INOCA: Ischemia in non-obstructive coronary arteries.

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.

Acute Coronary Syndrome in Women: An Update.

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.

Cardiovascular aging: spotlight on mitochondria.

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.

Percutaneous left ventricular assist devices in refractory cardiac arrest: The role of chest compressions.

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.

Effect of percutaneous ventricular assisted device on post-cardiac arrest myocardial dysfunction in swine model with prolonged cardiac arrest.

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/m2 (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/m2, 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.

Comprehensive Management of ANOCA, Part 1-Definition, Patient Population, and Diagnosis: JACC State-of-the-Art Review.

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.

Comprehensive Management of ANOCA, Part 2-Program Development, Treatment, and Research Initiatives: JACC State-of-the-Art Review.

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.

Predicting Contrast-induced Renal Complications.

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.

Multi-ancestry meta-analysis identifies 5 novel loci for ischemic stroke and reveals heterogeneity of effects between sexes and ancestries.

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.

A Geriatric Approach to Percutaneous Coronary Interventions in Older Adults, Part II: A JACC: Advances Expert Panel.

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.

Assessment and Management of Older Adults Undergoing PCI, Part 1: A JACC: Advances Expert Panel.

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.

Safety and efficacy of cerebral embolic protection devices for patients undergoing transcatheter aortic valve replacement: An updated meta-analysis.

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.

Haemodynamic impact of aortic balloon occlusion combined with percutaneous left ventricular assist device during cardiopulmonary resuscitation in a swine model of cardiac arrest.

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.

Identifiability of enzyme kinetic parameters in substrate competition: a case study of CD39/NTPDase1.

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.

Circulating Ectonucleotidases Signal Impaired Myocardial Perfusion at Rest and Stress.

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.

Site-level variability in the processes of care and outcomes over time among patients with COVID-19 and myocardial injury: Insights from the American Heart Association's COVID-19 Cardiovascular Disease Registry.

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.