Revascularization of Chronic Hibernating Myocardium Stimulates Myocyte Proliferation and Partially Reverses Chronic Adaptations to Ischemia

AbstractBackgroundThe time course and extent of recovery after revascularization of viable dysfunctional myocardium are variable. Although fibrosis is a major determinant, myocyte structural and molecular remodeling may also play important roles.ObjectivesThis study sought to determine whether persistent myocyte loss and/or irreversibility of protein changes that develop in hibernating myocardium have an impact on functional recovery in the absence of infarction.MethodsSwine implanted with a chronic left anterior descending artery (LAD) stenosis to produce hibernating myocardium underwent percutaneous revascularization, with serial functional recovery evaluated for 1 month (n = 12). Myocardial tissue was evaluated to assess myocyte size, nuclear density, and proliferation indexes in comparison with those of normal animals and nonrevascularized controls. Proteomic analysis by 2-dimensional differential in-gel electrophoresis was used to determine the reversibility of molecular adaptations of hibernating myocytes.ResultsAt 3 months, physiological features of hibernating myocardium were confirmed, with depressed LAD wall thickening and no significant infarction. Revascularization normalized LAD flow reserve, with no immediate change in LAD wall thickening. Regional LAD wall thickening slowly improved but remained depressed 1 month post–percutaneous coronary intervention. Surprisingly, revascularization was associated with histological evidence of myocytes re-entering the growth phase of the cell cycle and increases in the number of c-Kit+ cells. Myocyte nuclear density returned to normal, whereas regional myocyte hypertrophy regressed. Proteomic analysis demonstrated heterogeneous effects of revascularization. Up-regulated stress and cytoskeletal proteins normalized, whereas reduced contractile and metabolic proteins persisted.ConclusionsDelayed recovery of hibernating myocardium in the absence of scar may reflect persistent reductions in the amounts of contractile and metabolic proteins. Although revascularization appeared to stimulate myocyte proliferation, the persistence of small immature myocytes may have contributed to delayed functional recovery

Effects of statins on TH1 modulating cytokines in human subjects

Background. Activation of the innate immune system by cholesterol accelerates atherosclerosis. High levels or modified forms of cholesterol stimulate release of the inflammatory cytokines IL-12 and IL-18 that synergistically stimulate T lymphocytes to produce the atherogenic cytokine interferon-γ. While activation of the innate immune system by cholesterol is well-described in animal models and human subjects with high cholesterol levels or known atherosclerotic disease, the interaction of cholesterol and lipoproteins with the innate immune system in human subjects without known atherosclerosis is less well-described. The goal of our study was to assess the TH1 modulating cytokines IL-12 p40 and IL-18, and their counter regulatory cytokines IL-18 binding protein and IL-27, to determine if their levels are linked to cholesterol levels or other factors.Methods. We performed a blinded, randomized hypothesis-generating study in human subjects without known atherosclerotic disease. We measured serum lipids, lipoprotein levels, and collected plasma samples at baseline. Subjects were randomized to two weeks of therapy with atorvastatin, pravastatin, or rosuvastatin. Lipids and cytokine levels were measured after two weeks of statin treatment. Subjects were given a four-week statin-free period. At the end of the four-week statin-free period, venous blood was sampled again to determine if serum lipids returned to within 5% of their pre-statin levels. When lipid levels returned to baseline, subjects were again treated with the next statin in the randomization scheme. IL-12, IL-18, IL-18 binding protein, and IL-27 were measured at baseline and after each statin treatment to determine effects of statin treatment on their blood levels, and identify correlations with lipids and lipoproteins.Results. Therapy with statins revealed no significant change in the levels of IL-12, IL-18, IL-18 binding protein or IL-27 levels. We found that IL-18 levels positively correlate with total cholesterol levels (r2 = 0.15, p < 0.03), but not HDL or LDL cholesterol. In contrast, IL-12 p40 levels inversely correlated with total cholesterol (r2 = −0.17, p < 0.008), HDL cholesterol (r2 = −0.22, p < 0.002), and apolipoprotein A1 (r2 = −0.21, p < 0.002). Similarly, IL-18 binding protein levels inversely correlated with apolipoprotein A1 levels (r2 = −0.13, p < 0.02).Conclusions. Our findings suggest that total cholesterol levels positively regulate IL-18, while HDL cholesterol and apolipoprotein A1 may reduce IL-12 p40 and IL-18 binding protein levels. Additional studies in a larger patient population are needed to confirm these findings, and verify mechanistically whether HDL cholesterol can directly suppress IL-12 p40 and IL-18 binding protein levels in human subjects

LDL cholesterol modulates human CD34+ HSPCs through effects on proliferation and the IL-17 G-CSF axis.

BACKGROUND: Hypercholesterolemia plays a critical role in atherosclerosis. CD34+ CD45dim Lineage- hematopoietic stem/progenitor cells (HSPCs) give rise to the inflammatory cells linked to atherosclerosis. In mice, high cholesterol levels mobilize HSPCs into the bloodstream, and promote their differentiation to granulocytes and monocytes. The objective of our study was to determine how cholesterol levels affect HSPC quantity in humans. METHODS: We performed a blinded, randomized hypothesis generating study in human subjects (n=12) treated sequentially with statins of differing potencies to vary lipid levels. CD34+ HSPC levels in blood were measured by flow cytometry. Hematopoietic colony forming assays confirmed the CD34+ population studied as HSPCs with multlineage differentiation potential. Mobilizing cytokine levels were measured by ELISA. RESULTS: The quantity of HSPCs was 0.15 ± 0.1% of buffy coat leukocytes. We found a weak, positive correlation between CD34+ HSPCs and both total and LDL cholesterol levels (r(2)=0.096, p < 0.025). Additionally, we tested whether cholesterol modulates CD34+ HSPCs through direct effects or on the levels of mobilizing cytokines. LDL cholesterol increased cell surface expression of CXCR4, G-CSFR affecting HSPC migration, and CD47 mediating protection from phagocytosis by immune cells. LDL cholesterol also increased proliferation of CD34+ HSPCs (28 ± 5.7%, n=6, p < 0.03). Finally, the HSPC mobilizing cytokine G-CSF (r(2)=0.0683, p < 0.05), and its upstream regulator IL-17 (r(2)=0.0891, p < 0.05) both correlated positively with LDL cholesterol, while SDF-1 levels were not significantly affected. CONCLUSIONS: Our findings support a model where LDL cholesterol levels positively correlate with CD34+ HSPC levels in humans through effects on the levels of G-CSF via IL-17 promoting mobilization of HSPCs, and by direct effects of LDL cholesterol on HSPC proliferation. The findings are provocative of further study to determine if HSPCs, like cholesterol levels, are linked to CVD events

Correlation Between LDL Cholesterol and G-CSF Levels.

<p>LDL cholesterol and G-CSF levels were determined across all subjects at baseline and after all statin treatments. p < 0.05 using Pearson’s correlation.</p

Correlation Between LDL Cholesterol and IL-17 Levels.

<p>LDL cholesterol and IL-17 levels were determined across all subjects at baseline and after all statin treatments. p < 0.05 using Pearson’s correlation.</p

Vulnerability to climate change of United States marine mammal stocks in the western North Atlantic, Gulf of Mexico, and Caribbean.

Climate change and climate variability are affecting marine mammal species and these impacts are projected to continue in the coming decades. Vulnerability assessments provide a framework for evaluating climate impacts over a broad range of species using currently available information. We conducted a trait-based climate vulnerability assessment using expert elicitation for 108 marine mammal stocks and stock groups in the western North Atlantic, Gulf of Mexico, and Caribbean Sea. Our approach combined the exposure (projected change in environmental conditions) and sensitivity (ability to tolerate and adapt to changing conditions) of marine mammal stocks to estimate vulnerability to climate change, and categorize stocks with a vulnerability index. The climate vulnerability score was very high for 44% (n = 47) of these stocks, high for 29% (n = 31), moderate for 20% (n = 22), and low for 7% (n = 8). The majority of stocks (n = 78; 72%) scored very high exposure, whereas 24% (n = 26) scored high, and 4% (n = 4) scored moderate. The sensitivity score was very high for 33% (n = 36) of these stocks, high for 18% (n = 19), moderate for 34% (n = 37), and low for 15% (n = 16). Vulnerability results were summarized for stocks in five taxonomic groups: pinnipeds (n = 4; 25% high, 75% moderate), mysticetes (n = 7; 29% very high, 57% high, 14% moderate), ziphiids (n = 8; 13% very high, 50% high, 38% moderate), delphinids (n = 84; 52% very high, 23% high, 15% moderate, 10% low), and other odontocetes (n = 5; 60% high, 40% moderate). Factors including temperature, ocean pH, and dissolved oxygen were the primary drivers of high climate exposure, with effects mediated through prey and habitat parameters. We quantified sources of uncertainty by bootstrapping vulnerability scores, conducting leave-one-out analyses of individual attributes and individual scorers, and through scoring data quality for each attribute. These results provide information for researchers, managers, and the public on marine mammal responses to climate change to enhance the development of more effective marine mammal management, restoration, and conservation activities that address current and future environmental variation and biological responses due to climate change

Values used in the NOAA climate change web portal to generate climate exposure maps for 108 marine mammal stocks in the western North Atlantic, Gulf of Mexico, and Caribbean Sea.

Values used in the NOAA climate change web portal to generate climate exposure maps for 108 marine mammal stocks in the western North Atlantic, Gulf of Mexico, and Caribbean Sea.</p