VEGF‐C and Mortality in Patients With Suspected or Known Coronary Artery Disease

Background The lymphatic system has been suggested to play an important role in cholesterol metabolism and cardiovascular disease. However, the relationships of vascular endothelial growth factor‐C (VEGF‐C), a central player in lymphangiogenesis, with mortality and cardiovascular events in patients with suspected or known coronary artery disease are unknown. Methods and Results We performed a multicenter, prospective cohort study of 2418 patients with suspected or known coronary artery disease undergoing elective coronary angiography. The primary predictor was serum levels of VEGF‐C. The primary outcome was all‐cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events defined as a composite of cardiovascular death, non‐fatal myocardial infarction, and non‐fatal stroke. During the 3‐year follow‐up, 254 patients died from any cause, 88 died from cardiovascular disease, and 165 developed major adverse cardiovascular events. After adjustment for established risk factors, VEGF‐C levels were significantly and inversely associated with all‐cause death (hazard ratio for 1‐SD increase, 0.69; 95% confidence interval, 0.60–0.80) and cardiovascular death (hazard ratio, 0.67; 95% confidence interval, 0.53–0.87), but not with major adverse cardiovascular events (hazard ratio, 0.85; 95% confidence interval, 0.72–1.01). Even after incorporation of N‐terminal pro‐brain natriuretic peptide, contemporary sensitive cardiac troponin‐I, and high‐sensitivity C‐reactive protein into a model with established risk factors, the addition of VEGF‐C levels further improved the prediction of all‐cause death, but not that of cardiovascular death or major adverse cardiovascular events. Consistent results were observed within 1717 patients with suspected coronary artery disease. Conclusions In patients with suspected or known coronary artery disease, a low VEGF‐C value may independently predict all‐cause mortality.

[1]  S. Ylä-Herttuala,et al.  Cardiac Lymphatics – A New Avenue for Therapeutics? , 2017, Trends in Endocrinology & Metabolism.

[2]  S. K. Park,et al.  Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction. , 2013, Kidney international.

[3]  M. Fujita,et al.  α1-Antitrypsin low-density-lipoprotein serves as a marker of smoking-specific oxidative stress. , 2012, Journal of atherosclerosis and thrombosis.

[4]  P. Mulder,et al.  Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction , 2016, Circulation.

[5]  Robert Bittman,et al.  Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. , 2013, The Journal of clinical investigation.

[6]  R. Jain,et al.  Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. , 1997, Science.

[7]  J. Farey,et al.  Decreased Levels of Circulating Cancer-Associated Protein Biomarkers Following Bariatric Surgery , 2016, Obesity Surgery.

[8]  Yi-Wen Chang,et al.  The Role of the VEGF-C/VEGFRs Axis in Tumor Progression and Therapy , 2012, International journal of molecular sciences.

[9]  K. Alitalo,et al.  Critical requirement of VEGF-C in transition to fetal erythropoiesis. , 2016, Blood.

[10]  R. Frye,et al.  A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. , 1975, Circulation.

[11]  R. Ji Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis , 2011, Cellular and Molecular Life Sciences.

[12]  Kim Pin Yeo,et al.  Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. , 2013, Cell metabolism.

[13]  M. Pfeffer,et al.  Prognostic Significance of the Centers for Disease Control/American Heart Association High-Sensitivity C-Reactive Protein Cut Points for Cardiovascular and Other Outcomes in Patients With Stable Coronary Artery Disease , 2007, Circulation.

[14]  S. Tsai,et al.  The non-canonical role of vascular endothelial growth factor-C axis in cancer progression , 2015, Experimental biology and medicine.

[15]  B. Kwak,et al.  Lymphatic vessels: an emerging actor in atherosclerotic plaque development , 2015, European journal of clinical investigation.

[16]  Michael Detmar,et al.  Mechanisms of lymphatic metastasis. , 2014, The Journal of clinical investigation.

[17]  G. Gensini,et al.  A more meaningful scoring system for determining the severity of coronary heart disease. , 1983, The American journal of cardiology.

[18]  M. Pencina,et al.  Interpreting incremental value of markers added to risk prediction models. , 2012, American journal of epidemiology.

[19]  K. Alitalo,et al.  VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption , 2015, EMBO molecular medicine.

[20]  S. Solomon,et al.  Prognostic value of cardiac troponin I measured with a highly sensitive assay in patients with stable coronary artery disease. , 2013, Journal of the American College of Cardiology.

[21]  L. Køber,et al.  N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. , 2005, The New England journal of medicine.

[22]  R. Chevalier The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction. , 2016, American journal of physiology. Renal physiology.

[23]  M. Fujita,et al.  Distinct Characteristics of Circulating Vascular Endothelial Growth Factor-A and C Levels in Human Subjects , 2011, PloS one.

[24]  Anders Larsson,et al.  Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. , 2008, The New England journal of medicine.

[25]  C. Carr,et al.  Cardiac lymphatics are heterogeneous in origin and respond to injury , 2015, Nature.

[26]  K. Alitalo,et al.  VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. , 2009, Current opinion in cell biology.

[27]  P. Sucharda,et al.  Angiogenic factors are elevated in overweight and obese individuals , 2005, International Journal of Obesity.

[28]  K. Alitalo,et al.  Lymphatic System in Cardiovascular Medicine. , 2016, Circulation research.

[29]  K. Alitalo,et al.  A novel vascular endothelial growth factor, VEGF‐C, is a ligand for the Flt4 (VEGFR‐3) and KDR (VEGFR‐2) receptor tyrosine kinases. , 1996, The EMBO journal.

[30]  G. Oliver,et al.  Development of the mammalian lymphatic vasculature. , 2014, The Journal of clinical investigation.

[31]  K. Kotani,et al.  A novel oxidized low-density lipoprotein marker, serum amyloid A-LDL, is associated with obesity and the metabolic syndrome. , 2009, Atherosclerosis.

[32]  Yu-Jin Jung,et al.  Erythropoietin induces lymph node lymphangiogenesis and lymph node tumor metastasis. , 2011, Cancer research.

[33]  J. Partanen,et al.  Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins , 2004, Nature Immunology.