bradycardia in 26% and cardiac resynchronization in 74%. The lead was successfully deployed to the left ventricular septum in 30/35 (86%) and unsuccessful in the remaining 5/35 (14%). Septal late gadolinium enhancement was significantly less extensive in patients where left septal lead deployment was successful, compared those where it was unsuccessful (median 8%, IQR 2%-18% vs. median 54%, IQR 53%-57%, p < .001). CONCLUSIONS: The presence of septal scar appears to make it more challenging to deploy a lead to the left ventricular septum via the transeptal route. Additional implant tools or alternative approaches may be required in patients with extensive septal scar.

Maternal hypertensive traits and adverse outcome in pregnancy: a Mendelian randomization study.

INTRODUCTION: Hypertensive disorders of pregnancy are associated with adverse feto-maternal outcomes. Existing evidence is mostly limited to observational studies, which are liable to confounding and bias. This study investigated the causal relevance of component hypertensive indices on multiple adverse pregnancy outcomes using Mendelian randomization. METHODS: Uncorrelated ( r2  < 0.001) genome-wide significant ( P  < 5 × 10 -8 ) single-nucleotide polymorphisms associated with SBP, DBP and pulse pressure (PP) were selected as instrumental variables. Genetic association estimates for outcomes of preeclampsia or eclampsia, preterm birth, placental abruption and hemorrhage in early pregnancy were extracted from summary statistics of genome-wide association studies in the FinnGen cohort. Two-sample, inverse-variance weighted Mendelian randomization formed the primary analysis method. Odds ratios (OR) are presented per-10 mmHg higher genetically predicted hypertensive index. RESULTS: Higher genetically predicted SBP were associated with higher odds of preeclampsia or eclampsia [OR 1.81, 95% confidence interval (CI) 1.68-1.96, P  = 5.45 × 10 -49 ], preterm birth (OR 1.09, 95% CI 1.03-1.16, P  = 0.005) and placental abruption (OR 1.33, 95% CI 1.05-1.68, P  = 0.016). Higher genetically-predicted DBP was associated with preeclampsia or eclampsia (OR 2.54, 95% CI 2.21-2.92, P  = 5.35 × 10 -40 ). Higher genetically predicted PP was associated with preeclampsia or eclampsia (OR 1.68, 95% CI 1.47-1.92, P  = 1.9 × 10 -14 ) and preterm birth (OR 1.18, 95% CI 1.06-1.30, P  = 0.002). CONCLUSION: This study provides genetic evidence to support causal associations of SBP, DBP and PP on multiple adverse outcomes of pregnancy. SBP and PP were associated with the broadest range of adverse outcomes, suggesting that optimized management of blood pressure, particularly SBP, is a key priority to improve feto-maternal health.