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The Shock Academic Research Consortium is a multi-stakeholder group, including representatives from the US Food and Drug Administration and other government agencies, industry, and payers, convened to develop pragmatic consensus definitions useful for the evaluation of clinical trials enrolling patients with cardiogenic shock, including trials evaluating mechanical circulatory support devices. Several in-person and virtual meetings were convened between 2020 and 2022 to discuss the need for developing the standardized definitions required for evaluation of mechanical circulatory support devices in clinical trials for cardiogenic shock patients. The expert panel identified key concepts and topics by performing literature reviews, including previous clinical trials, while recognizing current challenges and the need to advance evidence-based practice and statistical analysis to support future clinical trials. For each category, a lead (primary) author was assigned to perform a literature search and draft a proposed definition, which was presented to the subgroup. These definitions were further modified after feedback from the expert panel meetings until a consensus was reached. This manuscript summarizes the expert panel recommendations focused on outcome definitions, including efficacy and safety., Competing Interests: Disclosures Dr Waksman reports serving on the advisory boards of Abbott Vascular, Boston Scientific, Medtronic, Philips IGT, and Pi-Cardia Ltd.; consulting for Abbott Vascular, Biotronik, Boston Scientific, Cordis, Medtronic, Philips IGT, Pi-Cardia Ltd., Swiss Interventional Systems/SIS Medical AG, Transmural Systems Inc., and Venous MedTech; receiving institutional grant support from Amgen, Biotronik, Boston Scientific, Chiesi, Medtronic, and Philips IGT; and investing in MedAlliance and Transmural Systems Inc. Dr Morrow is a member of the Thrombolysis in Myocardial Infarction Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, and Zora Biosciences. Dr Morrow has received consulting fees from Abbott Laboratories, ARCA Biopharma, Inflammatix, Merck & Co., Novartis, and Roche Diagnostics. Dr Spitzer reports institutional contracts for which he receives no direct compensation with Boston Scientific, Cardiawave, Edwards Lifesciences, Medtronic, Occlutech US, LLC, Shanghai Microport Medical Co. Ltd., NVT GmBH, Pie Medical Imaging, Siemens Healthcare GmBH. Dr Dickert receives research funding from the National Institutes of Health’s Agency for Healthcare Research and Quality and Data Safety Monitoring Board service for National Institutes of Health and Patient-Centered Outcomes Research Institute–funded studies. Dr Dickert reports consulting for and research funding from Abiomed, Inc. Dr Mebaaza reports receiving research grants, consulting, and receiving speaker fees from Roche Diagnostics and receiving speaker fees from Merck. Dr Fan reports personal fees from ALung Technologies, Aerogen, Baxter, GE Healthcare, Inspira, Vasomune, and Zoll Medical outside the submitted work. Dr Kormos is an employee (Division Vice President Global Medical Affairs Heart Failure) of Abbott Laboratories. Dr Proudfoot has received institutional funding from Abbott Vascular and BD Biosciences, all outside of the submitted work. Dr Simonton is an employee (Chief Medical Officer) of Abiomed, a Johnson & Johnson Company. Dr Damluji received a mentored patient-oriented research career development award from the National Heart, Lung, and Blood Institute (K23-HL153771-01). Dr Cutlip reports consulting for and research funding from Corvia Medical, MedAlliance, and Abiomed. Dr Nichol reports salary support from Medic One Foundation via the University of Washington; research funding from National Institutes of Health, Centers for Disease Control and Prevention, Abiomed Inc, Zoll Medical, RCE Technologies Inc., Zoll Circulation Inc., and Vapotherm Inc; and consulting for BrainCool AB, CPR Therapeutics Inc., Heartbeam Inc., Invero Health LLC, Kestra Medical Technologies Inc., and Orixha Inc.

Background: Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs)., Methods: Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score., Results: Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P =0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P <0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001)., Conclusions: In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk., Competing Interests: Disclosures R.A. is involved in research funded by the Bristol Myers Squibb-Pfizer alliance and a consultant for Lexicon Pharmaceuticals. C.R. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, and Zora Biosciences. Through his institution, he receives research grant support from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis. He receives honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, and Pfizer. A.K.K. reports research grants from Bayer Pharma AG and Sanofi. He reports personal fees from Anthos Therapeutics, Bayer Pharma AG, and Sanofi SA. M.P. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Woman’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, Softcell Medical Limited, The Medicines Company, and Zora Biosciences. D.E.S. has received research grants from Bristol Myers Squibb and has consulting agreements with Bristol Myers Squibb, Fitbit, Medtronic, and Pfizer. E.A.S. reports the following research grants to Beth Israel Deaconess Medical Center: National Institutes of Health/National Heart, Lung, and Blood Institute, Food and Drug Administration, BD, Boston Scientific, Cook, CSI, Laminate Medical, Medtronic, and Philips. He also endorses consulting/speaking with Abbott, Bayer, BD, Boston Scientific, Cook, Cordis, CSI, Inari, Medtronic, Philips, Shockwave, and VentureMed. J.P.P. receives grants for clinical research from Abbott, American Heart Association, Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips; and serves as a consultant to Abbott, Abbvie, Ablacon, Altathera, Biotronik, Boston Scientific, Bristol Myers Squibb, LivaNova, Medtronic, Milestone, ElectroPhysiology Frontiers, Pfizer, Sanofi, Philips, and Up-to-Date. C.S. reports that he is an employee of Biogen and owns Biogen stocks. R.W.Y. reports grants and consulting fees from Abbott Vascular, Boston Scientific, and Medtronic. The other authors report no conflicts.

Background: Whether genetics contribute to the rising prevalence of obesity or its cardiovascular consequences in today's obesogenic environment remains unclear. We sought to determine whether the effects of a higher aggregate genetic burden of obesity risk on body mass index (BMI) or cardiovascular disease (CVD) differed by birth year., Methods: We split the FHS (Framingham Heart Study) into 4 equally sized birth cohorts (birth year before 1932, 1932 to 1946, 1947 to 1959, and after 1960). We modeled a genetic predisposition to obesity using an additive genetic risk score (GRS) of 941 BMI-associated variants and tested for GRS-birth year interaction on log-BMI (outcome) when participants were around 50 years old (N=7693). We repeated the analysis using a GRS of 109 BMI-associated variants that increased CVD risk factors (type 2 diabetes, blood pressure, total cholesterol, and high-density lipoprotein) in addition to BMI. We then evaluated whether the effects of the BMI GRSs on CVD risk differed by birth cohort when participants were around 60 years old (N=5493)., Results: Compared with participants born before 1932 (mean age, 50.8 yrs [2.4]), those born after 1960 (mean age, 43.3 years [4.5]) had higher BMI (median, 25.4 [23.3-28.0] kg/m 2 versus 26.9 [interquartile range, 23.7-30.6] kg/m 2 ). The effect of the 941-variant BMI GRS on BMI and CVD risk was stronger in people who were born in later years (GRS-birth year interaction: P =0.0007 and P =0.04 respectively)., Conclusions: The significant GRS-birth year interactions indicate that common genetic variants have larger effects on middle-age BMI and CVD risk in people born more recently. These findings suggest that the increasingly obesogenic environment may amplify the impact of genetics on the risk of obesity and possibly its cardiovascular consequences.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources., Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations., Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis., Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Background: Differences in patient characteristics, changes in treatment algorithms, and advances in medical technology could each influence the applicability of older randomized trial results to contemporary clinical practice. The DAPT Study (Dual Antiplatelet Therapy) found that longer-duration DAPT decreased ischemic events at the expense of greater bleeding, but subsequent evolution in stent technology and clinical practice may attenuate the benefit of prolonged DAPT in a contemporary population. We evaluated whether the DAPT Study population is different from a contemporary population of US patients receiving percutaneous coronary intervention and estimated the treatment effect of extended-duration antiplatelet therapy after percutaneous coronary intervention in this more contemporary cohort., Methods: We compared the characteristics of drug-eluting stent-treated patients randomly assigned in the DAPT Study to a sample of more contemporary drug-eluting stent-treated patients in the National Cardiovascular Data Registry CathPCI Registry from July 2016 to June 2017. After linking trial and registry data, we used inverse-odds of trial participation weighting to account for patient and procedural characteristics and estimated a contemporary real-world treatment effect of 30 versus 12 months of DAPT after coronary stent procedures., Results: The US drug-eluting stent-treated trial cohort included 8864 DAPT Study patients, and the registry cohort included 568 540 patients. Compared with the trial population, registry patients had more comorbidities and were more likely to present with myocardial infarction and receive 2nd-generation drug-eluting stents. After reweighting trial results to represent the registry population, there was no longer a significant effect of prolonged DAPT on reducing stent thrombosis (reweighted treatment effect: -0.40 [95% CI, -0.99% to 0.15%]), major adverse cardiac and cerebrovascular events (reweighted treatment effect, -0.52 [95% CI, -2.62% to 1.03%]), or myocardial infarction (reweighted treatment effect, -0.97% [95% CI, -2.75% to 0.18%]), but the increase in bleeding with prolonged DAPT persisted (reweighted treatment effect, 2.42% [95% CI, 0.79% to 3.91%])., Conclusions: The differences between the patients and devices used in contemporary clinical practice compared with the DAPT Study were associated with the attenuation of benefits and greater harms attributable to prolonged DAPT duration. These findings limit the applicability of the average treatment effects from the DAPT Study in modern clinical practice.

Background: Marketing payments from the pharmaceutical industry to physicians have come under scrutiny due to their potential to influence clinical decision-making. Two proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) were approved by the US Food and Drug Administration in 2015 for reducing low-density lipoprotein cholesterol in high-risk patients, but their initial uptake was limited due to their high-cost and stringent prior authorization requirements. We sought to investigate the association between industry marketing and early adoption of PCSK9i among US physicians., Methods: We used nationwide databases of primary care physicians, cardiologists, and endocrinologists treating Medicare beneficiaries to examine the association between PCSK9i-related marketing payments in 2016 and the number of filled PCSK9i prescriptions in 2017, after adjusting for physician characteristics. In subgroup analyses, we stratified our analyses by physician specialty and prior experience with prescribing PCSK9i., Results: Among 209 840 physicians included in this analysis, 49 341 (24%) physicians received 292 941 PCSK9i-related marketing payments in 2016. The total value of these payments was $19 million, with a median payment of $61 per physician (interquartile range, $25-$132). Most payments (95%) were for meals, with a median of $14 per meal. The receipt of PCSK9i-related payments in 2016 was associated with increased PCSK9i prescription in 2017 (adjusted risk ratio, 3.18 [95% CI, 2.95-3.42]). This association was larger among primary care physicians (adjusted risk ratio, 6.67 [95% CI, 5.87-7.57]) than cardiologists (adjusted risk ratio, 2.00 [95% CI, 1.84-2.16]) and endocrinologists (adjusted risk ratio, 4.06 [95% CI, 2.95-5.59]). The association was observed across all types of payments., Conclusions: At a time when few physicians had experience with prescribing PCSK9i under strict prior authorization requirements, industry marketing payments to physicians for PCSK9i, predominantly in the form of meals, were associated with increased PCSK9i prescription in the subsequent year.

Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D)., Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D)., Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background., Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.

Background: Calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in CALM1 resulting in a p.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying the N98S mutation knocked into Calm1 replicate the human arrhythmia phenotype and to examine arrhythmia mechanisms., Methods: Mouse lines heterozygous for the Calm1 N98S allele (Calm1 N98S/+ ) were generated using CRISPR/Cas9 technology. Adult mutant mice and their wildtype littermates (Calm1 +/+ ) underwent electrocardiographic monitoring. Ventricular de- and repolarization was assessed in isolated hearts using optical voltage mapping. Action potentials and whole-cell currents and [Ca 2+ ] i , as well, were measured in single ventricular myocytes using the patch-clamp technique and fluorescence microscopy, respectively. The microelectrode technique was used for in situ membrane voltage monitoring of ventricular conduction fibers., Results: Two biologically independent knock-in mouse lines heterozygous for the Calm1 N98S allele were generated. Calm1 N98S/+ mice of either sex and line exhibited sinus bradycardia, QT c interval prolongation, and catecholaminergic bidirectional ventricular tachycardia. Male mutant mice also showed QRS widening. Pharmacological blockade and activation of β-adrenergic receptors rescued and exacerbated, respectively, the long-QT phenotype of Calm1 N98S/+ mice. Optical and electric assessment of membrane potential in isolated hearts and single left ventricular myocytes, respectively, revealed β-adrenergically induced delay of repolarization. β-Adrenergic stimulation increased peak density, slowed inactivation, and left-shifted the activation curve of I Ca.L significantly more in Calm1 N98S/+ versus Calm1 +/+ ventricular myocytes, increasing late I Ca.L in the former. Rapidly paced Calm1 N98S/+ ventricular myocytes showed increased propensity to delayed afterdepolarization-induced triggered activity, whereas in situ His-Purkinje fibers exhibited increased susceptibility for pause-dependent early afterdepolarizations. Epicardial mapping of Calm1 N98S/+ hearts showed that both reentry and focal mechanisms contribute to arrhythmogenesis., Conclusions: Heterozygosity for the Calm1 N98S mutation is causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTc interval prolongation, and bidirectional ventricular tachycardia. β-Adrenergically induced I Ca.L dysregulation contributes to the long-QT phenotype. Pause-dependent early afterdepolarizations and tachycardia-induced delayed afterdepolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constitute potential sources of arrhythmia in Calm1 N98S/+ hearts.

Propensity score-based methods or multiple regressions of the outcome are often used for confounding adjustment in analysis of observational studies. In either approach, a model is needed: A model describing the relationship between the treatment assignment and covariates in the propensity score-based method or a model for the outcome and covariates in the multiple regressions. The 2 models are usually unknown to the investigators and must be estimated. The correct model specification, therefore, is essential for the validity of the final causal estimate. We describe in this article a doubly robust estimator which combines both models propitiously to offer analysts 2 chances for obtaining a valid causal estimate and demonstrate its use through a data set from the Lindner Center Study.

Background: The risk of death or appropriate therapy varies widely among recipients of implantable cardioverter-defibrillators (ICDs). The goals of this study were to develop a risk prediction tool that jointly considers future outcome probabilities of ICD shock and death., Methods and Results: We performed a secondary analysis of patients receiving ICDs as part of the SCD-HeFT trial (Sudden Cardiac Death in Heart Failure Trial). We applied an illness-death regression model to jointly model both ICD shocks and death under the semi-competing risks framework, which predicts for each patient their probability of having received ICD shocks, dying, or both at any given point in time. Among 803 ICD recipients (mean age, 60 years; 23% women) followed for a median of 41.1 months, 430 (53.5%) patients completed the study without dying or receiving an ICD shock, 206 (25.7%) received at least 1 shock but survived, 113 (14.1%) died before experiencing a shock, and 54 (6.7%) received at least 1 shock and subsequently died. Predicted outcome probabilities based on baseline demographic and clinical variables reveal substantial heterogeneity in joint shock and death risks, both between patients at each time point and for each single patient across time. Overall, predictive performance for ICD shock and death individually was adequate, based on area under the curve at 5 years of 0.65 for shocks and of 0.79 for death., Conclusions: Our analysis of outcomes after ICD implantation provides an alternative predictive model for individual risk of death or ICD shocks. If validated, this may provide a useful tool for individualized counseling regarding likely outcomes after device implantation, while also informing the design of further studies to focus the clinical effectiveness and cost-effectiveness of ICD therapy., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00000609.

Background: The mitral isthmus is the critical element of perimitral reentrant tachycardias. Prolongation in transisthmus conduction time and differential pacing techniques are commonly used to determine block. However, these may not distinguish block from slow conduction or conduction via epicardial bridging connections. The aim of this study was to examine these standard criteria for mitral line block with endocardial and epicardial activation mapping., Methods: In 56 patients, posterior mitral line was performed using radiofrequency ablation. Conduction block was defined as transisthmus time (≥100 ms) and reversal of coronary sinus activation during pacing from the left atrial appendage. These results were compared with high-resolution activation mapping (Rhythmia) of the endocardium and epicardium via the coronary sinus., Results: Mitral block determined by pacing was achieved in 51 out of 56 (91%) patients. In 11 out of 51 (21.6%), activation mapping demonstrated residual endocardial (3/11; 27.2%) or epicardial (8/11; 72.7%) connections. Epicardial bridging connections were distant from the line (2.4±1.6 cm), inserting laterally at the proximal-middle coronary sinus and septally at the left atrial ridge. Patients with residual conduction were prone to complex circuits involving the epicardium (7/11; 63.6%). Mitral line block was achieved in 75% by targeting these insertion site(s). The transisthmus conduction time had limited predictive value for distinguishing block from pseudoblock., Conclusions: Standard criteria for posterior mitral line block may not distinguish block from pseudoblock. In particular, epicardial bridging connections can result in prolonged transisthmus conduction time and reversal in coronary sinus activation to falsely suggest block. These connections are a frequent cause for complex circuits, and their insertion site(s) can be targeted for ablation.

Background: Radiofrequency ablation using irrigated catheters is performed using a power-controlled mode. However, lesion size is dependent on current delivery at a particular impedance, such that a power value alone may not reflect actual energy delivery, resulting in lesion size variability at similar power settings. We hypothesized that modulating baseline impedance at fixed power settings affects ablation lesion dimensions., Methods: In 20 ex vivo swine hearts, radiofrequency ablation was performed using an irrigated catheter at a fixed power setting of 30 W per 20 seconds and a multistepped impedance load (100-210Ω). In 4 in vivo thigh muscle preparations and right atria, ablation was performed using similar power settings at 3 baseline impedances: low (90-130Ω), intermediate (131-180Ω), and high (181-224Ω). The relationship between baseline impedance, current, and lesion dimensions was examined., Results: Baseline impedance had a strong negative correlation with current squared ( I 2 ) for all experimental models: ex vivo (R=-0.94; P<0.0001), thigh muscle (R=-0.93; P<0.0001), and right atria (R=-0.94; P<0.0001). Lesion dimensions at similar power settings were highly variable and directly related to I 2 (width [R=0.853], depth [R=0.814]). In the thigh muscle, lesion depth was 8.2±0.7, 6.5±0.8, and 4.2±0.5 mm for low, intermediate, and high impedance, respectively ( P<0.0001). In right atria lines, low baseline impedance resulted in wider lines (7.2±1.4 mm) relative to intermediate (5.8±1.8 mm) and high impedance (4.7±1.7 mm; P<0.0001)., Conclusions: Radiofrequency ablation in a power control mode results in variable lesion dimensions that are partially related to differences in baseline impedance and current output. Ablation at a lower baseline impedance results in increased current output and lesion dimensions.

Background: Activation mapping of scar-related atrial tachycardias (ATs) can be difficult to interpret because of inaccurate time annotation of complex electrograms and passive diastolic activity. We examined whether integration of a vector map can help to describe patterns of propagation to better explain the mechanism and location of ATs., Methods: The investigational mapping algorithm calculates vectors and applies physiological constraints of electrical excitation in human atrial tissue to determine the arrhythmia source and circuit. Phase I consisted of retrospective evaluation in 35 patients with ATs. Phase II consisted of prospective validation in 20 patients with ATs. Macroreentry was defined as a continuous propagation in a circular path >30 mm; localized reentry was defined as a circular path ≤30 mm; a focal source had a centrifugal spread from a point source., Results: In phase I, standard activation mapping identified 28 of 40 ATs (70%): 25 macroreentry and 3 focal tachycardias. In the remaining 12 ATs, the mechanism and location could not be identified by activation and required entrainment or empirical ablation for termination (radiofrequency time, 17.3±6.6 minutes). In comparison, the investigational algorithm identified 37 of 40 (92.5%) ATs, including 5 macroreentry, 3 localized reentry, and 1 focal AT not identified by standard mapping. It also predicted the successful termination site of all 37 of 40 ATs. In phase II, the investigational algorithm identified 12 macroreentry, 6 localized reentry, and 2 focal tachycardias that all terminated with limited ablation (3.2±1.7 minutes). It identified 3 macroreentry, 3 localized reentry, and 1 focal AT not well characterized by standard mapping. The diagnosis of localized reentry was supported by highly curved vectors, resetting with increasing curve and termination with limited ablation (22±6 s)., Conclusions: Activation mapping integrating vectors can help determine the arrhythmia mechanism and identify its critical components. It has particular value for identifying complex macroreentrant circuits and for differentiating a focal source from a localized reentry.

Background: Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents ( I KAS ) are heterogeneously upregulated in failing hearts. We hypothesized that I KAS influences the location and stability of rotors during VF., Methods and Results: Optical mapping was performed on 9 rabbit hearts with pacing-induced heart failure. The epicardial right ventricular and left ventricular surfaces were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the action potential duration (APD 80 ) was determined, and VF was induced. Areas with a >50% increase in the maximum action potential duration (ΔAPD) after apamin infusion were considered to have a high I KAS distribution. At baseline, the distribution density of phase singularities during VF in high I KAS distribution areas was higher than in other areas (0.0035±0.0011 versus 0.0014±0.0010 phase singularities/pixel; P =0.004). In addition, high dominant frequencies also colocalized to high I KAS distribution areas (26.0 versus 17.9 Hz; P =0.003). These correlations were eliminated during VF after apamin infusion, as the number of phase singularities (17.2 versus 11.0; P =0.009) and dominant frequencies (22.1 versus 16.2 Hz; P =0.022) were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion, and the duration of VF decreased., Conclusions: The I KAS current influences the mechanism of VF in failing hearts as phase singularities, high dominant frequencies, and reentrant spiral waves all correlated to areas of high I KAS . Apamin eliminated this relationship and reduced VF vulnerability., (© 2017 American Heart Association, Inc.)

Objective: Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases., Methods: We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays, and quantitative tau measurements in postmortem brain samples from two progressive supranuclear palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging before death., Results: The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathological examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in gray and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined, with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments., Interpretation: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies. ANN NEUROL 2017;81:117-128., (© 2016 American Neurological Association.)

Study Design: Multicenter retrospective review., Objective: To compare the incidence of infection between vertical expandable prosthetic titanium rib (VEPTR) incision locations and determine if the infection risk increases in relation to presence of previous incisions and/or increased number of times incisions are opened., Summary of Background Data: Patients undergoing treatment for chest and spine deformity with VEPTR require multiple incisions that are opened repeatedly during expansion procedures., Methods: A prospective database (7 sites) and institutional database (2 sites), were queried to identify their 20 most recent patients with VEPTR with a minimum of 4 expansions for inclusion. A total of 103 patients were identified. Clinical and operative reports were reviewed to determine incision locations, number, and infection complications., Results: Twenty-five of 103 patients (24%) developed an infection during treatment. Six had multiple infections (range, 2-4), providing a total of 34 infection events. Patients averaged 6.4 expansion procedures and 13 total incisions. Infection rate at each incision site was not significantly different, in the range from 1% to 5%: paramedian (6 infections/23 patients with total 185 incisions, 3%), proximal midline (12/39; 224, 5%), thoracotomy (6/61; 455, 1%), iliac (5/37; 143, 4%), and distal midline (5/58; 148, 3%). Infection events occurred after an average of 3 times a particular incision was opened (95% confidence interval: 2.2-3.8). There was a trend toward higher infection rate with increased number of times a particular incision was opened. There was no increased infection rate in patients with surgical incisions prior to VEPTR (26%; 6/23) compared with patients not having prior incisions (24%; 19/80)., Conclusion: The incidence of infection in patients with 4 or more VEPTR lengthenings was 24% and did not differ across the various incision locations. Presence of prior surgical incisions was not a risk factor for infection. Surgeons should use the most appropriate incision in relation to their patient's pathology when using VEPTR while remaining vigilant for infection., Level of Evidence: 3.

Rationale: Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of high-density lipoprotein, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease. Approximately 14% of Americans with African ancestry carry 2 APOL1 risk alleles, accounting for the high chronic kidney disease burden in this population., Objective: We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African Americans., Methods and Results: We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and chronic kidney disease was confirmed (P=2.4×10(-6)). Among JHS participants with 2 APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without versus 37/280 events among participants with 2 risk alleles; odds ratio, 2.17; P=9.4×10(-4)). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without versus 37/101 events among participants with 2 risk alleles; odds ratio, 1.98; P=8.37×10(-3); JHS and WHI combined, P=8.5×10(-5); odds ratio, 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and chronic kidney disease., Conclusions: APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with 2 APOL1 risk alleles may benefit from intensive interventions to reduce CVD.