Background-Recent animal data suggest that vascular smooth muscle cells within the neointima of the vessel wall may originate from bone marrow, providing indirect evidence for circulating smooth muscle progenitor cells (SPCs). Evidence for circulating SPCs in human subjects does not exist, and the mechanism whereby such putative SPCs may home to sites of plaque formation is presently not understood but is likely to involve expression of specific surface adhesion molecules, such as integrins. In this study, we aimed to culture smooth muscle outgrowth cells (SOCs) from SPCs in human peripheral blood and characterize surface integrin expression on these cells. Methods and Results-Human mononuclear cells isolated from buffy coat were seeded on collagen type 1 matrix and outgrowth cells selected in endothelial growth medium (EGM-2) or EGM-2 and platelet-derived growth factor BB. Selection in platelet-derived growth factor BB-enriched medium caused rapid outgrowth and expansion of SOC to Ͼ40 population doublings in a 4-month period. These SOCs were positive for smooth muscle cell-specific ␣ actin (␣SMA), myosin heavy chain, and calponin on immunofluorescence and Western blotting and were also positive for CD34, Flt1, and Flk1 receptor but negative for Tie-2 receptor expression, suggesting a potential bone marrow angioblastic origin. In contrast, endothelial outgrowth cells (EOCs) grown in EGM-2 alone and the initial MNC population were negative for these smooth muscle-specific markers. Integrin ␣ 5 ␤ 1 expression by FACS and Western blotting was significantly increased in SOCs compared with EOCs, and this was confirmed by 8-fold greater adhesion of SOC to fibronectin (PϽ0.001), an effect that could be decreased using an ␣ 5 ␤ 1 antibody. Finally, SOC showed a significantly greater in vitro proliferative potential compared with EOCs of similar passage (PϽ0.001). Conclusions-This study demonstrates for the first time outgrowth of smooth muscle cells with a specific growth, adhesion, and integrin profile from putative SPC in human blood. These data have implications for our understanding of adult vascular smooth muscle cell differentiation, proliferation, and homing.

Background-The present study examined whether transplantation of adherent bone marrow-derived stem cells, termed pMultistem, induces neovascularization and cardiomyocyte regeneration that stabilizes bioenergetic and contractile function in the infarct zone and border zone (BZ) after coronary artery occlusion. Methods and Results-Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55Ϯ5.6% to 30Ϯ5.4% (magnetic resonance imaging). Four weeks after left anterior descending artery occlusion, BZ myocardium demonstrated profound bioenergetic abnormalities, with a marked decrease in subendocardial phosphocreatine/ATP ( 31 P magnetic resonance spectroscopy; 1.06Ϯ0.30 in infarcted hearts [nϭ9] versus 1.90Ϯ0.15 in normal hearts [nϭ8; PϽ0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34Ϯ0.29; nϭ7; PϽ0.05). The BZ protein expression of creatine kinase-mt and creatine kinase-m isoforms was significantly reduced in infarcted hearts but recovered significantly in response to cell transplantation. MRI demonstrated that the infarct zone systolic thickening fraction improved significantly from systolic "bulging" in untreated animals with myocardial infarction to active thickening (19.7Ϯ9.8%, PϽ0.01), whereas the left ventricular ejection fraction improved to 42.0Ϯ6.5% (PϽ0.05 versus myocardial infarction). Only 0.35Ϯ0.05% donor cells could be detected 4 weeks after left anterior descending artery ligation, independent of cell transplantation with or without immunosuppression with cyclosporine A (with cyclosporine A, nϭ6; no cyclosporine A, nϭ7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and Ϸ2%, respectively. Patchy spared myocytes in the infarct zone were found only in pMultistem transplanted hearts. Vascular density was significantly higher in both BZ and infarct zone of cell-treated hearts than in untreated myocardial infarction hearts (PϽ0.05). Conclusions-Thus, allogeneic pMultistem improved BZ energetics, regional contractile performance, and global left ventricular ejection fraction. These improvements may have resulted from paracrine effects that include increased vascular density in the BZ and spared myocytes in the infarct zone.

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Lipoprotein (a) [Lp(a)] has been associated with both anti-fibrinolytic and atherogenic effects. However, no direct link currently exists between this atherogenic lipoprotein and intravascular coagulation. The current study examined the binding and functional effects of Lp(a), its lipoprotein constituents, apoliprotein (a) [apo(a)] and low-density lipoprotein (LDL), and lysine-plasminogen (L-PLG), which shares significant homology with apo(a), on tissue factor pathway inhibitor (TFPI), a major regulator of tissue factor-mediated coagulation. Results indicate that Lp(a), apo(a), and PLG but not LDL bound recombinant TFPI (rTFPI) in vitro and that apo(a) bound to a region spanning the last 37 amino acid residues of the cterminus of TFPI. The apparent binding affinity for TFPI was much higher for Lp(a) (K D ϳ150 nM) compared to PLG (K D ϳ800 nM) and nanomolar concentrations of apo(a) (500 nM) inhibited PLG binding to TFPI. Lp(a) also inhibited in a concentration-dependent manner rTFPI activity and endothelial cell surface TFPI activity in vitro, whereas PLG had no such effect. Moreover physiologic concentrations of PLG (2 M) had no effect on the concentration-dependent inhibition of TFPI activity induced by Lp(a). In human atherosclerotic plaque, apo(a) and TFPI immunostaining were shown to coexist in smooth muscle cell-rich areas of the intima. These data suggest a novel mechanism whereby Lp(a) through its apo(a) moiety may promote thrombosis by binding and inactivating TFPI. , is an important inherited risk factor for atherosclerosis and myocardial infarction. 1,2 Recently, Kronenberg and colleagues 3 showed that Lp(a) concentrations predicted the risk of early atherosclerosis synergistically with LDL, whereas Lp(a) alone emerged as a leading independent risk factor for advanced atherosclerosis. The latter association with advanced atherosclerosis is of particular interest because it seems not to rely on conventional risk factors such as LDL but may be within the realm of procoagulant risk attributes contributing to plaque thrombosis. [3][4][5] Apo(a) contains multiple kringle IV-like domains, a kringle V-like domain, and a proteaselike domain that have significant homology with plasminogen (PLG). 6 Lp(a) accumulates in the vessel wall and inhibits binding of PLG to the cell surface, reducing plasmin generation and subsequent clot lysis. 7,8 This inhibition of PLG activation by Lp(a) also reduces active transforming growth factor-␤ (TGF ␤) production with consequent promotion of smooth muscle cell (SMC) proliferation. 9 These unique structural features of Lp(a) suggest this lipoprotein has both antifibrinolytic and atherogenic potential.The antifibrinolytic effects of Lp(a) notwithstanding, to date no mechanistic data exist to support a more direct role for this atherogenic lipoprotein in promotion of intravascular thrombosis. The lysine-binding characteristics of Lp(a) may be important in this regard, allowing the apo(a) portion of Lp(a) to bind several lysine-rich components of the coagulation system. A potenti...

BackgroundIn 2013 the Minnesota Resuscitation Consortium developed an organized approach for the management of patients resuscitated from shockable rhythms to gain early access to the cardiac catheterization laboratory (CCL) in the metro area of Minneapolis‐St. Paul.Methods and ResultsEleven hospitals with 24/7 percutaneous coronary intervention capabilities agreed to provide early (within 6 hours of arrival at the Emergency Department) access to the CCL with the intention to perform coronary revascularization for outpatients who were successfully resuscitated from ventricular fibrillation/ventricular tachycardia arrest. Other inclusion criteria were age >18 and <76 and presumed cardiac etiology. Patients with other rhythms, known do not resuscitate/do not intubate, noncardiac etiology, significant bleeding, and terminal disease were excluded. The primary outcome was survival to hospital discharge with favorable neurological outcome. Patients (315 out of 331) who were resuscitated from VT/VF and transferred alive to the Emergency Department had complete medical records. Of those, 231 (73.3%) were taken to the CCL per the Minnesota Resuscitation Consortium protocol while 84 (26.6%) were not taken to the CCL (protocol deviations). Overall, 197 (63%) patients survived to hospital discharge with good neurological outcome (cerebral performance category of 1 or 2). Of the patients who followed the Minnesota Resuscitation Consortium protocol, 121 (52%) underwent percutaneous coronary intervention, and 15 (7%) underwent coronary artery bypass graft. In this group, 151 (65%) survived with good neurological outcome, whereas in the group that did not follow the Minnesota Resuscitation Consortium protocol, 46 (55%) survived with good neurological outcome (adjusted odds ratio: 1.99; [1.07–3.72], P=0.03).ConclusionsEarly access to the CCL after cardiac arrest due to a shockable rhythm in a selected group of patients is feasible in a large metropolitan area in the United States and is associated with a 65% survival rate to hospital discharge with a good neurological outcome.

Background Using a swine model of postinfarction left ventricle (LV) remodeling, we investigated marrow-derived, multipotent progenitor cell (MPC) transplantation into hearts with acute myocardial infarction (AMI) via a novel transarterial catheter. Methods and Results The left anterior descending coronary artery was balloon-occluded after percutaneous transluminal angiography to generate AMI (60-minute no-flow ischemia). The transarterial catheter was then placed in the same coronary artery, and either 50×106 MPCs (cell group, n=6) or saline (control, n=6) was injected into the border zone (BZ) myocardium. LV function was assessed by magnetic resonance imaging before AMI and at 1 and 4 weeks after AMI, whereas myocardial energy metabolism was assessed by 31P-magnetic resonance spectroscopy at week 4. One week after AMI, the ejection fraction was significantly reduced in both groups from a baseline of ≈50% to 31.3±3.9% (cell group) and 33.3±3.1% (control). However, at week 4, the cell group had a significant recovery in ejection fraction. The functional improvements were accompanied by a significant improvement in myocardial bioenergetics. Histologic data demonstrated a 0.55% cell engraftment rate 4 weeks after MPC transplantation. Only 2% of engrafted cells were costaining positive for cardiogenic markers. Vascular density in the BZ was increased in the cell group. Conditioned medium from cultured MPCs contained high levels of vascular endothelial growth factor, which was increased in response to hypoxia. MPCs cocultured with cardiomyocytes inhibited changes in cardiomyocyte mitochondrial membrane potential and cytochrome c release induced by tumor necrosis factor-α. Conclusions Thus, a paracrine effect may contribute significantly to the observed therapeutic effects of MPC transplantation.

Transradial angiography and intervention continues to become increasingly common as an access site for coronary procedures. Since the first "Best Practices" paper in 2013, ongoing trials have shed further light onto the safest and most efficient methods to perform these procedures. Specifically, this document comments on the use of ultrasound to facilitate radial access, the role of ulnar artery access, the utility of non-invasive testing of collateral flow, strategies to prevent radial artery occlusion, radial access for primary PCI and topics that require further study.

Background: Heart disease is now considered an inflammatory process targeted primarily by medical therapy on lipid levels. Complementary and alternative medicine searches for novel non-pharmacologic therapy, including pursuing various diets. Animal studies and consumer literature suggest benefits of vinegar on lipid levels and diabetes mellitus. Our nonrandomized pilot study from our group suggested a benefit in raising high-density lipoprotein cholesterol (HDL-C). Based on this data, we conducted a randomized placebo controlled clinical trial to determine the effects of apple cider vinegar intake in those without diabetes mellitus on total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides, HDL-C, Hemoglobin A1C (Hgb-A1C) and measurement of inflammation with high sensitivity CRP levels (HS-CRP). Methods: A prospective randomized, double blind, placebo-controlled clinical trial consisting of 114 participants was conducted. Participants consumed 30 mL of either apple cider vinegar or placebo for two months. Measurements were collected at baseline, eight and sixteen weeks.