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Aging is a leading risk factor for the development of age-related diseases. However, how aging impacts human induced pluripotent stem cell (hiPSC) reprogramming, age-related epigenetic memory post-reprogramming, differentiation, and its potential applicability to cardiovascular regenerative medicine remains underexplored. We generated, characterized, and validated two hiPSC lines from human peripheral blood mononuclear cells (PBMCs) obtained from whole blood of young and older human donors. The two hiPSC lines expressed four pluripotency markers, have normal karyotypes and trilineage differentiation potential, and genetically match parental PBMCs. These lines are invaluable for regenerative medicine and exploring epigenetic-related molecular mechanisms that underlie aging and aging-related diseases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nadia Sutton reports financial support was provided by National Institutes of Health. Andre Monteiro da Rocha reports a relationship with Stembiosys Inc that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

This paper reviews the distinct clinical, pathophysiological, and therapeutic challenges faced by older women undergoing percutaneous coronary intervention (PCI). Older women present with a greater comorbidity burden, smaller coronary vessels, and post-menopausal hormonal changes, which increase procedural complexity and adverse cardiovascular outcomes. Despite these challenges, older women are less likely to receive evidence-based therapies, resulting in higher risks of major adverse cardiovascular events (MACE) and bleeding. The paper further discusses the limitations of current risk stratification tools and outlines strategies for improving outcomes through tailored procedural techniques and patient-centered care approaches in this underrepresented population., Competing Interests: Disclosure M.G. Nanna: Dr M.G. Nanna reports current research support from the American College of Cardiology Foundation, United States supported by the George F. and Ann Harris Bellows Foundation, the Patient-Centered Outcomes Research Institute, United States (PCORI), the Yale Claude D. Pepper Older Americans Independence Center (P30AG021342), and the National Institute on Aging, United States/National Institutes of Health from R03AG074067 (GEMSSTAR award). Dr M.G. Nanna also reports being a consultant for Heartflow and Merck. A.A. Damluji: A.A. Damluji receives research funding from the Pepper Scholars Program of the Johns Hopkins University, United States Claude D. Pepper Older Americans Independence Center funded by the National Institute on Aging P30-AG021334 and receives mentored patient-oriented research career development award from the National Heart, Lung, and Blood Institute K23-HL153771-04. N.R. Sutton: Dr N.R. Sutton reports current institutional research support from the Society for Cardiovascular Angiography and Interventions, Shockwave Medical, and the National Institute on Aging (5K76AG064426) and being a consultant or speaker for Abbott, Boston Scientific, Philips, and Zoll Medical., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion-even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as "aging" by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

CD39 (NTPDase1-nucleoside triphosphate diphosphohydrolase 1) is a membrane-tethered ectonucleotidase that hydrolyzes extracellular ATP to ADP and ADP to AMP. This enzyme is expressed in a variety of cell types and tissues and has broadly been recognized within vascular tissue to have a protective role in converting "danger" ligands (ATP) into neutral ligands (AMP). In this study, we investigate the enzyme kinetics of CD39 using a Michaelis-Menten modeling framework. We show how the unique situation of having a reaction product also serving as a substrate (ADP) complicates the determination of the governing kinetic parameters. Model simulations using values for the kinetic parameters reported in the literature do not align with corresponding time-series data. This dissonance is explained by CD39 kinetic parameters previously being determined by graphical/linearization methods, which have been shown to distort the underlying error structure and lead to inaccurate parameter estimates. Modern methods of estimating these kinetic parameters using nonlinear least squares are still challenging due to unidentifiable parameter interactions. We propose a workflow to accurately determine these parameters by isolating the ADPase and ATPase reactions and estimating the respective ADPase parameters and ATPase parameters with independent data sets. Theoretically, this ensures all kinetic parameters are identifiable and reliable for future prospective model simulations involving CD39. These kinds of mathematical models can be used to understand how circulating purinergic nucleotides affect disease etiology and potentially inform the development of corresponding therapies., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose of Review: The goal of this manuscript is to provide a concise summary of recent developments in the approach to and treatment of women with acute coronary syndrome (ACS)., Recent Findings: This review covers terminology updates relating to ACS and myocardial injury and infarction. Updates on disparities in recognition, treatments, and outcomes of women with ACS due to atherosclerotic coronary artery disease are covered. Other causes of ACS, including spontaneous coronary artery dissection and myocardial infarction with non-obstructive coronary artery disease are discussed, given the increased frequency in women compared with men. The review summarizes the latest on the unique circumstance of ACS in women who are pregnant or post-partum, including etiologies, diagnostic approaches, medication safety, and revascularization considerations. Compared with men, women with ACS have unique risk factors, presentations, and pathophysiology. Treatments known to be effective for men with atherosclerosis-related ACS are also effective for women; further work remains on reducing the disparities in diagnosis and treatment. Implementation of multimodality imaging will improve diagnostic accuracy and allow for targeted medical therapy in the setting of myocardial infarction with non-obstructive coronary artery disease., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This article provides a summary of the clinical spectrum of no obstructive coronary arteries. We describe the pathologies, invasive and noninvasive assessment, and management strategies., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N.R.S. is a consultant for Abbott and Philips and has received honoraria for speaking from Abbott, Philips, and Zoll. None of the other authors have any relevant disclosures., (© 2024 The Authors.)

Coronary microvascular dysfunction (CMD) can cause myocardial ischemia in patients presenting with angina without obstructive coronary artery disease (ANOCA). Evaluating for CMD by using the thermodilution technique offers a widely accessible means of assessing microvascular resistance. Through this technique, 2 validated indices, namely coronary flow reserve and the index of microcirculatory resistance, can be computed, facilitating investigation of the coronary microcirculation. The index of microcirculatory resistance specifically estimates minimum achievable microvascular resistance within the coronary microcirculation. We aim to review the bolus thermodilution method, outlining the fundamental steps for conducting measurements and introducing an algorithmic approach (CATH CMD) to systematically evaluate the coronary microcirculation. Embracing a standardized approach, exemplified by the CATH CMD algorithm, will facilitate adoption of this technique and streamline the diagnosis of CMD., (© 2024 The Author(s).)

Mitochondria are cellular organelles critical for ATP production and are particularly relevant to cardiovascular diseases including heart failure, atherosclerosis, ischemia-reperfusion injury, and cardiomyopathies. With advancing age, even in the absence of clinical disease, mitochondrial homeostasis becomes disrupted (e.g., redox balance, mitochondrial DNA damage, oxidative metabolism, and mitochondrial quality control). Mitochondrial dysregulation leads to the accumulation of damaged and dysfunctional mitochondria, producing excessive reactive oxygen species and perpetuating mitochondrial dysfunction. In addition, mitochondrial DNA, cardiolipin, and N -formyl peptides are potent activators of cell-intrinsic and -extrinsic inflammatory pathways. These age-related mitochondrial changes contribute to the development of cardiovascular diseases. This review covers the impact of aging on mitochondria and links these mechanisms to therapeutic implications for age-associated cardiovascular diseases.

The prevalence of calcification in obstructive coronary artery disease is on the rise. Percutaneous coronary intervention of these calcified lesions is associated with increased short-term and long-term risks. To optimize percutaneous coronary intervention results, there is an expanding array of treatment modalities geared toward calcium modification prior to stent implantation. The Society for Cardiovascular Angiography and Interventions, herein, puts forth an expert consensus document regarding methods to identify types of calcified coronary lesions, a central algorithm to help guide use of the various calcium modification strategies, tips for when using each treatment modality, and a look at future studies and trials for treating this challenging lesion subset., (© 2023 The Author(s).)

Background: It remains unclear if percutaneous left ventricular assist device (pLVAD) reduces post-cardiac arrest myocardial dysfunction., Methods: This is a prespecified analysis of a subset of swine that achieved return of spontaneous circulation (ROSC) in a study comparing pLVAD, transient aortic occlusion (AO), or both during cardiopulmonary resuscitation (CPR). Devices were initiated after 24 minutes of ventricular fibrillation cardiac arrest (8 min no-flow and 16 min mechanical CPR). AO was discontinued post-ROSC, and pLVAD support or standard care were continued. Beginning 60 minutes post-ROSC, pLVAD support was weaned to < 1.0 L/min and subsequently removed at 240 minutes. The primary outcome was cardiac index (CI), stroke volume index (SVI), and left ventricular ejection fraction (LVEF) at 240 minutes post-ROSC. Data are shown as mean (standard error)., Results: Seventeen swine achieved ROSC without complication and were included in this analysis (pLVAD group, n = 11 and standard care group, n = 6). For the primary outcomes, the pLVAD group had significantly higher CI of 4.2(0.3) vs. 3.1(0.4) L/min/m 2 (p = 0.043) and LVEF 60(3) vs. 49(4) % (p = 0.029) at 240 minutes after ROSC when compared with the standard care group, while SVI was not statistically significantly different (32[3] vs. 23[4] mL/min/m 2 , p = 0.054). During the first 60 minutes post-ROSC, the pLVAD group had significantly higher coronary perfusion pressure, lower LV stroke work index, and total pulmonary resistance index., Conclusion: These results suggest that early pLVAD support after ROSC is associated with better recovery myocardial function compared to standard care after prolonged cardiac arrest., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Recent studies describe an emerging role for percutaneous left ventricular assist devices such as Impella CP® as rescue therapy for refractory cardiac arrest. We hypothesized that the addition of mechanical chest compressions to percutaneous left ventricular assist device assisted CPR would improve hemodynamics by compressing the right ventricle and augmenting pulmonary blood flow and left ventricular filling. We performed a pilot study to test this hypothesis using a swine model of prolonged cardiac arrest., Methods: Eight Yorkshire swine were anesthetized, intubated, and instrumented for hemodynamic monitoring. They were subjected to untreated ventricular fibrillation for 5.75 (SD 2.90) minutes followed by mechanical chest compressions for a mean of 20.0 (SD 5.0) minutes before initiation of percutaneous left ventricular assist device. After percutaneous left ventricular assist device initiation, mechanical chest compressions was stopped ( n  = 4) or continued ( n  = 4). Defibrillation was attempted 4, 8 and 12 minutes after initiating percutaneous left ventricular assist device circulatory support., Results: The percutaneous left ventricular assist device + mechanical chest compressions group had significantly higher percutaneous left ventricular assist device flow prior to return of spontaneous heartbeat at four- and twelve-minutes after percutaneous left ventricular assist device initiation, and significantly higher end tidal CO2 at 4-minutes after percutaneous left ventricular assist device initiation, when compared with the percutaneous left ventricular assist device alone group. Carotid artery flow was not significantly different between the two groups., Conclusion: The addition of mechanical chest compressions to percutaneous left ventricular assist device support during cardiac arrest may generate higher percutaneous left ventricular assist device and carotid artery flow prior to return of spontaneous heartbeat compared to percutaneous left ventricular assist device alone. Further studies are needed to determine if this approach improves other hemodynamic parameters or outcomes after prolonged cardiac arrest., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘N.R.S. has received honoraria for speaking from Zoll, Cordis, and Shockwave and is a consultant for Abbott and Philips. The other authors declare no conflict of interest. C.H.H. is part of the Resuscitation Plus Editorial Board’., (© 2023 The Author(s).)

Chronic kidney disease is an independent risk factor for the development of coronary artery disease and overlaps with other risk factors such as hypertension and diabetes. Percutaneous coronary intervention is a cornerstone of therapy for coronary artery disease and requires contrast media, which can lead to renal injury. Identifying patients at risk for contrast-associated acute kidney injury (CA-AKI) is critical for preventing kidney damage, which is associated with both short- and long-term mortality. Determination of the potential risk for CA-AKI and a new need for dialysis using validated risk prediction tools identifies patients at high risk for this complication. Identification of patients at risk for renal injury after contrast exposure is the first critical step in prevention. Contrast media volume, age and sex of the patient, a history of chronic kidney disease and/or diabetes, clinical presentation, and hemodynamic and volume status are factors known to predict incident contrast-induced nephropathy. Recognition of at-risk patient subpopulations allows for targeted, efficient, and cost-effective strategies to reduce the risk of renal complications resulting from contrast media exposure., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Angina with nonobstructive coronary arteries (ANOCA) is increasingly recognized and may affect nearly one-half of patients undergoing invasive coronary angiography for suspected ischemic heart disease. This working diagnosis encompasses coronary microvascular dysfunction, microvascular and epicardial spasm, myocardial bridging, and other occult coronary abnormalities. Patients with ANOCA often face a high burden of symptoms and may experience repeated presentations to multiple medical providers before receiving a diagnosis. Given the challenges of establishing a diagnosis, patients with ANOCA frequently experience invalidation and recidivism, possibly leading to anxiety and depression. Advances in scientific knowledge and diagnostic testing now allow for routine evaluation of ANOCA noninvasively and in the cardiac catheterization laboratory with coronary function testing (CFT). CFT includes diagnostic coronary angiography, assessment of coronary flow reserve and microcirculatory resistance, provocative testing for endothelial dysfunction and coronary vasospasm, and intravascular imaging for identification of myocardial bridging, with hemodynamic assessment as needed., Competing Interests: Funding Support and Author Disclosures Dr Samuels has served as a consultant and on a Speakers Bureau for Abbott Vascular and Philips. Dr Shah has received research support from Abbott Vascular and the Food and Drug Administration of the U.S. Department of Health and Human Services. Dr Widmer has served on advisory boards for Abbott Vascular, Philips, and Medtronic; and has received research support from Cardiol Therapeutics. Dr Kobayashi has served as a consultant for Abbott Vascular. Dr Miner has received investigator-initiated research support from Abbott Vascular. Dr Jeremias has served as a consultant for Philips, Abbott Vascular, ACIST, Neovasc, and CathWorks. Dr Blair has received research support from Abbott Vascular and Philips; and is on a Speakers Bureau for Abbott Vascular. Dr Kearney has served as a consultant for Abbott Vascular, Abiomed, Boston Scientific, CSI, Medtronic, Teleflex, and Philips. Dr Wei has served on an advisory board for Abbott Vascular. Dr Park has received honoraria from Abbott Vascular and CSI. Dr Kesarwani has served as a consultant for Abbott Vascular. Dr Lerman has served on an advisory board for Philips/Volcano. Dr Prasad has served on an advisory board and/or as a consultant for Abbott Vascular, Boston Scientific, Cardiol Therapeutics, Conavi, Chiesi, and Neovasc. Dr Quesada has received partial support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) (award K23HL151867). Dr Reynolds has received research support from Abbott Vascular, Philips, and Siemens. Dr Smilowitz has served on an advisory board for Abbott Vascular; and has received partial support from the National Heart, Lung, and Blood Institute of the NIH (award K23HL150315). Dr Sutton has received honoraria for speaking or consulting from Abbott, Philips, Zoll, and Shockwave. Dr Sweeny has received honoraria from Abbott Vascular. Dr Henry has received research support and honoraria from Neovasc. Dr Moses has served as a consultant for Covanos; and has held equity in Orchestra BioMed and Covanos. Dr Fearon has received institutional research support from Abbott Vascular, Medtronic, and the NIH (5R33HL139929-05); has served as a consultant for CathWorks and Siemens; and has held stock options with HeartFlow. Dr Tremmel has received honoraria from and served on advisory boards for Abbott Vascular; has received honoraria and research funding from Boston Scientific; and has received honoraria from Shockwave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Centers specializing in coronary function testing are critical to ensure a systematic approach to the diagnosis and treatment of angina with nonobstructive coronary arteries (ANOCA). Management leveraging lifestyle, pharmacology, and device-based therapeutic options for ANOCA can improve angina burden and quality of life in affected patients. Multidisciplinary care teams that can tailor and titrate therapies based on individual patient needs are critical to the success of comprehensive programs. As coronary function testing for ANOCA is more widely adopted, collaborative research initiatives will be fundamental to improve ANOCA care. These efforts will require standardized symptom assessments and data collection, which will propel future large-scale clinical trials., Competing Interests: Funding Support and Author Disclosures Dr Smilowitz has served on an advisory board for Abbott Vascular and is supported, in part, by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL150315. Dr Prasad has served on an advisory board and/or as a consultant for Abbott Vascular, Boston Scientific, Cardinol, CONAVI, Chiesi, and Neovasc. Dr Widmer has served on advisory boards for Abbott Vascular, Philips, and Medtronic; and has received research support from Cardiol Therapeutics. Dr Quesada is supported, in part, by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL151867. Dr Sutton has received honoraria for speaking or consulting from Abbott, Philips, Zoll, and Shockwave. Dr Lerman has served on an advisory board for Philips/Volcano. Dr Reynolds has received research support from Abbott Vascular, Philips, and Siemens. Dr Kesarwani has a consulting agreement with Abbott Vascular. Dr Sweeny has received honoraria from Abbott Vascular. Dr Park has received honoraria from Abbott Vascular and CSI. Dr Blair has received research support from Abbott Vascular and Philips; and is on a Speakers Bureau for Abbott Vascular. Dr Jeremias has consulting agreements with Philips, Abbott Vascular, ACIST, Neovasc, and CathWorks. Dr Kearney has consulting agreements with Abbott Vascular, Abiomed, Boston Scientific, CSI, Medtronic, Teleflex, and Philips. Dr Kobayashi has a consulting agreement with Abbott Vascular. Dr Miner has received investigator-initiated research support from Abbott Vascular. Dr Samuels has served as a consultant and has served on a Speaker’s Bureau for Abbott Vascular and Philips. Dr Shah has received research support from Abbott Vascular and the FDA of the U.S. Department of Health and Human Services (HHS). Dr Wei has served on an advisory board for Abbott Vascular. Dr Fearon has received institutional research support from Abbott Vascular, Medtronic, and the NIH (5R33HL139929-05); has a consulting agreement with CathWorks and Siemens; and has stock options with HeartFlow. Dr Henry has received research support and honoraria from Neovasc. Dr Moses has served as a consultant for Covanos; and has equity in Orchestra BioMed and Covanos. Dr Tremmel has received honoraria from and served on advisory boards for Abbott Vascular; has received honoraria and research funding from Boston Scientific; and has received honoraria from Shockwave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Aim: To investigate the effect of tandem use of transient balloon occlusion of the descending aorta (AO) and percutaneous left ventricular assist device (pl-VAD) during cardiopulmonary resuscitation in a large animal model of prolonged cardiac arrest., Methods: Ventricular fibrillation was induced and left untreated for 8 minutes followed by 16 minutes of mechanical CPR (mCPR) in 24 swine, under general anesthesia. Animals were randomized to 3 treatment groups (n = 8 per group): A) pL-VAD (Impella CP®) B) pL-VAD+AO, and C) AO. Impella CP® and the aortic balloon catheter were inserted via the femoral arteries. mCPR was continued during treatment. Defibrillation was attempted 3 times starting at minute 28 and then every 4 minutes. Haemodynamic, cardiac function and blood gas measurements were recorded for up to 4 hours., Results: Coronary perfusion pressure (CoPP) in the pL-VAD+AO Group increased by a mean (SD) of 29.2(13.94) mmHg compared to an increase of 7.1(12.08) and 7.1(5.95) mmHg for groups pL-VAD and AO respectively (p = 0.02). Similarly, cerebral perfusion pressure (CePP) in pL-VAD+AO increased by a mean (SD) of 23.6 (6.11), mmHg compared with 0.97 (9.07) and 6.9 (7.98) mmHg for the other two groups (p < 0.001). The rate of return of spontaneous heartbeat (ROSHB) was 87.5%, 75%, and 100% for pL-VAD+AO, pL-VAD, and AO., Conclusion: Combined AO and pL-VAD improved CPR hemodynamics compared to either intervention alone in this swine model of prolonged cardiac arrest., Competing Interests: Declaration of Competing Interest N.R.S. has received honoraria for speaking from Zoll, Cordis, and Shockwave and is a consultant for Abbott and Philips. The other authors declare no conflict of interest. RWN is part of Resuscitation Editorial Board., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We review a comprehensive risk assessment approach for percutaneous coronary interventions in older adults and highlight the relevance of geriatric syndromes within that broader perspective to optimize patient-centered outcomes in interventional cardiology practice. Reflecting the influence of geriatric principles in older adults undergoing percutaneous coronary interventions, we propose a "geriatric" heart team to incorporate the expertise of geriatric specialists in addition to the traditional heart team members, facilitate uptake of the geriatric risk assessment into the preprocedural risk assessment, and address ways to mitigate these geriatric risks. We also address goals of care in older adults, highlighting common priorities that can impact shared decision making among older patients, as well as frequently encountered pharmacotherapeutic considerations in the older adult population. Finally, we clarify gaps in current knowledge and describe crucial areas for future investigation.

Background and Aims: Cerebral embolic protection (CEP) devices are employed to capture embolic debris and reduce the risk of stroke during transcatheter aortic valve replacement (TAVR). Evidence is mixed regarding the safety and efficacy of CEP. We aimed to summarize the safety and effectiveness of CEP use during TAVR., Methods: Electronic databases, including PubMed, PubMed Central, Scopus, Cochrane Library, and Embase, were searched using relevant search terms for articles relating to CEP. All relevant data from 20 studies were extracted into a standardized form. Statistical analyses were performed using Revman 5.4. Odds ratio (OR) or mean differences (MDs) were used to estimate the desired outcome with a 95% confidence interval (CI)., Results: Twenty studies (eight randomized controlled trials [RCTs]) involving 210,871 patients (19,261 in the CEP group and 191,610 in TAVR without the CEP group) were included. The use of CEP was associated with a lower odds of 30-day mortality by 39% (OR: 0.61, 95% CI: 0.53-0.70) and stroke by 31% (OR: 0.69, 95% CI: 0.52-0.92). Comparing devices, benefit in terms of mortality and stroke was observed with the use of the Sentinel device (Boston Scientific), but not among other devices. No differences were observed in the outcomes of acute kidney injury, major or life-threatening bleeding events, or major vascular complications between groups. When only RCTs were included, there were no observed differences in the primary or secondary outcomes for CEP versus no CEP use during TAVR., Conclusions: The totality of evidence suggests a net benefit for the use of CEP, weighted by studies in which the Sentinal device was used. However, given the RCT subanalysis, additional evidence is needed to identify patients at the highest risk of stroke for optimal decision-making., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Stroke is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, possibly due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetics of ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI) and further combined the results with previously published MegaStroke. Five novel loci for ischemic stroke ( LAMC1 , CALCRL , PLSCR1 , CDKN1A , and SWAP70 ) were identified after replication in four additional datasets. One previously reported locus showed significant ancestry heterogeneity ( ABO ), and one showed significant sex heterogeneity ( ALDH2 ). The ALDH2 association was male specific (males p = 1.67e-24, females p = 0.126) and was additionally observed only in the East Asian ancestry (male) samples. These findings emphasize the need for more diverse datasets with large sample sizes to further understand the genetic predisposition of stroke in different ancestry and sex groups., Competing Interests: N.R.S. is an advisor for Abbott, Philips, and Shockwave and has received honoraria for speaking from Zoll, Cordis. C.J.W.’s spouse works at Regeneron Pharmaceuticals., (© 2023 The Authors.)

As the population ages, older adults represent an increasing proportion of patients referred to the cardiac catheterization laboratory. Older adults are the highest-risk group for morbidity and mortality, particularly after complex, high-risk percutaneous coronary interventions. Structured risk assessment plays a key role in differentiating patients who are likely to derive net benefit vs those who have disproportionate risks for harm. Conventional risk assessment tools from national cardiovascular societies typically rely on 3 pillars: 1) cardiovascular risk; 2) physiologic and hemodynamic risk; and 3) anatomic and procedural risks. We propose adding a fourth pillar: geriatric syndromes, as geriatric domains can supersede all other aspects of risk.

Background Ectonucleotidases maintain vascular homeostasis by metabolizing extracellular nucleotides, modulating inflammation and thrombosis, and potentially, myocardial flow through adenosine generation. Evidence implicates dysfunction or deficiency of ectonucleotidases CD39 or CD73 in human disease; the utility of measuring levels of circulating ectonucleotidases as plasma biomarkers of coronary artery dysfunction or disease has not been previously reported. Methods and Results A total of 529 individuals undergoing clinically indicated positron emission tomography stress testing between 2015 and 2019 were enrolled in this single-center retrospective analysis. Baseline demographics, clinical data, nuclear stress test, and coronary artery calcium score variables were collected, as well as a blood sample. CD39 and CD73 levels were assessed as binary (detectable, undetectable) or continuous variables using ELISAs. Plasma CD39 was detectable in 24% of White and 8% of Black study participants ( P =0.02). Of the clinical history variables examined, ectonucleotidase levels were most strongly associated with underlying liver disease and not other traditional coronary artery disease risk factors. Intriguingly, detection of circulating ectonucleotidase was inversely associated with stress myocardial blood flow (2.3±0.8 mL/min per g versus 2.7 mL/min per g±1.1 for detectable versus undetectable CD39 levels, P <0.001) and global myocardial flow reserve (Pearson correlation between myocardial flow reserve and log(CD73) -0.19, P <0.001). A subanalysis showed these differences held true independent of liver disease. Conclusions Vasodilatory adenosine is the expected product of local ectonucleotidase activity, yet these data support an inverse relationship between plasma ectonucleotidases, stress myocardial blood flow (CD39), and myocardial flow reserve (CD73). These findings support the conclusion that plasma levels of ectonucleotidases, which may be shed from the endothelial surface, contribute to reduced stress myocardial blood flow and myocardial flow reserve.

Background: Elevated cardiac troponin (cTn) levels in patients with COVID-19 has been associated with worse outcomes. Guidelines on best practices of those patients remain uncertain., Methods: We included patients with COVID-19 and cTn above the assay-specific upper limit of normal (ULN) enrolled in the American Heart Association's COVID-19 registry between March 2020-January 2021. Site-level variability in invasive coronary angiography, LVEF assessment, ICU utilization, and inpatient mortality were determined by calculating adjusted median odds ratio (MOR) using hierarchical logistic regression models. Temporal trends were assessed with Cochran-Armitage trend test., Results: Among 32,636 patients, we included 6234 (19.4 %) with cTn above ULN (age 68.7 ± 16.0 years, 56.5 % male, 51.5 % Caucasian), of whom 1365 (21.6 %) had ≥5-fold elevations. Across 55 sites, the median rate of invasive coronary angiography was 0.1 % with adjusted MOR 1.5(1.0,2.3), median LVEF assessment was 25.5 %, MOR 3.0(2.2,3.9), ICU utilization was 41.7 %, MOR 2.2(1.8,2.6), and mortality was 20.9 %, MOR 1.7(1.5,2.0). Over time, we noted a significant increase in invasive coronary angiography (p-trend = 0.001), and LVEF assessment (p-trend<0.001), and reduction in mortality (p-trend<0.001), without significant change in ICU admissions (p-trend = 0.08). Similar variability and temporal trends were seen among patients with ≥5-fold cTn elevation., Conclusions: The use of invasive coronary angiography among patients with COVID-19 and myocardial injury was very low during the early pandemic. We found moderate institutional variability in processes of care with an uptrend in invasive catheterization and LVEF assessment, and downtrend in mortality. Comparative effectiveness studies are needed to examine whether variability in care is associated with differences in outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: The 10-year Atherosclerotic Cardiovascular Disease risk score is the standard approach to predict risk of incident cardiovascular events, and recently, addition of coronary artery disease (CAD) polygenic scores has been evaluated. Although age and sex strongly predict the risk of CAD, their interaction with genetic risk prediction has not been systematically examined. This study performed an extensive evaluation of age and sex effects in genetic CAD risk prediction., Methods: The population-based Norwegian HUNT2 (Trøndelag Health Study 2) cohort of 51 036 individuals was used as the primary dataset. Findings were replicated in the UK Biobank (372 410 individuals). Models for 10-year CAD risk were fitted using Cox proportional hazards, and Harrell concordance index, sensitivity, and specificity were compared., Results: Inclusion of age and sex interactions of CAD polygenic score to the prediction models increased the C-index and sensitivity by accounting for nonadditive effects of CAD polygenic score and likely countering the observed survival bias in the baseline. The sensitivity for females was lower than males in all models including genetic information. We identified a total of 82.6% of incident CAD cases by using a 2-step approach: (1) Atherosclerotic Cardiovascular Disease risk score (74.1%) and (2) the CAD polygenic score interaction model for those in low clinical risk (additional 8.5%)., Conclusions: These findings highlight the importance and complexity of genetic risk in predicting CAD. There is a need for modeling age- and sex-interaction terms with polygenic scores to optimize detection of individuals at high risk, those who warrant preventive interventions. Sex-specific studies are needed to understand and estimate CAD risk with genetic information.

Cardiovascular disease is the most common cause of death worldwide, especially beyond the age of 65 years, with the vast majority of morbidity and mortality due to myocardial infarction and stroke. Vascular pathology stems from a combination of genetic risk, environmental factors, and the biologic changes associated with aging. The pathogenesis underlying the development of vascular aging, and vascular calcification with aging, in particular, is still not fully understood. Accumulating data suggests that genetic risk, likely compounded by epigenetic modifications, environmental factors, including diabetes and chronic kidney disease, and the plasticity of vascular smooth muscle cells to acquire an osteogenic phenotype are major determinants of age-associated vascular calcification. Understanding the molecular mechanisms underlying genetic and modifiable risk factors in regulating age-associated vascular pathology may inspire strategies to promote healthy vascular aging. This article summarizes current knowledge of concepts and mechanisms of age-associated vascular disease, with an emphasis on vascular calcification.

Background: Racial and ethnic disparities in COVID-19 outcomes exist, but whether in-hospital care explains this difference is not known. We sought to determine racial and ethnic differences in demographics, comorbidities, in-hospital treatments, and in-hospital outcomes of patients hospitalized with COVID-19., Methods and Findings: This was a cohort study using MiCOVID-19, a multi-center, retrospective, collaborative quality improvement registry, which included data on patients hospitalized with COVID-19 across 38 hospitals in the State of Michigan. 2,639 adult patients with COVID-19 hospitalized at a site participating in the MiCOVID-19 Registry were randomly selected. Outcomes included in-hospital mortality, age at death, intensive care unit admission, and need for invasive mechanical ventilation by race and ethnicity. Baseline comorbidities differed by race and ethnicity. In addition, Black patients had higher lactate dehydrogenase, erythrocyte sedimentation rate, C-reactive protein, creatine phosphokinase, and ferritin levels. Black patients were less likely to receive dexamethasone and remdesivir compared with White patients (4.2% vs 14.3% and 2.2% vs. 11.8%, p < 0.001 for each). Black (18.7%) and White (19.6%) patients experienced greater mortality compared with Asian (13.0%) and Latino (5.9%) patients (p < 0.01). The mean age at death was significantly lower by 8 years for Black patients (69.4 ± 13.3 years) compared with White (77.9 ± 12.6), Asian (77.6 ± 6.6), and Latino patients (77.4 ± 15.5) (p < 0.001)., Conclusions: COVID-19 mortality appears to be driven by both pre-hospitalization clinical and social factors and potentially in-hospital care. Policies aimed at population health and equitable application of evidence-based medical therapy are needed to alleviate the burden of COVID-19., Competing Interests: N.R.S. has received honoraria for speaking from Zoll Medical and is a Cordis and Philips advisory board member. This does not alter our adherence to PLOS ONE policies on sharing data and materials. V.C. has received royalties from Wolters Kluwer publishing, Oxford University publishing, and Lippincott for sales of academic textbooks. All other authors have no disclosures.

Commercial motor vehicle (CMV) drivers have an increased risk for cardiometabolic risk factors and higher rates of cardiovascular disease relative to the general population. Lifestyle factors, including the sedentary nature of driving and lack of access to healthy foods, contribute to the disproportionately high cardiovascular disease (CVD) risk among commercial vehicle (CMV) drivers. Occupational physicals represent an important opportunity to reach populations with a high prevalence and incidence of coronary artery disease who may not otherwise seek preventive care. These visits are an opportunity to discuss primary and secondary prevention, including lifestyle topics such as diet and exercise, and potentially recommend or implement preventive medical therapy when indicated. Future iterations of licensing guidelines for drivers should seek to incorporate updated recommendations regarding diet, physical activity, and preventive pharmacologic therapies., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Sutton has served as an advisor to Abbott, Cordis, Shockwave, and Philips, and has received honoraria for speaking from Zoll, Shockwave, Cordis, and Abbott. All other authors have no disclosures., (© 2022 The Authors.)

Background: Previous studies have reported sex-specific differences in the presentation, mechanisms, and outcomes of acute myocardial infarction (AMI). We assessed differences between women and men in the incidence and in-hospital outcomes of left ventricular (LV) aneurysm complicating AMI., Methods: Hospitalizations for AMI with LV aneurysm were identified retrospectively in the National Inpatient Sample (NIS) from 2001 to 2017. Incidence and trends in in-hospital mortality, complications, length of stay and costs were analyzed in women and men., Results: A total of 16,334 AMI hospitalizations with concomitant LV aneurysm were identified including 6994 (42.8%) women and 9340 (57.2%) men. Among these hospitalizations, women had a higher incidence of LV aneurysm compared to men (0.16% vs. 0.14%; p < 0.001). Unadjusted in-hospital mortality was higher in women than men (12.7% vs. 7.2%; p < 0.001). After adjusting for demographic and baseline characteristics and excluding inter-hospital transfers, women with AMI complicated by LV aneurysm had 49% greater odds of in-hospital mortality than men (OR 1.49, 95% confidence interval 1.06-2.10, p = 0.02). Women with LV aneurysm were less likely than men to undergo percutaneous coronary intervention (28.5% vs. 35.4%; p < 0.001), bypass surgery (15.8% vs. 25.1%; p < 0.001), coronary atherectomy (0.8% vs. 1.9%; p = 0.009) and LV aneurysm surgery (7.8% vs. 11.1%; p = 0.001)., Conclusions: In this large population-based cohort study, women had a slightly higher incidence but dramatically higher in-hospital mortality associated with LV aneurysm complicating AMI compared to men. Further research is necessary to validate strategies to ensure that women receive guideline-directed therapy for AMI and LV aneurysm to address the sex disparity in mortality., Competing Interests: Dr. Sutton is part of the advisory committee for Cordis and has received speaking honoraria from Zoll. Dr. Sutton is also supported by a grant from the National Institute on Aging: 1K76AG064426-01A1. Dr. Goldsweig is supported by a grant from the National Institute of General Medical Sciences, 1U54GM115458, and the UNMC Center for Heart and Vascular Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH., (© 2022 The Authors.)

Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of myocardial infarction in young and middle-aged women that has gained increasing awareness in recent years. Its diagnosis presents a challenge. Invasive coronary angiography is the primary imaging modality for diagnosing SCAD; however, it carries risk in these patients, who have an increased predisposition to complications. Advances in CT technology enable robust noninvasive evaluation of the coronary arteries at low radiation doses and have been increasingly utilized for the diagnosis or resolution of SCAD, in hemodynamically stable patients or when diagnosis of SCAD is uncertain at invasive angiography, particularly in proximal vessels. However, criteria for the diagnosis of SCAD with use of coronary CT angiography (CCTA) have not been currently established, and sensitivity and specificity for diagnosis have not yet been defined. The appearance of SCAD at CCTA can be subtle and can be missed, especially in distal small-caliber coronary arteries; hence utilization of other noninvasive imaging multimodalities may help solve this diagnostic challenge. Accurate and prompt diagnosis is vital, as management of SCAD differs significantly from that of traditional atherosclerotic acute coronary syndromes, with conservative management preferred for the majority of SCAD patients, and invasive treatment reserved for those with ongoing or recurrent ischemia, heart failure, or hemodynamic compromise. The goal of this review is twofold: (a) to discuss the potential role of CCTA in the diagnosis of SCAD, and (b) to discuss the role of multimodality imaging that may improve diagnostic yield, guide management, and enable subsequent surveillance. An invited commentary by Ordovas is available online . Online supplemental material is available for this article. © RSNA, 2021.

Objective: To examine racial and ethnic disparities in clinical, financial, and mental health outcomes within a diverse sample of hospitalized COVID-19-positive patients in the 60 days postdischarge., Design: A cross-sectional study., Setting and Participants: A total of 2217 adult patients who were hospitalized with a COVID-19-positive diagnosis as evidenced by test (reverse-transcriptase polymerase chain reaction), a discharge diagnosis of COVID-19 (ICD-10 code U07.1), or strong documented clinical suspicion of COVID-19 but no testing completed or recorded owing to logistical constraints (n=24)., Methods: Patient records were abstracted for the Mi-COVID19 data registry, including the hospital and insurer data of patients discharged from one of 38 participating hospitals in Michigan between March 16, 2020, and July 1, 2020. Registry data also included patient responses to a brief telephone survey on postdischarge employment, mental and emotional health, persistence of COVID-19-related symptoms, and medical follow-up. Descriptive statistics were used to summarize data; analysis of variance and Pearson chi-squared test were used to evaluate racial and ethnic variances among patient outcomes and survey responses., Results: Black patients experienced the lowest physician follow-up postdischarge (n = 65, 60.2%) and the longest delays in returning to work (average 35.5 days). More than half of hospital readmissions within the 60 days following discharge were among nonwhite patients (n = 144, 55%). The majority of postdischarge deaths were among white patients (n = 153, 21.5%), most of whom were discharged on palliative care (n = 103). Less than a quarter of patients discharged back to assisted living, skilled nursing facilities, or subacute rehabilitation facilities remained at those locations in the 60 days following discharge (n = 48)., Conclusions and Implications: Increased attention to postdischarge care coordination is critical to reducing negative health outcomes following a COVID-19-related hospitalization., (Copyright © 2021 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

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Optimal treatment of stable ischemic heart disease for those in the transportation industry is considered in the context of the individual's health, as well as with the perspective that sudden impairment could have catastrophic consequences for others. This article focuses on two high risk occupations that one may encounter in practice: commercial motor vehicle drivers and commercial pilots. This article discusses coronary heart disease in patients in high risk occupations and covers current guideline recommendations for screening, treatment, and secondary prevention. The importance of the complimentary perspectives of the regulatory agency, medical examiners, physicians, and pilot or driver are considered in this narrative review, as are considerations for future guideline updates.

There is a need for therapeutic approaches to prevent and mitigate the effects of Coronavirus Disease (2019) (COVID-19). The histone deacetylase (HDAC) inhibitor valproic acid, which has been available for the therapy of epilepsy for many years, is a drug that could be repurposed for patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This article will review the reasons to consider valproic acid as a potential therapeutic to prevent severe COVID-19. Valproic acid could reduce angiotensin-converting enzyme 2 and transmembrane serine protease 2 expression, required for SARS-CoV-2 viral entry, and modulate the immune cellular and cytokine response to infection, thereby reducing end-organ damage. The combined anti-thrombotic, anti-platelet, and anti-inflammatory effects of valproic acid suggest it could be a promising therapeutic target for COVID-19., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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COVID-19 has had a substantial impact on clinical care and lifestyles globally. The State of Michigan reports over 80,000 positive COVID-19 tests between March 1, 2020 and July 29, 2020. We surveyed 8,041 Michigan Medicine biorepository participants in late June 2020. We found that 55% of COVID-19 cases reported no known exposure to family members or to someone outside the house diagnosed with COVID-19. A significantly higher rate of COVID-19 cases were employed as essential workers (45% vs 19%, p = 9x10-12). COVID-19 cases reporting a fever were more likely to require hospitalization (categorized as severe; OR = 4.4 [95% CI: 1.6-12.5, p = 0.005]) whereas respondents reporting rhinorrhea was less likely to require hospitalization (categorized as mild-to-moderate; OR = 0.16 [95% CI: 0.04-0.73, p = 0.018]). African-Americans reported higher rates of being diagnosed with COVID-19 (OR = 4.0 [95% CI: 2.2-7.2, p = 5x10-6]), as well as higher rates of exposure to family or someone outside the household diagnosed with COVID-19, an annual household income < $40,000, living in rental housing, and chronic diseases. During the Executive Order in Michigan, African Americans, women, and the lowest income group reported worsening health behaviors and higher overall concern for the potential detrimental effects of the pandemic. The higher risk of contracting COVID-19 observed among African Americans may be due to the increased rates of working as essential employees, lower socioeconomic status, and exposure to known positive cases. Continued efforts should focus on COVID-19 prevention and mitigation strategies, as well as address the inequality gaps that result in higher risks for both short-term and long-term health outcomes., Competing Interests: We disclose that Dr. Willer’s spouse works for Regeneron Pharmaceuticals Inc., and that Dr. Brummett is a consultant for Heron Therapeutics and Alosa Health. These disclosures do not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose of Review: The incidence of arterial calcification increases with age, can occur independently of atherosclerosis and hyperlipidemia, contributes to vessel stiffening, and is associated with adverse cardiovascular outcomes. Here, we provide an up-to-date review of how aging leads to arterial calcification and discuss potential therapies., Recent Findings: Recent research suggests that mitochondrial dysfunction (impaired efficiency of the respiratory chain, increased reactive oxygen species production, and a high mutation rate of mitochondrial DNA), cellular senescence, ectonucleotidases, and extrinsic factors such as hyperglycemia promote age-determined calcification. We discuss the future potential impact of antilipidemics, senolytics, and poly(ADP-ribose)polymerases inhibitors on age-associated arterial calcification., Summary: Understanding how mechanisms of aging lead to arterial calcification will allow us to pinpoint prospective strategies to mitigate arterial calcification, even after the effects of aging have already begun to occur.

Chronic kidney disease is a major risk factor for developing coronary artery disease, serving as an independent risk factor while overlapping with other risk factors. Percutaneous coronary intervention is a cornerstone of therapy for coronary artery disease and requires contrast media, which can contribute to renal injury. Identifying patients at risk for contrast-induced nephropathy is critical for preventing renal injury, which is associated with short- and long-term mortality. Determination of the potential risk for contrast-induced nephropathy and a new need for dialysis using validated risk prediction tools is a method of identifying patients at high risk for this complication., Competing Interests: Disclosure The authors have no disclosures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: CD73 is an ectonucleotidase which catalyzes the conversion of AMP (adenosine monophosphate) to adenosine. Adenosine has been shown to be anti-inflammatory and vasorelaxant. The impact of ectonucleotidases on age-dependent atherosclerosis remains unclear. Our aim was to investigate the role of CD73 in age-dependent accumulation of atherosclerosis. Approach and results: Mice doubly deficient in CD73 and ApoE (apolipoprotein E; ( cd73 - /- /apoE -/- ) were generated, and the extent of aortic atherosclerotic plaque was compared with apoE -/- controls at 12, 20, 32, and 52 weeks. By 12 weeks of age, cd73 -/- /apoE -/- mice exhibited a significant increase in plaque (1.4±0.5% of the total vessel surface versus 0.4±0.1% in apoE -/- controls, P <0.005). By 20 weeks of age, this difference disappeared (2.9±0.4% versus 3.3±0.7%). A significant reversal in phenotype emerged at 32 weeks (9.8±1.2% versus 18.3±1.4%; P <0.0001) and persisted at the 52 week timepoint (22.4±2.1% versus 37.0±2.1%; P <0.0001). The inflammatory response to aging was found to be comparable between cd73 -/- /apoE -/- mice and apoE -/- controls. A reduction in lipolysis in CD73 competent mice was observed, even with similar plasma lipid levels ( cd73 -/- /apoE -/- versus apoE -/- at 12 weeks [16.2±0.7 versus 9.5±1.4 nmol glycerol/well], 32 weeks [24.1±1.5 versus 7.4±0.4 nmol/well], and 52 weeks [13.8±0.62 versus 12.7±2.0 nmol/well], P <0.001)., Conclusions: At early time points, CD73 exerts a subtle antiatherosclerotic influence, but with age, the pattern reverses, and the presence of CD73 promoted suppression of lipid catabolism.