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Sarcoidosis is a complex disease with heterogeneous clinical presentations that can affect virtually any organ. Although the lung is typically the most common organ involved, combined pulmonary and cardiac sarcoidosis (CS) account for most of the morbidity and mortality associated with this disease. Pulmonary sarcoidosis can be asymptomatic or result in impairment in quality of life and end-stage, severe, and/or life-threatening disease. The latter outcome is seen almost exclusively in those with fibrotic pulmonary sarcoidosis, which accounts for 10% to 20% of pulmonary sarcoidosis patients. CS is problematic to diagnose and may cause significant morbidity and death from heart failure or ventricular arrhythmias. The diagnosis of CS usually requires surrogate cardiac imaging biomarkers, as endomyocardial biopsy has relatively low yield, even with directed electrophysiological mapping. Treatment of CS is often multifactorial, involving a combination of antigranulomatous therapy and pharmacotherapy for cardiac arrhythmias and/or heart failure in addition to device placement and cardiac transplantation.

Highlights •The middle arterial layer, the tunica media, is composed of circumferentially arranged layers of VSMCs that are separated by concentrically arranged elastic lamellae, a form of ECM. •Advances in genetics and proteomics approaches have facilitated dramatic progress in our understanding of the key role of the ECM in vascular health and disease. •The emerging discoveries regarding the role of ECM in the vasculature hold promise to be developed into novel clinical disease biomarkers and even future therapies.

Objectives: The aim of this study was to evaluate the impact of initial deployment orientation of SAPIEN 3, Evolut, and ACURATE-neo transcatheter heart valves on their final orientation and neocommissural overlap with coronary arteries. Background: Coronary artery access and redo transcatheter aortic valve replacement (TAVR) following initial TAVR may be influenced by transcatheter heart valve orientation. In this study the impact of transcatheter heart valve deployment orientation on commissural alignment was evaluated. Methods: Pre-TAVR computed tomography and procedural fluoroscopy were analyzed in 828 patients who underwent TAVR (483 SAPIEN 3, 245 Evolut, and 100 ACURATE-neo valves) from March 2016 to September 2019 at 5 centers. Coplanar fluoroscopic views were coregistered to pre-TAVR computed tomography to determine commissural alignment. Severe overlap between neocommissural posts and coronary arteries was defined as 0° to 20° apart. The SAPIEN 3 had 1 commissural post crimped at 3, 6, 9, and 12 o'clock. The Evolut “Hat” marker and ACURATE-neo commissural post at deployment were classified as center back (CB), inner curve (IC), outer curve (OC), or center front (CF) and matched with final orientation. Results: Initial SAPIEN 3 crimped orientation had no impact on commissural alignment. Evolut “Hat” at OC or CF at initial deployment had less severe overlap than IC or CB (p < 0.001) against the left main (15.7% vs. 66.0%) and right coronary (7.1% vs. 51.1%) arteries. Tracking Evolut “Hat” at OC of the descending aorta (n = 107) improved OC at deployment from 70.2% to 91.6% (p = 0.002) and reduced coronary artery overlap by 36% to 60% (p < 0.05). ACURATE-neo commissural post at CB or IC during deployment had less coronary artery overlap compared to CF or OC (p < 0.001), with intentional alignment successful in 5 of 7 cases. Conclusions: This is the first systematic evaluation of commissural alignment in TAVR. More than 30% to 50% of cases had overlap with 1 or both coronary arteries. Initial SAPIEN 3 orientation had no impact on alignment, but specific initial orientations of Evolut and ACURATE improved alignment. Optimizing valve alignment to avoid coronary artery overlap will be important in coronary artery access and redo TAVR.

Macrophages are integral components of cardiac tissue and exert profound effects on the healthy and diseased heart. Paradigm shifting studies using advanced molecular techniques have revealed significant complexity within these macrophage populations that reside in the heart. In this final of a 4-part review series covering the macrophage in cardiovascular disease, the authors review the origins, dynamics, cell surface markers, and respective functions of each cardiac macrophage subset identified to date, including in the specific scenarios of myocarditis and after myocardial infarction. Looking ahead, a deeper understanding of the diverse and often dichotomous functions of cardiac macrophages will be essential for the development of targeted therapies to mitigate injury and orchestrate recovery of the diseased heart. Moreover, as macrophages are critical for cardiac healing, they are an emerging focus for therapeutic strategies aimed at minimizing cardiomyocyte death, ameliorating pathological cardiac remodeling, and for treating heart failure and after myocardial infarction.

It has long been recognized that the bone marrow is the primary site of origin for circulating monocytes that may later become macrophages in atherosclerotic lesions. However, only in recent times has the complex relationship among the bone marrow, monocytes/macrophages, and atherosclerotic plaques begun to be understood. Moreover, the systemic nature of these interactions, which also involves additional compartments such as extramedullary hematopoietic sites (i.e., spleen), is only just becoming apparent. In parallel, progressive advances in imaging and cell labeling techniques have opened new opportunities for in vivo imaging of monocyte/macrophage trafficking in atherosclerotic lesions and at the systemic level. In this Part 3 of a 4-part review series covering the macrophage in cardiovascular disease, the authors intersect systemic biology with advanced imaging techniques to explore monocyte and macrophage dynamics in the cardiovascular system, with an emphasis on how events at the systemic level might affect local atherosclerotic plaque biology.

Atherosclerosis is characterized by the retention of modified lipoproteins in the arterial wall. These modified lipoproteins activate resident macrophages and the recruitment of monocyte-derived cells, which differentiate into mononuclear phagocytes that ingest the deposited lipoproteins to become “foam cells”: a hallmark of this disease. In this Part 2 of a 4-part review series covering the macrophage in cardiovascular disease, we critically review the contributions and relevant pathobiology of monocytes, macrophages, and foam cells as relevant to atherosclerosis. We also review evidence that via various pathways, a failure of the resolution of inflammation is an additional key aspect of this disease process. Finally, we consider the likely role played by genomics and biological networks in controlling the macrophage phenotype in atherosclerosis. Collectively, these data provide substantial insights on the atherosclerotic process, while concurrently offering numerous molecular and genomic candidates that appear to hold great promise for selective targeting as clinical therapies.

Macrophages represent one of the most numerous and diverse leukocyte types in the body. Furthermore, they are important regulators and promoters of many cardiovascular disease programs. Their functions range from sensing pathogens to digesting cell debris, modulating inflammation, and producing key cytokines and other regulatory factors throughout the body. Macrophage research has undergone a renaissance in recent years, which has propelled a newfound interest in their heterogeneity as well as a new understanding of ontological differences in their development. In addition, recent technological advances such as single-cell mass-cytometry by time-of-flight have enabled phenotype and functional analyses of individual immune myeloid cells, including macrophages, at unprecedented resolution. In this Part 1 of a 4-part review series covering the macrophage in cardiovascular disease, we focus on the basic principles of macrophage development, heterogeneity, phenotype, tissue-specific differentiation, and functionality as a basis to understand their role in cardiovascular disease.

Background: To compare outcomes among transcatheter aortic valve replacement (TAVR) performed via transaortic (TAo) and subclavian (SCL) approaches. Many patients are not amenable for TAVR via the ...

[Background]: Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content. [Objectives]: This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis. [Methods]: Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre/+);ROSA26(EYFP/+) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI. [Results]: Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3+Col1A1+ cells in the heart after MI. [Conclusions]: The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes., This work was supported by grants SAF2017-82436R and RTC2017-6283 from MINEICO, S2017/BMD-3686 from Comunidad de Madrid, CIVP18A3864 from Fundación Ramón Areces and CIBERCV (funded by the Instituto de Salud Carlos III), Fondos FEDER, and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award IK2BX003922 (to Dr. DeLeon-Pennell).

Summary Mesenchymal stem cells (MSCs) reportedly exist in a vascular niche occupying the outer adventitial layer. However, these cells have not been well characterized in vivo in medium- and large-sized arteries in humans, and their potential pathological role is unknown. To address this, healthy and diseased arterial tissues were obtained as surplus surgical specimens and freshly processed. We identified that CD90 marks a rare adventitial population that co-expresses MSC markers including PDGFRα, CD44, CD73, and CD105. However, unlike CD90, these additional markers were widely expressed by other cells. Human adventitial CD90+ cells fulfilled standard MSC criteria, including plastic adherence, spindle morphology, passage ability, colony formation, and differentiation into adipocytes, osteoblasts, and chondrocytes. Phenotypic and transcriptomic profiling, as well as adoptive transfer experiments, revealed a potential role in vascular disease pathogenesis, with the transcriptomic disease signature of these cells being represented in an aortic regulatory gene network that is operative in atherosclerosis., Highlights • We identify, in situ and in vivo, adventitial CD90+ MSCs in human arteries • Human adventitial CD90+ cells fulfill all criteria for an MSC population • Other markers, such as CD44 and PDGFRα, were non-specific for adventitial MSCs • The CD90+ MSC transcriptomic signature suggests a major role in vascular disease, MSCs reportedly exist in a specific vascular niche, but these cells have not been well characterized in medium- and large-sized human arteries. To address this, surplus arterial tissues were obtained at surgery and freshly processed. We show that CD90 marks a human adventitial MSC population, with the CD90+ MSC transcriptomic signature being represented in an atherosclerotic regulatory gene network.

The optimal periprocedural imaging strategy during transcathether aortic valve replacement (TAVR) performed under moderate sedation is debated. Transthoracic echocardiography (TTE) provides suboptimal views due to poorer resolution and patient positioning, whereas use of transesophageal echocardiography (TEE) under moderate sedation is not widely utilized. The aim of our study was to compare the value of TTE in comparison with TEE guidance under moderate sedation during TAVR. The study population included 144 consecutive patients (mean age 83 ± 11 years, 78 (54%) females) who had TAVR under moderate sedation using either a TTE (n = 96) or TEE (n = 48). We compared procedural outcomes using propensity score matching. There were no significant inter-group differences in age, sex, ejection fraction, aortic valve area, pressure gradients, creatinine or type of valve used. The procedural time was significantly shorter in the TEE group (P < 0.001) and associated with a lower need for periprocedural aortograms (7.7 ± 1.9 vs 8.2 ± 1.9, P = 0.022) and a lower occurrence of acute kidney injury (1 vs 11, P = 0.047). The 1:1 propensity score matching also showed a lower procedural time (P = 0.032), number of aortograms (P = 0.014) and a trend toward lower acute kidney injury in the TEE group (P = 0.077). TAVR guidance using TEE is associated with a lower fluoroscopic time, a lower need for additional aortograms and trend in lower occurrence of post-TAVR acute kidney injury.

Transcatheter aortic valve replacement (TAVR) is expanding to younger patients, but feasibility of TAVR in failing transcatheter aortic valves (TAVs) remains unknown. We determined the feasibility of TAV-in-TAV after Edwards SAPIEN 3 (S3) (Edwards Lifesciences, Irvine, California) TAVR by evaluating

The Cardiovascular Research Center (CVRC) at Icahn School of Medicine at Mount Sinai was established in 2007 and is focused on advancing our knowledge of cardiovascular diseases and translating these discoveries into effective therapies. The CVRC is currently housed in The Leon and Norma Hess Center for Science and Medicine, a state-of-the-art clinical and research facility in New York’s Upper East Side. The Center is part of the Mount Sinai Health System, comprised of the Icahn School of Medicine at Mount Sinai and 7 other hospital campuses throughout the New York Metropolitan Area. Since its inception, the CVRC has grown to include ≈75 members composed of physicians, physician-scientists, postdoctoral fellows, research scientists, and technicians. Our team of lead investigators and researchers work across platforms to investigate cardiac and stem cell biology, tissue engineering, vector biology, cardiac physiology, electrophysiology, vascular diseases, metabolic disorders, imaging, and clinical trials. Close collaboration and shared vision among the investigators glean fundamental insights into cardiovascular physiology and pathobiology, which illuminate potential avenues for therapeutic treatment. The Center currently has 2 full professors, 5 associate professors, 10 assistant professors, and 4 instructors in medicine/cardiology. In 2017, total National Institutes of Health funding increased to >14 million dollars. In addition to 15 R01s, 3 K awards, and an F30, the CVRC is home to 3 Transatlantic Leducq Foundation grants, 4 American Heart Association postdoctoral fellowships, 4 American Heart Association Scientist Development grants, an American Heart Association Strategically Focused Research Network, a Department of Defence Concept Award, and a National Institutes of Health S10 Shared Instrument grant. We have also recently acquired funding from 2 biotechnology companies. Figure shows the junior and senior investigators at the Cardiovascular Research Center. Figure. Junior and senior investigators at the Cardiovascular Research Center . Front row (left to right): Anthony Fargnoli, Irene Turnbull, Ah …

Introduction Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy of unknown etiology, affecting mostly middle-aged women. It is characterized by stenotic lesions of the vascular wall in middle-size arteries, sometimes associated with dissection, aneurysm or tortuosity. Objective We aim at identifying genetic causes of FMD to better understand its mechanism and relation with other vasculopathies. Methods We report results from the first genome-wide association meta-analysis of six studies including 1962 FMD cases and 7100 controls. We integrated genetic association with arterial gene expression using transcriptome-wide association analysis. To identify FMD associated variants located in regulatory elements, we determined open chromatin regions in artery-derived primary cells using ATAC-Seq and estimated heritability and genetic correlation of FMD with other vascular traits and diseases using LD Score regression. Results We found an estimate of SNP-based heritability compatible with a polygenic feature for FMD and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identified one additional locus (SLC24A3). We found that FMD associated variants were located in arterial-specific regulatory elements. Target genes were broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We found significant genetic overlap between FMD and blood pressure, although hypertension was not confounding the genetic association with FMD. We also report an important genetic overlap with migraine, intracranial aneurysm, coronary artery disease and LDL cholesterol. Conclusion We identified several loci related to vascular contraction, suggesting that altered vascular tonicity may play a role in the pathogenesis of FMD. We find that FMD is genetically close to several vascular diseases where vascular integrity is impaired.

Objectives The aims of this study were to describe the authors’ initial experience with combined coronary artery positron emission tomographic (PET) and magnetic resonance (MR) imaging using 18 F-fluorodeoxyglucose ( 18 F-FDG) and 18 F-sodium fluoride ( 18 F-NaF) radiotracers, describe common problems and their solutions, and demonstrate the feasibility of coronary PET/MR imaging in appropriate patients. Background Recently, PET imaging has been applied to the aortic valve and regions of atherosclerosis. 18 F-FDG PET imaging has become established for imaging inflammation in atherosclerosis in the aorta and carotid arteries. Moreover, 18 F-NaF has emerged as a novel tracer of active microcalcification in the aortic valve and coronary arteries. Coronary PET imaging remains challenging because of the small caliber of the vessels and their complex motion. Currently, most coronary imaging uses combined PET and computed tomographic imaging, but there is increasing enthusiasm for PET/MR imaging because of its reduced radiation, potential to correct for motion, and the complementary information available from cardiac MR in a single scan. Methods Twenty-three patients with diagnosed or documented risk factors for coronary artery disease underwent either 18 F-FDG or 18 F-NaF PET/MR imaging. Standard breath-held MR-based attenuation correction was compared with a novel free-breathing approach. The impact on PET image artifacts and the interpretation of vascular uptake were evaluated semiquantitatively by expert readers. Moreover, PET reconstructions with more algorithm iterations were compared visually and by target-to-background ratio. Results Image quality was significantly improved by novel free-breathing attenuation correction. Moreover, conspicuity of coronary uptake was improved by increasing the number of algorithm iterations from 3 to 6. Elevated radiotracer uptake could be localized to individual coronary lesions using both 18 F-FDG (n = 1, maximal target-to-background ratio = 1.61) and 18 F-NaF (n = 7, maximal target-to-background ratio = 1.55 ± 0.37), including in 1 culprit plaque post–myocardial infarction confirmed by myocardial late gadolinium enhancement. Conclusions The authors provide the first demonstration of successful, low-radiation (7.2 mSv) PET/MR imaging of inflammation and microcalcification activity in the coronary arteries. However, this requires specialized approaches tailored to coronary imaging for both attenuation correction and PET reconstruction.

Oxidative stress occurs whenever the release of reactive oxygen species (ROS) exceeds endogenous antioxidant capacity. In this paper, we review the specific role of several cardiovascular risk factors in promoting oxidative stress: diabetes, obesity, smoking, and excessive pollution. Specifically, the risk of developing heart failure is higher in patients with diabetes or obesity, even with optimal medical treatment, and the increased release of ROS from cardiac mitochondria and other sources likely contributes to the development of cardiac dysfunction in this setting. Here, we explore the role of different ROS sources arising in obesity and diabetes, and the effect of excessive ROS production on the development of cardiac lipotoxicity. In parallel, contaminants in the air that we breathe pose a significant threat to human health. This paper provides an overview of cigarette smoke and urban air pollution, considering how their composition and biological effects have detrimental effects on cardiovascular health.

Vascular disease and heart failure impart an enormous burden in terms of global morbidity and mortality. Although there are many different causes of cardiac and vascular disease, most causes share an important pathological mechanism: oxidative stress. In the failing heart, oxidative stress occurs in the myocardium and correlates with left ventricular dysfunction. Reactive oxygen species (ROS) negatively affect myocardial calcium handling, cause arrhythmia, and contribute to cardiac remodeling by inducing hypertrophic signaling, apoptosis, and necrosis. Similarly, oxidative balance in the vasculature is tightly regulated by a wealth of pro- and antioxidant systems that orchestrate region-specific ROS production and removal. Reactive oxygen species also regulate multiple vascular cell functions, including endothelial and smooth muscle cell growth, proliferation, and migration; angiogenesis; apoptosis; vascular tone; host defenses; and genomic stability. However, excessive levels of ROS promote vascular disease through direct and irreversible oxidative damage to macromolecules, as well as disruption of redox-dependent vascular wall signaling processes.

The generation of reactive oxygen species (ROS) is a fundamental aspect of normal human biology. However, when ROS generation exceeds endogenous antioxidant capacity, oxidative stress arises. If unchecked, ROS production and oxidative stress mediate tissue and cell damage that can spiral in a cycle of inflammation and more oxidative stress. This article is part 1 of a 3-part series covering the role of oxidative stress in cardiovascular disease. The broad theme of this first paper is the mechanisms and biology of oxidative stress. Specifically, the authors review the basic biology of oxidative stress, relevant aspects of mitochondrial function, and stress-related cell death pathways (apoptosis and necrosis) as they relate to the heart and cardiovascular system. They then explore telomere biology and cell senescence. As important regulators and sensors of oxidative stress, telomeres are segments of repetitive nucleotide sequence at each end of a chromosome that protect the chromosome ends from deterioration.

AIMS There is a lack of a reliable technique to quantify coronary artery calcification (CAC). Hence, we used optical coherence tomography (OCT) to quantitate three-dimensional CAC volume to examine its association with plaque characteristics. METHODS AND RESULTS A total of 250 patients with stable angina undergoing OCT imaging before PCI were included. CAC volume was calculated from every frame of the culprit lesion and divided into tertiles (low, intermediate and high). Quantitative calcium characteristics were assessed in 107 patients who underwent both OCT and IVUS. Increase in CAC volume was associated with reduced lipid volume index, lipid length and number of lipid plaques. Diabetes and LDL cholesterol predicted less coronary calcification whereas age and prior MI predicted increased CAC after adjusting for all clinical factors. Lipid volume index (ρ=-0.001 [-0.003 to -0.00003]; p=0.04) and mean calcium depth (ρ=-0.02 [-0.02 to -0.01]; p=0.000) were inversely related to CAC volume after adjusting for all OCT characteristics, whereas cap thickness increased with increase in CAC volume (ρ=0.01 [0.002-0.03]; p=0.02) only in unadjusted analysis. Regression analysis demonstrated a significant correlation between calcium length (ρ=0.83; p

The assessment of both the pattern and activity of myocardial injury has important implications for the clinical management of patients with cardiovascular disease. Comprehensive evaluation of these has previously been challenging using a single imaging modality. Cardiac magnetic resonance (CMR)

Background The 2020 American Heart Association Impact Goal aims to improve cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular disease and stroke by 20%. A large step toward this goal would be to better understand and take advantage of the significant intersection between behavior and biology across the entire life-span. In the proposed FAMILIA studies, we aim to directly address this major knowledge and clinical health gap by implementing an integrated family-centric health promotion intervention and focusing on the intersection of environment and behavior, while understanding the genetic and biologic basis of cardiovascular disease. Methods We plan to recruit 600 preschool children and their 600 parents or caregivers from 12-15 Head Start schools in Harlem, NY, and perform a 2:1 (2 intervention/1 control) cluster randomization of the schools. The preschool children will receive our intensive 37-hour educational program as the intervention for 4 months. For the adults, those in the "intervention" group will be randomly assigned to 1 of 2 intervention programs: an "individual-focused" or "peer-to-peer based." The primary outcome in children will be a composite score of knowledge (K), attitudes (A), habits (H), related to body mass index Z score (B), exercise (E), and alimentation (A) (KAH-BEA), using questionnaires and anthropometric measurements. For adults, the primary outcome will be a composite score for behaviors/outcomes related to blood pressure, exercise, weight, alimentation (diet) and tobacco (smoking; Fuster-BEWAT score). Saliva will be collected from the children for SNP genotyping, and blood will be collected from adults for RNA sequencing to identify network models and predictors of primary prevention outcomes. Conclusion The FAMILIA studies seek to demonstrate that targeting a younger age group (3-5 years) and using a family-based approach may be a critical strategy in promoting cardiovascular health across the life-span.

Studies have shown worse outcome for women compared with men after percutaneous coronary intervention (PCI), especially in the presence of diabetes mellitus (DM). We aimed to investigate the risk of ischemic events after PCI in women versus men stratified by the presence or absence of DM. A total of 17,154 consecutive patients from a single-center PCI registry enrolled from January 2009 to December 2014 were categorized accordingly: female/non-DM, female/DM, male/non-DM, and male/DM. End points included death and myocardial infarction (MI) at 1 year. Of the overall population, 15% (n = 2,631) were female/non-DM, 17% (n = 2,891) were female/DM, 38% (n = 6,483) were male/non-DM, and 30% (n = 5,149) were male/DM. Within the 4 study groups, female/DM had the highest risk, whereas female/non-DM and male/DM showed similar risks and male/non-DM showed lowest risk for death (4.64% vs 3.08% vs 2.93% vs 2.31%; p-trend0.0001 over all groups and p = 0.69 between female/non-DM and male/DM, respectively) and MI (4.15% vs 3.99% vs 3.71% vs 2.55%; p trend0.0001 over all groups and p = 0.97 between female/non-DM and male/DM, respectively). After multivariate adjustment findings were largely unchanged suggesting highest risk for adverse events in diabetic women compared with other groups and comparable risks for death and MI in nondiabetic women compared with diabetic men. In conclusion, these findings highlight the combined influence of DM and female gender as strong determinants of post-PCI risk while also illustrating "risk equivalence" between nondiabetic women versus diabetic men.

This study sought to identify an algorithm for the use of distal embolic protection on the basis of angiographic lesion morphology and vascular anatomy for patients undergoing atherectomy for femoropopliteal lesions.Atherectomy has been shown to create more embolic debris than angioplasty alone. Distal embolic protection has been shown to be efficacious in capturing macroemboli; however, no consensus exists for the appropriate lesions to use distal embolic protection during atherectomy.Patients with symptomatic lower extremity peripheral artery disease treated with atherectomy and distal embolic protection were evaluated to identify potential predictors of DE. Plaque collected from the SilverHawk nose cone subset was sent to pathology for analysis to evaluate the accuracy of angiography in assessing plaque morphology.Significant differences were found in lesion length (142.1 ± 62.98 vs. 56.91 ± 41.04; p = 0.0001), low-density lipoprotein (82.3 ± 40.3 vs. 70.9 ± 23.2; p = 0.0006), vessel runoff (1.18 ± 0.9 vs. 1.8 ± 0.9; p = 0.0001), chronic total occlusion (131 vs. 10; p = 0.001), in-stent restenosis (33 vs. 6; p = 0.0081), and calcified lesions (136 vs. 65; p 0.001). In simple logistic regression analysis lesion length, reference vessel diameter, chronic total occlusion, runoff vessels, and in-stent restenosis were found to be strongly associated with macroemboli. Angiographic assessment of plaque morphology was accurate. Positive predictive value of 92.31, negative predictive value of 95.35, sensitivity of 92.31, and specificity of 95.35 for calcium; positive predictive value of 95.56, negative predictive value of 100, sensitivity of 100, and specificity of 92.31 for atherosclerotic plaque. Thrombus/in-stent restenosis was correctly predicted.Chronic total occlusion, in-stent restenosis, thrombotic, calcific lesions40 mm, and atherosclerotic lesions140 mm identified by peripheral angiography necessitate concomitant filter use during atherectomy to prevent embolic complications.

Background: Despite extensive evidence demonstrating the beneficial effects of statins on clinical outcomes, the mechanisms underlying these effects remain elusive.Objectives: This study as...

Endothelial-to-mesenchymal-transition (EndoMT) is a cellular process often initiated by the growth factor β (TGFβ) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2E-KO) augments the magnitude of embryonic EndoMT, resulting in thicken cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2E-KO mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.

Background Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. Results We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. Conclusion In sum, by integrating genetic and electronic medical record data, and leveraging one of the world’s largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation. Electronic supplementary material The online version of this article (10.1186/s12920-019-0542-3) contains supplementary material, which is available to authorized users.

Medium-sized and large arteries consist of 3 layers: the tunica intima, tunica media, and tunica adventitia. The tunica media accounts for the bulk of the vessel wall and is the chief determinant of mechanical compliance. It is primarily composed of circumferentially arranged layers of vascular smooth muscle cells that are separated by concentrically arranged elastic lamellae; a form of extracellular matrix (ECM). The tunica media is separated from the tunica intima and tunica adventitia, the innermost and outermost layers, respectively, by the internal and external elastic laminae. This second part of a 4-part JACC Focus Seminar discusses the contributions of the ECM to vascular homeostasis and pathology. Advances in genetics and proteomics approaches have fostered significant progress in our understanding of vascular ECM. This review highlights the important role of the ECM in vascular disease and the prospect of translating these discoveries into clinical disease biomarkers and potential future therapies.

The current trends of unhealthy lifestyle behaviors in underserved communities are disturbing. Thus, effective health promotion strategies constitute an unmet need.The purpose of this study was to assess the impact of 2 different lifestyle interventions on parents/caregivers of children attending preschools in a socioeconomically disadvantaged community.The FAMILIA (Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health) study is a cluster-randomized trial involving 15 Head Start preschools in Harlem, New York. Schools, and their children's parents/caregivers, were randomized to receive either an "individual-focused" or "peer-to-peer-based" lifestyle intervention program for 12 months or control. The primary outcome was the change from baseline to 12 months in a composite health score related to blood pressure, exercise, weight, alimentation, and tobacco (Fuster-BEWAT Score [FBS]), ranging from 0 to 15 (ideal health = 15). To assess the sustainability of the intervention, this study evaluated the change of FBS at 24 months. Main pre-specified secondary outcomes included changes in FBS subcomponents and the effect of the knowledge of presence of atherosclerosis as assessed by bilateral carotid/femoral vascular ultrasound. Mixed-effects models were used to test for intervention effects.A total of 635 parents/caregivers were enrolled: mean age 38 ± 11 years, 83% women, 57% Hispanic/Latino, 31% African American, and a baseline FBS of 9.3 ± 2.4 points. The mean within-group change in FBS from baseline to 12 months was ∼0.20 points in all groups, with no overall between-group differences. However, high-adherence participants to the intervention exhibited a greater change in FBS than their low-adherence counterparts: 0.30 points (95% confidence interval: 0.03 to 0.57; p = 0.027) versus 0.00 points (95% confidence interval: -0.43 to 0.43; p = 1.0), respectively. Furthermore, the knowledge by the participant of the presence of atherosclerosis significantly boosted the intervention effects. Similar results were sustained at 24 months.Although overall significant differences were not observed between intervention and control groups, the FAMILIA trial highlights that high adherence rates to lifestyle interventions may improve health outcomes. It also suggests a potential contributory role of the presentation of atherosclerosis pictures, providing helpful information to improve future lifestyle interventions in adults.

Precision medicine promises to dramatically improve patient outcomes and reduce health care costs through a shift in focus from disease treatment to prevention and individualized therapies. For families with inherited cardiomyopathies, efforts to date have been directed toward discovery and functional characterization of single disease-causing variants. With advances in sequencing, the cataloging of personal genetic variation has been expedited, providing improved insights into the key importance of the genes in which variants occur. These advances have propelled seminal opportunities for successful variant-targeted disease-reversing therapy. New challenges have also emerged-particularly interpretation of the rapidly rising numbers of "variants of unknown significance." For treatments based on patient genotype to be feasible on a wider scale, these obstacles need to be overcome. Here the authors focus on genetics of dilated cardiomyopathy and provide a roadmap for implementing genomic information into future patient management.

Historically, the gold standard for treating acute uncomplicated type B aortic dissection (TBAD) has been aggressive medical therapy to achieve optimal heart rate and blood pressure control. However, recent data have demonstrated that a significant proportion of patients with medically managed acute uncomplicated TBAD have late aorta-related complications, such as aneurysmal degeneration, that increase mortality and often necessitate surgical intervention. In this review, the authors review existing literature on uncomplicated TBAD and highlight contemporary surgical and medical strategies to manage this condition. Looking ahead, efforts are underway to identify and characterize a high-risk subgroup of acute uncomplicated TBAD patients who may benefit from early intervention.

Background: Antiretroviral therapy (ART) for HIV infection increases risk for coronary artery disease (CAD), presumably by causing dyslipidemia and increased atherosclerosis. We applied systems pharmacology to identify and validate specific regulatory gene networks through which ART drugs may promote CAD. Methods: Transcriptional responses of human cell lines to 15 ART drugs retrieved from the Library of Integrated Cellular Signatures (overall 1127 experiments) were used to establish consensus ART gene/transcriptional signatures. Next, enrichments of differentially expressed genes and gene-gene connectivity within these ART-consensus signatures were sought in 30 regulatory gene networks associated with CAD and CAD-related phenotypes in the Stockholm Atherosclerosis Gene Expression study. Results: Ten of 15 ART signatures were significantly enriched both for differential expression and connectivity in a specific atherosclerotic arterial wall regulatory gene network (AR-RGN) causal for CAD involving RNA processing genes. An atherosclerosis in vitro model of cholestryl ester-loaded foam cells was then used for experimental validation. Treatments of these foam cells with ritonavir, nelfinavir, and saquinavir at least doubled cholestryl ester accumulation ( P =0.02, 0.0009, and 0.02, respectively), whereas RNA silencing of the AR-RGN top key driver, PQBP1 (polyglutamine binding protein 1), significantly curbed cholestryl ester accumulation following treatment with any of these ART drugs by >37% ( P Conclusions: By applying a novel systems pharmacology data analysis framework, 3 commonly used ARTs (ritonavir, nelfinavir, and saquinavir) were found altering the activity of AR-RGN, a regulatory gene network promoting foam cell formation and risk of CAD. Targeting AR-RGN or its top key driver PQBP1 may help reduce CAD side effects of these ART drugs.

Endovascular treatment of arterial diseases has become first-line in most cases due to improved technology. However, until recently, excessive atherosclerotic calcification has been a major limiting factor in the endovascular management of peripheral arterial disease, as well as vascular access for endovascular aneurysm repair (EVAR) and transcatheter aortic valve replacement (TAVR). The Peripheral Intravascular Lithotripsy (IVL) System (Shockwave Medical, Inc., Fremont California) applies pulsatile mechanical energy under fluoroscopic guidance to disrupt calcified lesions. The purpose of this paper is to introduce IVL in the treatment of calcific access vessels in preparation for EVAR and TAVR, as well as peripheral arterial disease applications to enhance luminal gain. Using the IVL System, angioplasty can be performed with lower pressures, which may minimize arterial dissection. Further, the lithotripsy effect on calcium will enhance vessel compliance. We describe several cases where IVL was applied successfully and present additional cases that may have benefitted from the use of this technology.

This article is a comprehensive document on the diagnosis and management of fibromuscular dysplasia (FMD), which was commissioned by the working group ‘Hypertension and the Kidney’ of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM). This document updates previous consensus documents/scientific statements on FMD published in 2014 with full harmonization of the position of European and US experts. In addition to practical consensus-based clinical recommendations, including a consensus protocol for catheter-based angiography and percutaneous angioplasty for renal FMD, the document also includes the first analysis of the European/International FMD Registry and provides updated data from the US Registry for FMD. Finally, it provides insights on ongoing research programs and proposes future research directions for understanding this multifaceted arterial disease.

Background Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. Results We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. Conclusion In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation. Correction in: BMC MEDICAL GENOMICS, Volume: 12, Issue: 1, Article Number: 154, DOI: 10.1186/s12920-019-0573-9

Background: High-intensity statins (HIS) are recommended for secondary prevention following percutaneous coronary intervention (PCI). We aimed to describe temporal trends and determinants of HIS prescriptions after PCI in a usual-care setting. Methods: All patients with age ≤75 years undergoing PCI between January 2011 and May 2016 at an urban, tertiary care center and discharged with available statin dosage data were included. HIS were defined as atorvastatin 40 or 80 mg, rosuvastatin 20 or 40 mg, and simvastatin 80 mg. Results: A total of 10,495 consecutive patients were included. Prevalence of HIS prescriptions nearly doubled from 36.6% in 2011 to 60.9% in 2016 (P

Plaque rupture (PR) leading to coronary thrombosis is the main cause of death in patients with chronic kidney disease (CKD) [(1)][1]. Lipid content, macrophage infiltration, and plaque neovascularization are associated features of plaque vulnerability, which can be identified in vivo by optical

BACKGROUND In patients treated with bare metal stents and first-generation drug-eluting stents (DES) smaller stent diameter (SD) has been associated with worse long term outcomes after percutaneous coronary intervention (PCI). Data on the impact of small SD on outcomes after PCI with second-generation DES is scarce. METHODS Consecutive patients treated with second-generation DES between 2010 and 2016 were included in a single tertiary center. Patients were grouped according to SD: ≤2.50 mm, 2.75 ≤ 3.00 mm, 3.25 ≤ 3.50 mm, and >3.50 mm. One-year event rates were estimated using the Kaplan-Meier method and adjusted hazard ratios were generated using Cox regression analysis. The primary endpoint was major adverse cardiac events (MACE; death, myocardial infarction [MI], or target vessel revascularization [TVR]). RESULTS Of the 17,607 patients who underwent PCI with second-generation DES, 32.6% (n = 5,741) had SD ≤2.5 mm, 39.1% (n = 6,890) had SD 2.75 ≤ 3.0 mm, 22.2% (n = 3,910) had SD 3.25 ≤ 3.5 mm, and 6.1% (n = 1,066) had SD >3.5 mm. At 1 year, MACE rates were 10.5%, 9.5%, 8.0%, and 8.0%, respectively, with increasing SD (p = .006). TVR rates decreased with increasing SD (7.2%, 5.8%, 4.7%, and 3.3%, respectively [p

Intensive low-density lipoprotein cholesterol (LDL-C) reduction with statins is recommended after elective percutaneous coronary intervention (PCI). We aimed to evaluate adherence to guideline-recommended statin therapy (GRST) and the rate of residual cholesterol risk (RCR) at follow-up after elective PCI. All patients who underwent elective PCI between January 2010 and May 2016 were prospectively included in this single-center study. GRST was defined as high-intensity statin (HIS) therapy for patients ≤75 years old and moderate-intensity statin (MIS) or HIS therapy for patients75 years. RCR at follow-up was defined as50% decrease in LDL-C with HIS or30% with MIS for statin-naïve patients and as LDL-C70 mg/dL for nonstatin-naïve patients. A total of 2,653 patients were included, with 1,304 (49.2%) discharged with GRST. There was a significant increase in the number of patients discharged with GRST over time from 44.2% in 2010 to 63.0% in 2016 (p0.001). Conversely, RCR at follow-up was present in 1,120 patients (42.2%) overall and remained stable over time. Risk factors of RCR at follow-up were female gender (odds ratio [OR]: 1.38; 95% confidence interval [CI] 1.13 to 1.70), previous myocardial infarction (OR: 1.37; 95% CI 1.12 to 1.64), smoking (OR: 1.30; 95% CI 1.01 to 1.67), higher LDL-C level at baseline (OR: 1.22; 95% CI 1.18 to 1.25). The presence of RCR was associated with an increased adjusted risk of death within 1 year of the second LDL-C measurement (adjHR: 2.78; 95% CI 1.15 to 6.67). In conclusion, although the rate of GRST at discharge has improved significantly over time in patients who underwent elective PCI, the prevalence of RCR at follow-up has not changed appreciably suggesting that further implementation of guidelines as well as novel or more intensive pharmacotherapy may be warranted.

Preschool-based interventions offer promise to instill healthy behaviors in children, which can be a strategy to reduce the burden of cardiovascular disease later. However, their efficacy in underserved communities is not well established.The purpose of this study was to assess the impact of a preschool-based health promotion educational intervention in an underserved community.This cluster-randomized controlled study involved 15 Head Start preschools in Harlem, New York. Schools and their children were randomized 3:2 to receive either a 4-month (50 h) educational intervention to instill healthy behaviors in relation to diet, physical activity, body/heart awareness, and emotion management; or their standard curriculum (control). The primary outcome was the change from baseline in the overall knowledge, attitudes, and habits (KAH) score of the children at 5 months. As secondary outcomes, we evaluated the changes in KAH subcomponents and emotion comprehension. Linear mixed-effects models were used to test for intervention effects.The authors enrolled 562 preschool children age 3 to 5 years, 51% female, 54% Hispanic/Latino, and 37% African-American. Compared with the control group, the mean relative change from baseline in the overall KAH score was ∼2.2 fold higher in the intervention group (average absolute difference of 2.86 points; 95% confidence interval: 0.58 to 5.14; p = 0.014). The maximal effect was observed in children who received75% of the curriculum. Physical activity and body/heart awareness components, and knowledge and attitudes domains, were the main drivers of the effect (p values 0.05). Changes in emotion comprehension trended toward favoring intervened children.This multidimensional school-based educational intervention may be an effective strategy for establishing healthy behaviors among preschoolers from a diverse and socioeconomically disadvantaged community. Early primordial prevention strategies may contribute to reducing the global burden of cardiovascular disease. (Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health [FAMILIA]; NCT02343341).

Background Genetic variants currently known to affect coronary artery disease (CAD) risk explain less than one-quarter of disease heritability. The heritability contribution of gene regulatory networks (GRNs) in CAD, which are modulated by both genetic and environmental factors, is unknown. Objectives This study sought to determine the heritability contributions of single nucleotide polymorphisms affecting gene expression (eSNPs) in GRNs causally linked to CAD. Methods Seven vascular and metabolic tissues collected in 2 independent genetics-of-gene-expression studies of patients with CAD were used to identify eSNPs and to infer coexpression networks. To construct GRNs with causal relations to CAD, the prior information of eSNPs in the coexpression networks was used in a Bayesian algorithm. Narrow-sense CAD heritability conferred by the GRNs was calculated from individual-level genotype data from 9 European genome-wide association studies (GWAS) (13,612 cases, 13,758 control cases). Results The authors identified and replicated 28 independent GRNs active in CAD. The genetic variation in these networks contributed to 10.0% of CAD heritability beyond the 22% attributable to risk loci identified by GWAS. GRNs in the atherosclerotic arterial wall (n = 7) and subcutaneous or visceral abdominal fat (n = 9) were most strongly implicated, jointly explaining 8.2% of CAD heritability. In all, these 28 GRNs (each contributing to >0.2% of CAD heritability) comprised 24 to 841 genes, whereof 1 to 28 genes had strong regulatory effects (key disease drivers) and harbored many relevant functions previously associated with CAD. The gene activity in these 28 GRNs also displayed strong associations with genetic and phenotypic cardiometabolic disease variations both in humans and mice, indicative of their pivotal roles as mediators of gene–environmental interactions in CAD. Conclusions GRNs capture a major portion of genetic variance and contribute to heritability beyond that of genetic loci currently known to affect CAD risk. These networks provide a framework to identify novel risk genes/pathways and study molecular interactions within and across disease-relevant tissues leading to CAD.

Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.

In the drug eluting stent (DES) era, repeat in-stent restenosis (ISR) of the same coronary lesion, despite percutaneous coronary intervention (PCI), is a rare but challenging problem that has not been reported. We aim to describe what we propose as the occurrence of "resistant"-ISR (R-ISR) in the DES era, including angiographic patterns and outcomes. We defined R-ISR as the recurrence of an ISR episode after successful treatment of the same lesion. We identified 276 consecutive patients with 291 lesions who had R-ISR between May 2003 and June 2012. Quantitative coronary angiography (QCA) was performed for the first and second ISR episodes. Outcomes at one year, including death, myocardial infarction (MI), and target lesion failure (TLF), were analyzed. Patients with R-ISR had a high frequency of diabetes (62%), chronic kidney disease (39%), bifurcation lesions (51%), and moderate to severe calcified lesions (52%). The most common pattern of R-ISR was focal (77%). R-ISR lesions were treated with DES implantation (55%) or balloon-only strategy (45%). The mortality rate and TLF at 2-years were 9.3% and 51% respectively. The overall 2-year TLF rate did not vary with the originally implanted stent, angiographic pattern (focal versus diffuse), or revascularization strategy. R-ISR appears to consist predominantly of focal lesions and occurs in patients at high clinical and angiographic risk, conceivably owing to their unique diabetic and coronary calcification profile. Clinical outcomes are suboptimal irrespective of angiographic pattern or treatment strategy, indicating the recalcitrant nature of the disease, and need for aggressive treatment of cardiovascular risk factors and novel interventional approaches. In the drug eluting stent (DES) era, repeat in-stent restenosis (ISR) of the same lesion, despite percutaneous coronary intervention, is a rare and challenging problem. We described the "resistant"-ISR (R-ISR) phenomena in the DES era, i.e. the recurrence of an ISR after a successful treatment of that same episode. We identified 276 consecutive patients with R-ISR, who presented with a high clinical and angiographic risk, conceivably owing to their unique diabetic and coronary calcification profile. The most common pattern of R-ISR was focal. The overall 2-year TLF rate exceeded 50% and did not vary significantly with the original stent implanted, angiographic pattern, or type of percutaneous revascularization. © 2016 Wiley Periodicals, Inc.

Over the past two decades, several populations of cardiac stem cells have been described in the adult mammalian heart. For the most part, however, their lineage origins and in vivo functions remain largely unexplored. This Review summarizes what is known about different populations of embryonic and adult cardiac stem cells, including KIT+, PDGFRα+, ISL1+ and SCA1+ cells, side population cells, cardiospheres and epicardial cells. We discuss their developmental origins and defining characteristics, and consider their possible contribution to heart organogenesis and regeneration. We also summarize the origin and plasticity of cardiac fibroblasts and circulating endothelial progenitor cells, and consider what role these cells have in contributing to cardiac repair.

Cardiac fibrosis (CF) is associated with increased ventricular stiffness and diastolic dysfunction and is an independent predictor of long-term clinical outcomes of patients with heart failure (HF). We previously showed that the matricellular CCN5 protein is cardioprotective via its ability to inhibit CF and preserve cardiac contractility.This study examined the role of CCN5 in human heart failure and tested whether CCN5 can reverse established CF in an experimental model of HF induced by pressure overload.Human hearts were obtained from patients with end-stage heart failure. Extensive CF was induced by applying transverse aortic constriction for 8 weeks, which was followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight weeks following gene transfer, cellular and molecular effects were examined.Expression of CCN5 was significantly decreased in failing hearts from patients with end-stage heart failure compared to nonfailing hearts. Trichrome staining and myofibroblast content measurements revealed that the established CF had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated with inhibition of the transforming growth factor beta signaling pathway. CCN5 significantly inhibited endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical processes for CF progression, both in vivo and in vitro. In addition, CCN5 induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts, both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway specifically in myofibroblasts, which may have been due the ability of CCN5 to inhibit the activity of NFκB, an antiapoptotic molecule.CCN5 can reverse established CF by inhibiting the generation of and enhancing apoptosis of myofibroblasts in the myocardium. CCN5 may provide a novel platform for the development of targeted anti-CF therapies.