Soluble fms-Like Tyrosine Kinase-1 and Endothelial Adhesion Molecules (Intercellular Cell Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1) as Predictive Markers for Blood Pressure Reduction After Renal Sympathetic Denervation

Renal sympathetic denervation (RSD) is a treatment option for patients with resistant arterial hypertension, but in some patients it is not successful. Predictive parameters on the success of RSD remain unknown. The angiogenic factors soluble fms-like tyrosine kinase-1 (sFLT-1), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) are known to be associated with endothelial dysfunction, vascular remodeling, and hypertension. We evaluated whether sFLT-1, ICAM-1, and VCAM-1 are predictive markers for blood pressure reduction after RSD. Consecutive patients (n=55) undergoing renal denervation were included. Venous serum samples for measurement of sFlt-1, ICAM-1, and VCAM-1 were collected before and 6 months after RSD. A therapeutic response was defined as an office systolic blood pressure reduction of >10 mm Hg 6 months after RSD. A significant mean office systolic blood pressure reduction of 31.2 mm Hg was observed in 46 patients 6 months after RSD. Nine patients were classified as nonresponders, with a mean systolic blood pressure reduction of 4.6 mm Hg. At baseline, sFLT-1 levels were significantly higher in responders than in nonresponders (P<0.001) as were ICAM-1 (P<0.001) and VCAM-1 levels (P<0.01). The areas under the curve for sFLT-1, ICAM-1, and VCAM-1 were 0.82 (interquartile range, 0.718–0.921; P<0.001), 0.754 (0.654–0.854; P<0.001), and 0.684 (0.564–804; P=0.01), respectively, demonstrating prediction of an RSD response. Responders showed significantly higher serum levels of sFLT-1, ICAM-1, and VCAM-1 at baseline compared with nonresponders. Thus, this study identified for the first time potential biomarkers with a predictive value indicating a responder or nonresponder before renal denervation.

[1]  J. Staessen,et al.  Blood pressure changes after renal denervation at 10 European expert centers , 2013, Journal of Human Hypertension.

[2]  H. Krum,et al.  Ambulatory Blood Pressure Changes After Renal Sympathetic Denervation in Patients With Resistant Hypertension , 2013, Circulation.

[3]  H. Krum,et al.  Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial , 2010, The Lancet.

[4]  H. Krum,et al.  Renal sympathetic-nerve ablation for uncontrolled hypertension. , 2009, The New England journal of medicine.

[5]  Krzysztof Bartus,et al.  Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study , 2009, The Lancet.

[6]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2009, Circulation.

[7]  Daniel W. Jones,et al.  Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. , 2008, Circulation.

[8]  T. Hökfelt,et al.  Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2-dependent activation of α1- and α2-adrenoceptors on renal sensory nerve fibers , 2007 .

[9]  K. Aonuma,et al.  Contributory role of VEGF overexpression in endothelin-1-induced cardiomyocyte hypertrophy. , 2007, American journal of physiology. Heart and circulatory physiology.

[10]  Piotr Ponikowski,et al.  2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). , 2007, European heart journal.

[11]  K. Furie,et al.  Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2007, Circulation.

[12]  M. Haberka,et al.  Plasma concentrations of adhesion molecules and chemokines in patients with essential hypertension. , 2005, Pharmacological reports : PR.

[13]  M. Sirois,et al.  Vascular Endothelial Growth Factor (VEGF)-A165-induced Prostacyclin Synthesis Requires the Activation of VEGF Receptor-1 and -2 Heterodimer* , 2005, Journal of Biological Chemistry.

[14]  R. Gaiser,et al.  Circulating Angiogenic Factors and the Risk of Preeclampsia , 2005 .

[15]  K. Gourgoulianis,et al.  Circulating adhesion molecules levels in type 2 diabetes mellitus and hypertension. , 2005, International journal of cardiology.

[16]  K. Reynolds,et al.  Global burden of hypertension: analysis of worldwide data , 2005, The Lancet.

[17]  G. Lip,et al.  Platelet indexes in relation to target organ damage in high-risk hypertensive patients: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). , 2004, Journal of the American College of Cardiology.

[18]  K. Reddy,et al.  Burden of non-communicable diseases in South Asia , 2004, BMJ : British Medical Journal.

[19]  G. Lip,et al.  Relationship of homocysteine to markers of platelet and endothelial activation in "high risk" hypertensives: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. , 2004, International journal of cardiology.

[20]  K. Rahn,et al.  Sympathetic Nerve Activity in End-Stage Renal Disease , 2002, Circulation.

[21]  P. Crean,et al.  Prediction of cardiovascular risk using soluble cell adhesion molecules. , 2002, European heart journal.

[22]  D. Bates,et al.  Regulation of microvascular permeability by vascular endothelial growth factors * , 2002, Journal of anatomy.

[23]  G. Lip,et al.  Plasma levels of vascular endothelial growth factor and its soluble receptor (SFlt-1) in essential hypertension. , 2001, The American journal of cardiology.

[24]  P. Ridker,et al.  Soluble P-Selectin and the Risk of Future Cardiovascular Events , 2001, Circulation.

[25]  R. Singh,et al.  Prevalence of type 2 diabetes mellitus and risk of hypertension and coronary artery disease in rural and urban population with low rates of obesity. , 1998, International journal of cardiology.

[26]  H. Granger,et al.  VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. , 1998, American journal of physiology. Heart and circulatory physiology.

[27]  R. Macko,et al.  Elevated levels of circulating cell adhesion molecules in uncomplicated essential hypertension. , 1997, American journal of hypertension.

[28]  N. Ferrara,et al.  The biology of vascular endothelial growth factor. , 1997, Endocrine reviews.

[29]  G. Lip,et al.  Soluble adhesion molecule P-selectin and endothelial dysfunction in essential hypertension: implications for atherogenesis? A preliminary report. , 1995, Journal of hypertension.

[30]  S. Maxwell,et al.  Increased levels of the soluble adhesion molecule E‐selectin in essential hypertension , 1994, Journal of hypertension.

[31]  Lippincott Williams Wilkins,et al.  National High Blood Pressure Education Program Working Group Report on Hypertension in Diabetes , 1994, Hypertension.

[32]  D. Phillips,et al.  PECAM-1 is required for transendothelial migration of leukocytes , 1993, The Journal of experimental medicine.

[33]  J. Fiddes,et al.  The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. , 1991, The Journal of biological chemistry.

[34]  C. Triggle,et al.  Structural and functional consequence of neonatal sympathectomy on the blood vessels of spontaneously hypertensive rats. , 1987, Hypertension.

[35]  J B Stokes,et al.  The national high blood pressure education program. , 1974, Journal of the American Pharmaceutical Association.

[36]  D. Clark Effects of Immunosympathectomy on Development of High Blood Pressure in Genetically Hypertensive Rats , 1971, Circulation research.

[37]  W. R. Hatrick On Diabetes , 1862, Glasgow medical journal.

[38]  Philippe Van De Borne,et al.  Guidelines for the management of arterial hypertension , 2014 .

[39]  W. Elliott Resistant Hypertension: Diagnosis, Evaluation, and Treatment: A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research , 2009 .

[40]  S. Kiley,et al.  Renal vascular endothelial growth factor in neonatal obstructive nephropathy. I. Endogenous VEGF. , 2007, American journal of physiology. Renal physiology.

[41]  R. Schmieder,et al.  Guidelines for management of arterial hypertension , 2007 .

[42]  T. Hökfelt,et al.  Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2-dependent activation of alpha1- and alpha2-adrenoceptors on renal sensory nerve fibers. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.