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Background: Levels of free myeloperoxidase (MPO), a cardiovascular risk marker, have been reported to decline with standard care. Whether such declines signify decreased risk of mortality remains unknown., Design: Cox proportional hazard models were generated using data from a retrospective cohort study of prospectively collected measures., Participants: Patients (3,658) who had MPO measurements and LDL-C ≥ 90 mg/dL during 2011-2015 were selected based on a stratified random sampling on MPO risk level. Baseline MPO was either low (<470 pmol/L), moderate (470-539 pmol/L), or high (≥540 pmol/L)., Main Outcomes and Measures: First occurrence of MACE (myocardial infarction, stroke, coronary revascularization, or all-cause death)., Results: Mean age was 66.5 years, and 64.7% were women. During a mean 6.5-year follow-up, crude incidence per 1000 patient years was driven by death. The incidence and all-cause death was highest for patients with high MPO (21.2; 95% CI, 19.0-23.7), then moderate (14.6; 95% CI, 11.5-18.5) and low (2.3; 95% CI, 1.2-4.6) MPO. After adjusting for age, sex, and cardiovascular risk factors, risk of cardiovascular death did not differ significantly between patients with high and low MPO (HR, 1.57; 95% CI, 0.56-4.39), but patients with high MPO had greater risk of non-cardiovascular (HR, 6.15; 95% CI, 2.27-16.64) and all-cause (HR, 3.83; 95% CI, 1.88-7.78) death. During follow-up, a 100 pmol/L decrease in MPO correlated with a 5% reduction in mortality (HR, 0.95; 95% CI, 0.93-0.97) over 5 years., Conclusions: Free circulating MPO is a strong marker of risk of mortality. Monitoring changes in MPO levels over time may provide insight into changes in physiology that mark a patient for increased risk of mortality., Competing Interests: Dr. Penn is the founder of Cleveland HeartLab, Inc and a consulting Medical Director for Quest Diagnostics Center of Excellence for Cardiometabolic Testing at Cleveland HeartLab. Dr. Saghir is an employee of Quest Diagnostics, including salary and equity holdings. Dr. David Wrenn is an employee of Quest Diagnostics, including salary and equity holdings. Dr. Klemes is the Chief Medical Officer of MDVIP, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Penn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Researchers routinely evaluate novel biomarkers for incorporation into clinical risk models, weighing tradeoffs between cost, availability, and ease of deployment. For risk assessment in population health initiatives, ideal inputs would be those already available for most patients. We hypothesized that common hematologic markers (eg, hematocrit), available in an outpatient complete blood count without differential, would be useful to develop risk models for cardiovascular events., Methods: We developed Cox proportional hazards models for predicting heart attack, ischemic stroke, heart failure hospitalization, revascularization, and all-cause mortality. For predictors, we used 10 hematologic indices (eg, hematocrit) from routine laboratory measurements, collected March 2016 to May 2017 along with demographic data and diagnostic codes. As outcomes, we used neural network-based automated event adjudication of 1 028 294 discharge summaries. We trained models on 23 238 patients from one hospital in Boston and evaluated them on 29 671 patients from a second one. We assessed calibration using Brier score and discrimination using Harrell's concordance index. In addition, to determine the utility of high-dimensional interactions, we compared our proportional hazards models to random survival forest models., Results: Event rates in our cohort ranged from 0.0067 to 0.075 per person-year. Models using only hematology indices had concordance index ranging from 0.60 to 0.80 on an external validation set and showed the best discrimination when predicting heart failure (0.80 [95% CI, 0.79-0.82]) and all-cause mortality (0.78 [0.77-0.80]). Compared with models trained only on demographic data and diagnostic codes, models that also used hematology indices had better discrimination and calibration. The concordance index of the resulting models ranged from 0.75 to 0.85 and the improvement in concordance index ranged up to 0.072. Random survival forests had minimal improvement over proportional hazards models., Conclusions: We conclude that low-cost, ubiquitous inputs, if biologically informative, can provide population-level readouts of risk.

While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic "buckets." Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased "omic" approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.

Membrane phospholipid metabolism forms lysophospholipids, which possess unique biochemical and biophysical properties that influence membrane structure and dynamics. However, lysophospholipids also function as ligands for G-protein-coupled receptors that influence embryonic development, postnatal physiology, and disease. The 2 most well-studied species-lysophosphatidic acid and S1P (sphingosine 1-phosphate)-are particularly relevant to vascular development, physiology, and cardiovascular diseases. This review summarizes the role of lysophosphatidic acid and S1P in vascular developmental processes, endothelial cell biology, and their roles in cardiovascular disease processes. In addition, we also point out the apparent connections between lysophospholipid biology and the Wnt (int/wingless family) pathway, an evolutionarily conserved fundamental developmental signaling system. The discovery that components of the lysophospholipid signaling system are key genetic determinants of cardiovascular disease has warranted current and future research in this field. As pharmacological approaches to modulate lysophospholipid signaling have entered the clinical sphere, new findings in this field promise to influence novel therapeutic strategies in cardiovascular diseases.

Background: Whole-genome sequencing (WGS) costs are falling, yet, outside oncology, this information is seldom used in adult clinics. We piloted a rapid WGS (rWGS) workflow, focusing initially on estimating power for a feasibility study of introducing genome information into acute cardiovascular care., Methods: A prospective implementation study was conducted to test the feasibility and clinical utility of rWGS in acute cardiovascular care. rWGS was performed on 50 adult patients with acute cardiovascular events and cardiac arrest survivors, testing for primary and secondary disease-causing variants, cardiovascular-related pharmacogenomics, and carrier status for recessive diseases. The impact of returning rWGS results on short-term clinical care of participants was investigated. The utility of polygenic risk scores to stratify coronary artery disease was also assessed., Results: Pathogenic variants, typically secondary findings, were identified in 20% (95% CI, 11.7-34.3). About 60% (95% CI, 46.2-72.4) of participants were carriers for one or more recessive traits, most commonly in HFE and SERPINA1 genes. Although 64% (95% CI, 50.1-75.9) of participants carried at least one pharmacogenetic variant of cardiovascular relevance, these were actionable in only 14% (95% CI, 7-26.2). Coronary artery disease prevalence among participants at the 95th percentile of polygenic risk score was 88.2% (95% CI, 71.8-95.7)., Conclusions: We demonstrated the feasibility of rWGS integration into the inpatient management of adults with acute cardiovascular events. Our pilot identified pathogenic variants in one out of 5 acute vascular patients. Integrating rWGS in clinical care will progressively increase actionability.

Introduction: Our understanding of the complexity of cardiovascular disease pathophysiology remains very incomplete and has hampered cardiovascular drug development over recent decades. The prevalence of cardiovascular diseases and their increasing global burden call for novel strategies to address disease biology and drug discovery. Areas covered: This review describes the recent history of cardiovascular drug discovery using in vivo phenotype-based screening in zebrafish. The rationale for the use of this model is highlighted and the initial efforts in the fields of disease modeling and high-throughput screening are illustrated. Finally, the advantages and limitations of in vivo zebrafish screening are discussed, highlighting newer approaches, such as genome editing technologies, to accelerate our understanding of disease biology and the development of precise disease models. Expert opinion: Full understanding and faithful modeling of specific cardiovascular disease is a rate-limiting step for cardiovascular drug discovery. The resurgence of in vivo phenotype screening together with the advancement of systems biology approaches allows for the identification of lead compounds which show efficacy on integrative disease biology in the absence of validated targets. This strategy bypasses current gaps in knowledge of disease biology and paves the way for successful drug discovery and downstream molecular target identification.

Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized., Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences., Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed., Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = -3.2; 95% CI: -6.4 to -0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90)., Conclusions: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The utility of a transitions-of-care (TOC) pharmacist intervention focused on improving the quality and safety of the medication process for high-risk cardiovascular patients was evaluated., Methods: A quality-improvement initiative was developed for patients with heart failure or acute coronary syndrome followed longitudinally at a hospital's outpatient cardiovascular clinic. The TOC pharmacist intervention occurred either before a patient's outpatient cardiovascular clinic appointment or during a hospitalization. The major outcome analyzed was the number of unplanned hospital readmissions within 30 days. Additional endpoints evaluated included the time to healthcare utilization, number of medication discrepancies identified, percentage of therapeutic recommendations accepted by a provider, number of medication access issues resolved, patient cost savings, patient satisfaction, and mean time spent on an intervention by the pharmacist per patient encounter., Results: A total of 118 patients received the TOC pharmacist intervention. A total of 516 medication discrepancies were identified and corrected, with 55.6% of discrepancies involving cardiovascular medications. A total of 244 recommendations for therapeutic optimization were provided, with an 81% provider acceptance rate and a 100% patient satisfaction rate. Fifty-five patients were provided with medication cost savings, and medication-access issues were resolved for 8 patients. A TOC pharmacist spent means of 98 and 73 minutes on patient education and coordination of care during inpatient and ambulatory encounters, respectively. The 30-day hospital readmission rate for patients with heart failure was reduced by 20%., Conclusion: A TOC pharmacist intervention improved the quality and safety of care across both inpatient and ambulatory settings for high-risk cardiovascular patients at our institution., Competing Interests: DisclosuresThe authors have declared no potential conflicts of interest., (Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

The completion of the Human Genome Project has unleashed a wealth of human genomics information, but it remains unclear how best to implement this information for the benefit of patients. The standard approach of biomedical research, with researchers pursuing advances in knowledge in the laboratory and, separately, clinicians translating research findings into the clinic as much as decades later, will need to give way to new interdisciplinary models for research in genomic medicine. These models should include scientists and clinicians actively working as teams to study patients and populations recruited in clinical settings and communities to make genomics discoveries-through the combined efforts of data scientists, clinical researchers, epidemiologists, and basic scientists-and to rapidly apply these discoveries in the clinic for the prediction, prevention, diagnosis, prognosis, and treatment of cardiovascular diseases and stroke. The highly publicized US Precision Medicine Initiative, also known as All of Us, is a large-scale program funded by the US National Institutes of Health that will energize these efforts, but several ongoing studies such as the UK Biobank Initiative; the Million Veteran Program; the Electronic Medical Records and Genomics Network; the Kaiser Permanente Research Program on Genes, Environment and Health; and the DiscovEHR collaboration are already providing exemplary models of this kind of interdisciplinary work. In this statement, we outline the opportunities and challenges in broadly implementing new interdisciplinary models in academic medical centers and community settings and bringing the promise of genomics to fruition., Competing Interests: The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest., (© 2018 American Heart Association, Inc.)

Rationale: Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking., Objective: Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance., Methods and Results: Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011-2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|>0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to P <9.5e -46 for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pVo 2 ) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements ( P <0.01). Compared with a probabilistic model, including 23 independent predictors of pVo 2 and pVo 2 itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold ( P <0.0001; 95% CI, 2.2-8.1) and 2.8-fold ( P =0.0018; 95% CI, 1.5-5.2) increase in hazard for age- and pVo 2 -adjusted all-cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk-stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort., Conclusions: Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pVo 2 that predict hospitalization in patients with exercise intolerance., (© 2018 American Heart Association, Inc.)

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care., (© 2015 American Heart Association, Inc.)

Purpose of Review: The review is designed to outline the major developments in genetic testing in the cardiovascular arena in the past year or so. This is an exciting time in genetic testing as whole exome and whole genome approaches finally reach the clinic. These new approaches offer insight into disease causation in families in which this might previously have been inaccessible, and also bring a wide range of interpretative challenges., Recent Findings: Among the most significant recent findings has been the extent of physiologic rare coding variation in the human genome. New disease genes have been identified through whole exome studies in neonatal arrhythmia, congenital heart disease and coronary artery disease that were simply inaccessible with other techniques. This has not only shed light on the challenges of genetic testing at this scale, but has also sharply defined the limits of prior gene-panel focused testing. As novel therapies targeting specific genetic subsets of disease become available, genetic testing will become a part of routine clinical care., Summary: The pace of change in sequencing technologies has begun to transform clinical medicine, and cardiovascular disease is no exception. The complexity of such studies emphasizes the importance of real-time communication between the genetics laboratory and genetically informed clinicians. New efforts in data and knowledge management will be central to the continued advancement of genetic testing.

Clinical and molecular genetics are inextricably linked. In the last two decades genetic studies have revealed the causes of several forms of structural heart disease. Recent work is extending the insights from inherited arrhythmias and cardiomyopathies to other forms of heart disease. In this review we outline the current state of the art for the genetics of adult structural heart disease, in particular the cardiomyopathies, valvular heart disease and aortic disease. The general approaches are described with a focus on clinical relevance, while potential areas for imminent innovation in diagnosis and therapeutics are highlighted.

Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic 'buckets'. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased 'omic' approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development. [ABSTRACT FROM AUTHOR]

An editorial is presented which discusses the state-of-the-art strategies to assess the causality of newly identified variants in potential cardiovascular disease genes. It mentions the discovery of numerous disease genes for cardiomyopathies, arrhythmias, aortopathies, and other disorders through genetic and genomic studies which demontsrate complex relationships between genotype and phenotype.

The authors reflect on the insights from genome-wide associations (GWAs). Topics include correlation between common variants and peripheral or tissue-specific expression quantitative trait loci (eQTL), a study by N. A. M. Almontashiri and colleagues on disruption of specific transcription factor (TF) binding sites, and a phenotype gap in modern human genetics.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and challenges the capacity of health care systems globally. Atherosclerosis is the underlying pathophysiological entity in two-thirds of patients with CVD. When considering that atherosclerosis develops over decades, there is potentially great opportunity for prevention of associated events such as myocardial infarction and stroke. Subclinical atherosclerosis has been identified in its early stages in young individuals; however, there is no consensus on how to prevent progression to symptomatic disease. Given the growing burden of CVD, a paradigm shift is required—moving from late management of atherosclerotic CVD to earlier detection during the subclinical phase with the goal of potential cure or prevention of events. Studies must focus on how precision medicine using imaging and circulating biomarkers may identify atherosclerosis earlier and determine whether such a paradigm shift would lead to overall cost savings for global health. [Display omitted] • Early-stage subclinical atherosclerosis can be identified in young individuals, but evidence-based strategies are needed to prevent progression of disease and clinical events. • Precision medicine using imaging and circulating biomarkers could facilitate early identification of atherosclerosis and the development of curative interventions. • A paradigm shift based on these principles could reduce the global burden of CVD with enormous implications for population health. [ABSTRACT FROM AUTHOR]

The article comments on the impact of pharmacotherapy on mortality and morbidity in cardiovascular disease and also refers to an article published within the issue related to the same.

The Precision Medicine Initiative recently announced by President Barack Obama seeks to move the field of precision medicine more rapidly into clinical care. Precision medicine revolves around the concept of integrating individual-level data including genomics, biomarkers, lifestyle and other environmental factors, wearable device physiological data, and information from electronic health records to ultimately provide better clinical care to individual patients. The Precision Medicine Initiative as currently structured will primarily fund efforts in cancer genomics with longer-term goals of advancing precision medicine to all areas of health, and will be supported through creation of a 1 million person cohort study across the United States. This focused effort on precision medicine provides scientists, clinicians, and patients within the cardiovascular community an opportunity to work together boldly to advance clinical care; the community needs to be aware and engaged in the process as it progresses. This article provides a framework for potential involvement of the cardiovascular community in the Precision Medicine Initiative, while highlighting significant challenges for its successful implementation. [ABSTRACT FROM AUTHOR]

Abstract: Altered mechanical loading of the heart leads to hypertrophy, decompensated heart failure and fatal arrhythmias. However, the molecular mechanisms that link mechanical and electrical dysfunction remain poorly understood. Growing evidence suggest that ventricular electrical remodeling (VER) is a process that can be induced by altered mechanical stress, creating persistent electrophysiological changes that predispose the heart to life-threatening arrhythmias. While VER is clearly a physiological property of the human heart, as evidenced by “T wave memory”, it is also thought to occur in a variety of pathological states associated with altered ventricular activation such as bundle branch block, myocardial infarction, and cardiac pacing. Animal models that are currently being used for investigating stretch-induced VER have significant limitations. The zebrafish has recently emerged as an attractive animal model for studying cardiovascular disease and could overcome some of these limitations. Owing to its extensively sequenced genome, high conservation of gene function, and the comprehensive genetic resources that are available in this model, the zebrafish may provide new insights into the molecular mechanisms that drive detrimental electrical remodeling in response to stretch. Here, we have established a zebrafish model to study mechano-electrical feedback in the heart, which combines efficient genetic manipulation with high-precision stretch and high-resolution electrophysiology. In this model, only 90 min of ventricular stretch caused VER and recapitulated key features of VER found previously in the mammalian heart. Our data suggest that the zebrafish model is a powerful platform for investigating the molecular mechanisms underlying mechano-electrical feedback and VER in the heart. [Copyright &y& Elsevier]