Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-β signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. ‘Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events.

Fibromuscular dysplasia (FMD) involving the coronary arteries is an uncommon but important condition that can present as acute coronary syndrome, left ventricular dysfunction, or potentially sudden cardiac death. Although the classic angiographic “string of beads” that may be observed in renal artery FMD does not occur in coronary arteries, potential manifestations include spontaneous coronary artery dissection, distal tapering or long, smooth narrowing that may represent dissection, intramural hematoma, spasm, or tortuosity. Importantly, FMD must be identified in at least one other noncoronary arterial territory to attribute any coronary findings to FMD. Although there is limited evidence to guide treatment, many lesions heal spontaneously; thus, a conservative approach is generally preferred. The etiology is poorly understood, but there are ongoing efforts to better characterize FMD and define its genetic and molecular basis. This report reviews the clinical course of FMD involving the coronary arteries and provides guidance for diagnosis and treatment strategies.

Aims Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. Methods and results Females with ‘multifocal’ FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios  = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. Conclusion FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

SummaryMesenchymal 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.

Summary A library of well-characterized human induced pluripotent stem cell (hiPSC) lines from clinically healthy human subjects could serve as a useful resource of normal controls for in vitro human development, disease modeling, genotype-phenotype association studies, and drug response evaluation. We report generation and extensive characterization of a gender-balanced, racially/ethnically diverse library of hiPSC lines from 40 clinically healthy human individuals who range in age from 22 to 61 years. The hiPSCs match the karyotype and short tandem repeat identities of their parental fibroblasts, and have a transcription profile characteristic of pluripotent stem cells. We provide whole-genome sequencing data for one hiPSC clone from each individual, genomic ancestry determination, and analysis of mendelian disease genes and risks. We document similar transcriptomic profiles, single-cell RNA-sequencing-derived cell clusters, and physiology of cardiomyocytes differentiated from multiple independent hiPSC lines. This extensive characterization makes this hiPSC library a valuable resource for many studies on human biology.

Background : Many patients with amyloid cardiomyopathy (ACM) develop advanced heart failure, and durable mechanical circulatory support (MCS) may be a consideration. However, data describing clinical outcomes after MCS in this population is limited. Methods : Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) with dilated cardiomyopathy (DCM, n=19,921), non-amyloid restrictive cardiomyopathy (RCM, n=248), or ACM (n=46) between 2005 and 2017 were included. Patient and device characteristics were compared between cardiomyopathy groups. The primary endpoint was the cumulative incidence of death with heart transplantation as a competing risk. Results : Patients with ACM (n=46) were older (61 years [IQR 55-69 years] versus 58 years [IQR 49-66 years] for DCM and 55 years [IQR 46-62 years] for non-amyloid RCM, p<0.001) and INTERMACS profile 1 (30.4% versus 17.9% for DCM and 21.0% for non-amyloid RCM, p=0.04) at device implantation. Use of biventricular support (biventricular assist device or total artificial heart) was highest for ACM patients (41.3% versus 6.7% and 19.4% for DCM and non-amyloid RCM patients, respectively, p=0.014). The cumulative incidence of death was highest for patients with ACM than with DCM or non-amyloid RCM (p<0.001) but did not differ significantly between groups for those who required biventricular MCS. Conclusions : Compared to DCM or non-amyloid RCM patients who received durable MCS, those with ACM experienced the highest use of biventricular support and the worst survival. These data highlight concerns with the use of durable MCS for ACM patients.

The history of revascularization for cardiac ischemia dates back to the early 1960's when the first coronary artery bypass graft procedures were performed in humans. With this 50 year history of providing a new vasculature to ischemic and hibernating myocardium, a profound depth of experience has been amassed in clinical cardiovascular medicine as to what does, and does not work in the context of cardiac revascularization, alleviating ischemia and adequacy of myocardial perfusion. These issues are of central relevance to contemporary cell-based cardiac regenerative approaches. While the cardiovascular cell therapy field is surging forward on many exciting fronts, several well accepted clinical axioms related to the cardiac arterial supply appear to be almost overlooked by some of our current basic conceptual and experimental cell therapy paradigms. We present here information drawn from five decades of the clinical revascularization experience, review relevant new data on vascular formation via cell therapy, and put forward the case that for optimal cell-based cardiac regeneration due attention must be paid to providing an adequate vascular supply.

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