<div><h4>Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors: JACC State-of-the-Art Review.</h4><i>Figtree GA, Vernon ST, Harmer JA, Gray MP, ... Nicholls SJ, CRE for CAD Collaborators</i><br /><AbstractText>Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed.</AbstractText><br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 26 Sep 2023; 82:1343-1359</small></div>

<div><h4>PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation.</h4><i>Perike S, Gonzalez-Gonzalez FJ, Abu-Taha I, Damen FW, ... Wehrens XHT, McCauley MD</i><br /><b>Background</b><br />Atrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility.<br /><b>Methods</b><br />Right atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies.<br /><b>Results</b><br />In human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (<i>P</i>=2.0×10<sup>-</sup><sup>2</sup>; n=12 and 12 in each group) with >40% reduction in MLC2a phosphorylation (<i>P</i>=1.4×10<sup>-</sup><sup>6</sup>; n=12 and 12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (<i>P</i>=2.9×10<sup>-2</sup> and 6.7×10<sup>-3</sup>, respectively; n=8 and 8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a and dephosphorylation of MLC2a. Mice treated with lentiviral PPP1R12C vector demonstrated a 150% increase in left atrial size versus controls (<i>P</i>=5.0×10<sup>-</sup><sup>6</sup>; n=12, 8, and 12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in mice treated with lentiviral PPP1R12C vector was significantly higher than in controls (<i>P</i>=1.8×10<sup>-2</sup> and 4.1×10<sup>-2</sup>, respectively; n=6, 6, and 5).<br /><b>Conclusions</b><br />Patients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.<br /><br /><br /><br /><small>Circ Res: 22 Sep 2023; epub ahead of print</small></div>

<div><h4>Oral Anticoagulation Use and Left Atrial Appendage Occlusion in LAAOS III.</h4><i>Connolly SJ, Healey JS, Belley-Cote EP, Balasubramanian K, ... Yusuf S, Whitlock RP</i><br /><b>Background</b><br />LAAOS III (Left Atrial Appendage Occlusion Study III) showed that left atrial appendage (LAA) occlusion reduces the risk of ischemic stroke or systemic embolism in patients with atrial fibrillation undergoing cardiac surgery. This article examines the effect of LAA occlusion on stroke reduction according to variation in the use of oral anticoagulants (OACs).<br /><b>Methods</b><br />Information regarding OAC use was collected at every follow-up visit. Adjusted proportional hazards modeling, including using landmarks of hospital discharge, 1 and 2 years after randomization, evaluated the effect of LAA occlusion on the risk of ischemic stroke or systemic embolism, according to OAC use. Adjusted proportional hazard modeling, with OAC use as a time-dependent covariate, was also performed to assess the effect of LAA occlusion, according to OAC use throughout the study.<br /><b>Results</b><br />At hospital discharge, 3027 patients (63.5%) were receiving a vitamin K antagonist, and 879 (18.5%) were receiving a non-vitamin K antagonist oral anticoagulant (direct OAC), with no difference in OAC use between treatment arms. There were 2887 (60.5%) patients who received OACs at all follow-up visits, 1401 (29.4%) who received OAC at some visits, and 472 (9.9%) who never received OACs. The effect of LAA occlusion on the risk of ischemic stroke or systemic embolism was consistent after discharge across all 3 groups: hazard ratios of 0.70 (95% CI, 0.51-0.96), 0.63 (95% CI, 0.43-0.94), and 0.76 (95% CI, 0.32-1.79), respectively. An adjusted proportional hazards model with OAC use as a time-dependent covariate showed that the reduction in stroke or systemic embolism with LAA occlusion was similar whether patients were receiving OACs or not.<br /><b>Conclusions</b><br />The benefit of LAA occlusion was consistent whether patients were receiving OACs or not. LAA occlusion provides thromboembolism reduction in patients independent of OAC use.<br /><br /><br /><br /><small>Circulation: 21 Sep 2023; epub ahead of print</small></div>

<div><h4>Existing Nongated CT Coronary Calcium Predicts Operative Risk in Patients Undergoing Noncardiac Surgeries (ENCORES).</h4><i>Choi DY, Hayes D, Maidman SD, Dhaduk N, ... Donnino R, Smilowitz NR</i><br /><b>Background</b><br />Preoperative cardiovascular risk stratification before noncardiac surgery is a common clinical challenge. Coronary artery calcium scores from ECG-gated chest computed tomography (CT) imaging are associated with perioperative events. At the time of preoperative evaluation, many patients will not have had ECG-gated CT imaging, but will have had nongated chest CT studies performed for a variety of noncardiac indications. We evaluated relationships between coronary calcium severity estimated from previous nongated chest CT imaging and perioperative major clinical events (MCE) after noncardiac surgery.<br /><b>Methods</b><br />We retrospectively identified consecutive adults age ≥45 years who underwent in-hospital, major nongated surgery from 2016 to 2020 at a large academic health system composed of 4 acute care centers. All patients had nongated (contrast or noncontrast) chest CT imaging performed within 1 year before surgery. Coronary calcium in each vessel was retrospectively graded from absent to severe using a 0 to 3 scale (absent, mild, moderate, severe) by physicians blinded to clinical data. The estimated coronary calcium burden (ECCB) was computed as the sum of scores for each coronary artery (0 to 9 scale). A Revised Cardiac Risk Index was calculated for each patient. Perioperative MCE was defined as all-cause death or myocardial infarction within 30 days of surgery.<br /><b>Results</b><br />A total of 2554 patients (median age, 68 years; 49.7% women; median Revised Cardiac Risk Index, 1) were included. The median time interval from nongated chest CT imaging to nongated surgery was 15 days (interquartile range, 3-106 days). The median ECCB was 1 (interquartile range, 0-3). Perioperative MCE occurred in 136 (5.2%) patients. Higher ECCB values were associated with stepwise increases in perioperative MCE (0: 2.9%, 1-2: 3.7%, 3-5: 8.0%; 6-9: 12.6%, <i>P</i><0.001). Addition of ECCB to a model with the Revised Cardiac Risk Index improved the C-statistic for MCE (from 0.675 to 0.712, <i>P</i>=0.018), with a net reclassification improvement of 0.428 (95% CI, 0.254-0.601, <i>P</i><0.0001). An ECCB ≥3 was associated with 2-fold higher adjusted odds of MCE versus an ECCB <3 (adjusted odds ratio, 2.11 [95% CI, 1.42-3.12]).<br /><b>Conclusions</b><br />Prevalence and severity of coronary calcium obtained from existing nongated chest CT imaging improve preoperative clinical risk stratification before nongated surgery.<br /><br /><br /><br /><small>Circulation: 21 Sep 2023; epub ahead of print</small></div>

<div><h4>Simultaneous Targeting of IL-1-Signaling and IL-6-Trans-Signaling Preserves Human Pulmonary Endothelial Barrier Function During a Cytokine Storm.</h4><i>Colás-Algora N, Muñoz-Pinillos P, Cacho-Navas C, Avendaño-Ortiz J, ... López-Collazo E, Millán J</i><br /><b>Background</b><br />Systemic inflammatory diseases, such as sepsis and severe COVID-19, provoke acute respiratory distress syndrome in which the pathological hyperpermeability of the microvasculature, induced by uncontrolled inflammatory stimulation, causes pulmonary edema. Identifying the inflammatory mediators that induce human lung microvascular endothelial cell barrier dysfunction is essential to find the best anti-inflammatory treatments for critically ill acute respiratory distress syndrome patients.<br /><b>Methods</b><br />We have compared the responses of primary human lung microvascular endothelial cells to the main inflammatory mediators involved in cytokine storms induced by sepsis and SARS-CoV2 pulmonary infection and to sera from healthy donors and severely ill patients with sepsis. Endothelial barrier function was measured by electric cell-substrate impedance sensing, quantitative confocal microscopy, and Western blot.<br /><b>Results</b><br />The human lung microvascular endothelial cell barrier was completely disrupted by IL (interleukin)-6 conjugated with soluble IL-6R (IL-6 receptor) and by IL-1β, moderately affected by TNF (tumor necrosis factor)-α and IFN (interferon)-γ and unaffected by other cytokines and chemokines, such as IL-6, IL-8, MCP (monocyte chemoattractant protein)-1 and MCP-3. The inhibition of IL-1 and IL-6R simultaneously, but not separately, significantly reduced endothelial hyperpermeability on exposing human lung microvascular endothelial cells to a cytokine storm consisting of 8 inflammatory mediators or to sera from patients with sepsis. Simultaneous inhibition of IL-1 and JAK (Janus kinase)-STAT (signal transducer and activator of transcription protein), a signaling node downstream IL-6 and IFN-γ, also prevented septic serum-induced endothelial barrier disruption.<br /><b>Conclusions</b><br />These findings strongly suggest a major role for both IL-6 trans-signaling and IL-1β signaling in the pathological increase in permeability of the human lung microvasculature and reveal combinatorial strategies that enable the gradual control of pulmonary endothelial barrier function in response to a cytokine storm.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 21 Sep 2023; epub ahead of print</small></div>

<div><h4>Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.</h4><i>Cheng YC, Hsieh ML, Lin CJ, Chang CMC, ... Kamp TJ, Hsieh PCH</i><br /><b>Background</b><br />Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs.<br /><b>Methods</b><br />We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in NOD-SCID mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated.<br /><b>Results</b><br />We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion.<br /><b>Conclusions</b><br />These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.<br /><br /><br /><br /><small>Circulation: 21 Sep 2023; epub ahead of print</small></div>

<div><h4>Association of Coronary Artery Calcium Detected by Routine Ungated CT Imaging With Cardiovascular Outcomes.</h4><i>Peng AW, Dudum R, Jain SS, Maron DJ, ... Sandhu AT, Rodriguez F</i><br /><b>Background</b><br />Coronary artery calcium (CAC) is a strong predictor of cardiovascular events across all racial and ethnic groups. CAC can be quantified on nonelectrocardiography (ECG)-gated computed tomography (CT) performed for other reasons, allowing for opportunistic screening for subclinical atherosclerosis.<br /><b>Objectives</b><br />The authors investigated whether incidental CAC quantified on routine non-ECG-gated CTs using a deep-learning (DL) algorithm provided cardiovascular risk stratification beyond traditional risk prediction methods.<br /><b>Methods</b><br />Incidental CAC was quantified using a DL algorithm (DL-CAC) on non-ECG-gated chest CTs performed for routine care in all settings at a large academic medical center from 2014 to 2019. We measured the association between DL-CAC (0, 1-99, or ≥100) with all-cause death (primary outcome), and the secondary composite outcomes of death/myocardial infarction (MI)/stroke and death/MI/stroke/revascularization using Cox regression. We adjusted for age, sex, race, ethnicity, comorbidities, systolic blood pressure, lipid levels, smoking status, and antihypertensive use. Ten-year atherosclerotic cardiovascular disease risk was calculated using the pooled cohort equations.<br /><b>Results</b><br />Of 5,678 adults without ASCVD (51% women, 18% Asian, 13% Hispanic/Latinx), 52% had DL-CAC >0. Those with DL-CAC ≥100 had an average 10-year ASCVD risk of 24%; yet, only 26% were on statins. After adjustment, patients with DL-CAC ≥100 had increased risk of death (HR: 1.51; 95% CI: 1.28-1.79), death/MI/stroke (HR: 1.57; 95% CI: 1.33-1.84), and death/MI/stroke/revascularization (HR: 1.69; 95% CI: 1.45-1.98) compared with DL-CAC = 0.<br /><b>Conclusions</b><br />Incidental CAC ≥100 was associated with an increased risk of all-cause death and adverse cardiovascular outcomes, beyond traditional risk factors. DL-CAC from routine non-ECG-gated CTs identifies patients at increased cardiovascular risk and holds promise as a tool for opportunistic screening to facilitate earlier intervention.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 19 Sep 2023; 82:1192-1202</small></div>

<div><h4>Acquired risk factors and incident atrial fibrillation according to age and genetic predisposition.</h4><i>Wang N, Yu Y, Sun Y, Zhang H, ... Wang B, Lu Y</i><br /><b>Background:</b><br/>and aims</b><br />Atrial fibrillation (AF) is the most common sustained arrhythmia in adults. Investigations of risk factor profiles for AF according to age and genetic risk groups are essential to promote individualized strategies for the prevention and control of AF.<br /><b>Methods</b><br />A total of 409 661 participants (mean age, 56 years; 46% men) free of AF at baseline and with complete information about risk factors were included from the UK Biobank cohort. The hazard ratios and population-attributable risk (PAR) percentages of incident AF associated with 23 risk factors were examined, including 3 social factors, 7 health behaviours, 6 cardiometabolic factors, 6 clinical comorbidities, and the genetic risk score (GRS), across 3 age groups (40-49, 50-59, and 60-69 years) and 3 genetic risk groups (low, moderate, and high GRS).<br /><b>Results</b><br />After a follow-up of 5 027 587 person-years, 23 847 participants developed AF. Most cardiometabolic factors and clinical comorbidities showed a significant interaction with age, whereby the associations were generally strengthened in younger groups (Pinteraction < .002). However, only low LDL cholesterol, renal dysfunction, and cardiovascular disease showed a significant interaction with genetic risk, and the associations with these factors were stronger in lower genetic risk groups (Pinteraction < .002). Cardiometabolic factors consistently accounted for the largest number of incident AF cases across all age groups (PAR: 36.2%-38.9%) and genetic risk groups (34.0%-41.9%), with hypertension and overweight/obesity being the two leading modifiable factors. Health behaviours (PAR: 11.5% vs. 8.7%) and genetic risk factors (19.1% vs. 14.3%) contributed to more AF cases in the 40-49 years group than in the 60-69 years group, while the contribution of clinical comorbidities remained relatively stable across different age groups. The AF risk attributable to overall cardiometabolic factors (PAR: 41.9% in the low genetic risk group and 34.0% in the high genetic risk group) and clinical comorbidities (24.7% and 15.9%) decreased with increasing genetic risk. The impact of social factors on AF was relatively low across the groups by age and genetic risk.<br /><b>Conclusions</b><br />This study provided comprehensive information about age- and genetic predisposition-related risk factor profiles for AF in a cohort of UK adults. Prioritizing risk factors according to age and genetic risk stratifications may help to achieve precise and efficient prevention of AF.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 19 Sep 2023; epub ahead of print</small></div>

<div><h4>Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.</h4><i>Aggarwal R, Ruff CT, Virdone S, Perreault S, ... Shen C, Yeh RW</i><br /><b>Background</b><br />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).<br /><b>Methods</b><br />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.<br /><b>Results</b><br />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 <i>P</i>=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%; <i>P</i><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; <i>P</i> for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; <i>P</i> 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; <i>P</i> for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; <i>P</i> for difference <0.001).<br /><b>Conclusions</b><br />In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.<br /><br /><br /><br /><small>Circulation: 19 Sep 2023; 148:936-946</small></div>

<div><h4>Supra-Normal Left Ventricular Function.</h4><i>Ono R, Falcão LM</i><br /><AbstractText>Heart failure (HF) is often categorized by left ventricular (LV) ejection fraction (LVEF). A new category of HF characterized by supra-normal LVEF (>65%), named HF with supra-normal ejection fraction (HFsnEF), has been recently proposed. Some studies reported that patients with supra-normal LVEF might have an increased risk of long-term major adverse cardiovascular events and U-shaped mortality patterns. Currently, the prognosis of HFsnEF is not well established but seems to be associated with an increased risk of long-term major adverse cardiovascular events. It has been reported that HFsnEF is more prevalent in women and is associated with higher prevalence of nonischemic HF, higher blood urea nitrogen plasma levels, lower levels of natriuretic peptides, and to be less likely treated with β blockers. The pathophysiology of HFsnEF would be associated with microvascular dysfunction because of microvascular inflammation or reduced coronary flow reserve, and low stroke volume index with smaller cardiac chamber dimensions and concentric LV geometry. In this study, we systematically reviewed published data on patients with s supra-normal LV function and reported its definition, proposed pathophysiology, phenotypes, diagnostic strategy, and prognosis.</AbstractText><br /><br />Copyright © 2023 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 19 Sep 2023; 207:84-92</small></div>

<div><h4>Association between left ventricular apical-to-basal strain ratio and conduction disorders after aortic valve replacement.</h4><i>Laenens D, Stassen J, Galloo X, Myagmardorj R, Marsan NA, Bax JJ</i><br /><b>Background</b><br />The aim of the study was to evaluate whether left ventricular apical-to-basal longitudinal strain differences, representing advanced basal interstitial fibrosis, are associated with conduction disorders after aortic valve replacement (AVR) in patients with severe aortic stenosis.<br /><b>Methods</b><br />Patients with aortic stenosis undergoing AVR were included. The apical-to-basal strain ratio was calculated by dividing the average strain of the basal segments by the average strain of the apical segments. Values >1.9 were considered abnormal, as previously described. All patients were followed-up for the occurrence of complete left or right bundle branch block, or permanent pacemaker implantation within 2 years after AVR. Subgroup analysis was performed in patients undergoing transcatheter AVR.<br /><b>Results</b><br />Two hundred seventy-four patients were included (74 years (IQR 65, 80), 46.4% male). During a median follow-up of 12.2 months (IQR 0.2, 24.3), 74 patients (27%) developed complete bundle branch block or were implanted with a permanent pacemaker. These patients more often had an abnormal apical-to-basal strain ratio. Cumulative event-free survival analysis showed worse outcome in patients with an abnormal apical-to-basal strain ratio (Log rank χ<sup>2</sup> 7.258, p = 0.007). In multivariable cox regression analysis, an abnormal apical-to-basal strain ratio was the only independent factor associated with the occurrence of complete bundle branch block or permanent pacemaker implantation after adjusting for other factors previously shown to be associated with conduction disorders after AVR. Subgroup analysis confirmed the independent association of an abnormal apical-to-basal strain ratio with conduction disorders after transcatheter AVR.<br /><b>Conclusion</b><br />The apical-to-basal strain ratio is independently associated with conduction disorders after AVR and could guide risk stratification in patients potentially at risk for pacemaker implantation.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>J Am Soc Echocardiogr: 18 Sep 2023; epub ahead of print</small></div>

<div><h4>Cerebral embolic protection during transcatheter heart interventions.</h4><i>Jimenez Diaz VA, Kapadia SR, Linke A, Mylotte D, ... Settergren M, Puri R</i><br /><AbstractText>Stroke remains a devastating complication of transcatheter aortic valve replacement (TAVR), with the incidence of clinically apparent stroke seemingly fixed at around 3% despite TAVR\'s significant evolution during the past decade. Embolic showers of debris (calcium, atheroma, valve material, foreign material) are captured in the majority of patients who have TAVR using a filter-based cerebral embolic protection device (CEPD). Additionally, in systematic brain imaging studies, the majority of patients receiving TAVR exhibit new cerebral lesions. Mechanistic studies have shown reductions in the volume of new cerebral lesions using CEPDs, yet the first randomised trial powered for periprocedural stroke within 72 hours of a transfemoral TAVR failed to meet its primary endpoint of showing superiority of the SENTINEL CEPD. The present review summarises the clinicopathological rationale for the development of CEPDs, the evidence behind these devices to date and the emerging recognition of cerebral embolisation in many non-TAVR transcatheter procedures. Given the uniqueness of each of the various CEPDs under development, specific trials tailored to their designs will need to be undertaken to broaden the CEPD field, in addition to evaluating the role of CEPD in non-TAVR transcatheter heart interventions. Importantly, the cost-effectiveness of these devices will require assessment to broaden the adoption of CEPDs globally.</AbstractText><br /><br /><br /><br /><small>EuroIntervention: 18 Sep 2023; 19:549-570</small></div>

<div><h4>Mental Health Conditions Among Children and Adolescents With Congenital Heart Disease: A Danish Population-Based Cohort Study.</h4><i>Miles KG, Farkas DK, Laugesen K, Sørensen HT, Kasparian NA, Madsen N</i><br /><b>Background</b><br />Despite the known mental health burden among children with congenital heart disease (CHD), the literature is constrained by a lack of comparison cohorts and population-based follow-up data. We examined the incidence of mental health conditions among children with CHD, relative to 3 comparison cohorts.<br /><b>Methods</b><br />This population-based cohort study identified all children with CHD (<18 years of age; n=16 473) in Denmark from 1996 to 2017, through linkage of individual-level data across national registries. This allowed for complete follow-up of the population. Comparison cohorts included children from the general population (n=162 204), siblings of children with CHD (n=20 079), and children with non-CHD major congenital anomalies (n=47 799). Mental health conditions were identified using inpatient and outpatient hospital discharge codes, prescription data, and data on use of community-based psychology, psychiatry, and psychotherapy services. We computed cumulative incidence by 18 years of age, incidence rates, and adjusted hazard ratios (aHRs) using Cox regression. aHRs accounted for sex, year of CHD diagnosis, parental mental health, and socioeconomic status. All estimates were stratified by age, sex, and CHD complexity.<br /><b>Results</b><br />The cumulative incidence of mental health conditions by 18 years of age in the CHD cohort was 35.1% (95% CI, 34.0%-36.1%), corresponding to aHRs of 1.64 (95% CI, 1.58-1.71), 1.41 (95% CI, 1.30-1.52), and 1.02 (95% CI, 0.98-1.07) compared with the general population, sibling, and major congenital anomaly cohorts, respectively. Mental health incidence rates showed prominent peaks in early childhood and adolescence. Males and children with severe or single-ventricle CHD demonstrated higher incidence rates of mental health conditions relative to females and children with mild or moderate CHD, respectively. Compared with the general population and sibling cohorts, incidence rates and aHRs in the CHD cohort were highest for severe stress reactions, attention deficit/hyperactivity disorder, intellectual disability, and autism spectrum disorder. Compared with children in the major congenital anomaly cohort, the aHRs were close to 1.<br /><b>Conclusions</b><br />More than one-third of children with CHD were diagnosed or treated for a mental health condition by 18 years of age. Mental health conditions began early in life and were most prominent among males and children with severe or single-ventricle heart disease.<br /><br /><br /><br /><small>Circulation: 18 Sep 2023; epub ahead of print</small></div>

<div><h4>2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.</h4><i>Lavonas EJ, Akpunonu PD, Arens AM, Babu KM, ... Drennan IR, American Heart Association</i><br /><AbstractText>In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, β-adrenergic receptor antagonists (also known as β-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.</AbstractText><br /><br /><br /><br /><small>Circulation: 18 Sep 2023; epub ahead of print</small></div>

<div><h4>Aetiology, ejection fraction and mortality in chronic heart failure: a mediation analysis.</h4><i>Fritz J, Belovari K, Ulmer H, Zaruba MM, ... Bauer A, Poelzl G</i><br /><b>Objective</b><br />Clinical decision making in chronic heart failure (CHF) is based primarily on left ventricular ejection fraction (LVEF), and only secondarily on aetiology of the underlying disease. Our aim was to investigate the mediating role of LVEF in the relationship between aetiology and mortality.<br /><b>Methods</b><br />Using data of 2056 Austrian patients with CHF (mean age 57.2 years; mean follow-up 8.8 years), effects of aetiology on LVEF and overall mortality were estimated using multivariable-adjusted linear and Cox regression models. In causal mediation analyses, we decomposed the total effect of aetiology on mortality into direct and indirect (mediated through LVEF) effects.<br /><b>Results</b><br />For the analysed aetiologies (dilated (DCM, n=1009) and hypertrophic (HCM, n=89) cardiomyopathy; ischaemic (IHD, n=529) and hypertensive (HHD, n=320) heart disease; cardiac amyloidosis (CA, n=109)), the effect of LVEF on mortality was similar (HR<sub>5%-points lower LVEF</sub>=1.07, 95% CI 1.04 to 1.10; p<sub>interaction</sub>=0.718). HCM and CA were associated with significantly higher, and IHD and DCM with significantly lower LVEF compared with other aetiologies. Compared with respective other aetiologies, the corresponding total effect HRs for mortality were 0.77 (95% CI 0.67 to 0.89), 0.47 (95% CI 0.25 to 0.88), 1.40 (95% CI 1.21 to 1.62), 0.79 (95% CI 0.67 to 0.95) and 2.36 (95% CI 1.81 to 3.08) for DCM, HCM, IHD, HHD and CA, respectively. CA had the highest mortality despite a HR<sub>indirect effect</sub> of 0.74 (95% CI 0.65 to 0.83). For all other aetiologies, <20% of the total mortality effects were mediated through LVEF.<br /><b>Conclusions</b><br />The direct effect of aetiology on mortality dominates the indirect effect through LVEF. Therefore, clarification of aetiology is as important as measurement of LVEF.<br /><br />© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>Heart: 18 Sep 2023; epub ahead of print</small></div>

<div><h4>DNA Damage and Nuclear Morphological Changes in Cardiac Hypertrophy Are Mediated by SNRK Through Actin Depolymerization.</h4><i>Stanczyk P, Tatekoshi Y, Shapiro JS, Nayudu K, ... Chang HC, Ardehali H</i><br /><b>Background</b><br />Proper nuclear organization is critical for cardiomyocyte function, because global structural remodeling of nuclear morphology and chromatin structure underpins the development and progression of cardiovascular disease. Previous reports have implicated a role for DNA damage in cardiac hypertrophy; however, the mechanism for this process is not well delineated. AMPK (AMP-activated protein kinase) family of proteins regulates metabolism and DNA damage response (DDR). Here, we examine whether a member of this family, SNRK (SNF1-related kinase), which plays a role in cardiac metabolism, is also involved in hypertrophic remodeling through changes in DDR and structural properties of the nucleus.<br /><b>Methods</b><br />We subjected cardiac-specific <i>Snrk</i><sup>-/-</sup> mice to transaortic banding to assess the effect on cardiac function and DDR. In parallel, we modulated SNRK in vitro and assessed its effects on DDR and nuclear parameters. We also used phosphoproteomics to identify novel proteins that are phosphorylated by SNRK. Last, coimmunoprecipitation was used to verify Destrin (DSTN) as the binding partner of SNRK that modulates its effects on the nucleus and DDR.<br /><b>Results</b><br />Cardiac-specific <i>Snrk</i><sup>-/-</sup> mice display worse cardiac function and cardiac hypertrophy in response to transaortic banding, and an increase in DDR marker pH2AX (phospho-histone 2AX) in their hearts. In addition, in vitro <i>Snrk</i> knockdown results in increased DNA damage and chromatin compaction, along with alterations in nuclear flatness and 3-dimensional volume. Phosphoproteomic studies identified a novel SNRK target, DSTN, a member of F-actin depolymerizing factor proteins that directly bind to and depolymerize F-actin. SNRK binds to DSTN, and DSTN downregulation reverses excess DNA damage and changes in nuclear parameters, in addition to cellular hypertrophy, with SNRK knockdown. We also demonstrate that SNRK knockdown promotes excessive actin depolymerization, measured by the increased ratio of G-actin to F-actin. Last, jasplakinolide, a pharmacological stabilizer of F-actin, rescues the increased DNA damage and aberrant nuclear morphology in SNRK-downregulated cells.<br /><b>Conclusions</b><br />These results indicate that SNRK is a key player in cardiac hypertrophy and DNA damage through its interaction with DSTN. This interaction fine-tunes actin polymerization to reduce DDR and maintain proper cardiomyocyte nuclear shape and morphology.<br /><br /><br /><br /><small>Circulation: 18 Sep 2023; epub ahead of print</small></div>