Multiple Biomarkers and the Risk of Incident Hypertension

An understanding of mechanisms underlying the development of essential hypertension is critical for designing prevention and treatment strategies. Selected biomarkers may be elevated before the onset of hypertension, but previous studies are limited by cross-sectional designs or a focus on single biomarkers. We prospectively studied 1456 nonhypertensive individuals who had baseline measurement of 9 biomarkers: C-reactive protein (inflammation); fibrinogen (inflammation and thrombosis); plasminogen activator inhibitor-1 (fibrinolytic potential); aldosterone, renin, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide (neurohormonal activity); homocysteine (renal function and oxidant stress); and urinary albumin/creatinine ratio (glomerular endothelial function). Incident hypertension, defined as blood pressure ≥140/90 mm Hg or antihypertensive therapy, developed in 232 participants over a mean follow-up of 3 years. After adjustment for clinical risk factors, the biomarker panel was significantly associated with incident hypertension (P=0.002). Three (of 9) biomarkers were significantly related to incident hypertension on backward elimination (multivariable-adjusted odds ratios, per SD increment in biomarker): C-reactive protein (1.26; 95% CI: 1.05 to 1.51), plasminogen activator inhibitor-1 (1.28; 95% CI: 1.05 to 1.57), and urinary albumin/creatinine ratio (1.21; 95% CI: 1.02 to 1.43). The incidence of hypertension was 4.5, 6.4, and 9.9 per 100 person years for participants with 0, 1, and ≥2 elevated biomarkers, respectively (elevation defined as ≥1 SD above the mean). The threshold of ≥2 elevated biomarkers for predicting hypertension was associated with high specificity (0.92) but low sensitivity (0.15). Biomarkers of inflammation, reduced fibrinolytic potential, and low-grade albuminuria are jointly associated with the incidence of hypertension. These data support the premise that abnormalities in multiple biological pathways antedate the onset of overt hypertension.

[1]  Benjamin J. Epstein,et al.  Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure , 2007 .

[2]  E. Reisin,et al.  Hypertension and the Metabolic Syndrome , 2005, The American journal of the medical sciences.

[3]  A. Divani,et al.  Prevalence and trends of prehypertension and hypertension in United States: National Health and Nutrition Examination Surveys 1976 to 2000. , 2005, Medical science monitor : international medical journal of experimental and clinical research.

[4]  J. Pratt,et al.  Aldosterone increases plasminogen activator inhibitor-1 synthesis in rat cardiomyocytes , 2005, Molecular and Cellular Endocrinology.

[5]  P. Fesler,et al.  Relative glomerular hyperfiltration in primary aldosteronism. , 2005, Journal of the American Society of Nephrology : JASN.

[6]  D. Levy,et al.  Low-Grade Albuminuria and the Risks of Hypertension and Blood Pressure Progression , 2005, Circulation.

[7]  D. Levy,et al.  Relations of Serum Uric Acid to Longitudinal Blood Pressure Tracking and Hypertension Incidence , 2005, Hypertension.

[8]  S. Del Prato,et al.  Low-Grade Inflammation and Microalbuminuria in Hypertension , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[9]  F. Boomsma,et al.  Validation of a new automated renin assay. , 2004, Clinical chemistry.

[10]  D. Levy,et al.  Serum aldosterone and the incidence of hypertension in nonhypertensive persons. , 2004, The New England journal of medicine.

[11]  R. Dluhy,et al.  Aldosterone--villain or bystander? , 2004, The New England journal of medicine.

[12]  N. Ganguly,et al.  Oxygen free radicals in essential hypertension , 1992, Molecular and Cellular Biochemistry.

[13]  K. Borch-Johnsen,et al.  Albuminuria reflects widespread vascular damage , 1989, Diabetologia.

[14]  S. Grundy.  Inflammation, hypertension, and the metabolic syndrome. , 2003, JAMA.

[15]  P. Ridker,et al.  C-reactive protein and the risk of developing hypertension. , 2003, JAMA.

[16]  Christopher J. Lyon,et al.  Effect of plasminogen activator inhibitor-1 in diabetes mellitus and cardiovascular disease. , 2003, The American journal of medicine.

[17]  D. Levy,et al.  Plasma Homocysteine, Hypertension Incidence, and Blood Pressure Tracking: The Framingham Heart Study , 2003, Hypertension.

[18]  Daniel W. Jones,et al.  Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. , 2003, Hypertension.

[19]  J. Whitworth,et al.  2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension , 2003, Journal of hypertension.

[20]  Daniel W. Jones,et al.  The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. , 2003, JAMA.

[21]  Pasquale Strazzullo,et al.  Altered Renal Handling of Sodium in Human Hypertension: Short Review of the Evidence , 2003, Hypertension.

[22]  S. Verma,et al.  C-Reactive Protein Upregulates Angiotensin Type 1 Receptors in Vascular Smooth Muscle , 2003, Circulation.

[23]  D. Levy,et al.  Plasma Brain Natriuretic Peptide Levels and Blood Pressure Tracking in the Framingham Heart Study , 2003, Hypertension.

[24]  G. Curhan,et al.  High-normal blood pressure and microalbuminuria. , 2003, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[25]  S. Devaraj,et al.  C-Reactive Protein Increases Plasminogen Activator Inhibitor-1 Expression and Activity in Human Aortic Endothelial Cells: Implications for the Metabolic Syndrome and Atherothrombosis , 2003, Circulation.

[26]  J. Ingelfinger,et al.  Is microanatomy destiny? , 2003, The New England journal of medicine.

[27]  P. Cassano,et al.  Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988-1994. , 2002, American journal of epidemiology.

[28]  G. Berglund,et al.  Blood Pressure Increase and Incidence of Hypertension in Relation to Inflammation-Sensitive Plasma Proteins , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[29]  R. D'Agostino,et al.  Association Between Increased Homocysteine Levels and Impaired Fibrinolytic Potential: Potential Mechanism for Cardiovascular Risk , 2002, Thrombosis and Haemostasis.

[30]  J. Manson,et al.  Interrelationships Among Circulating Interleukin-6, C-Reactive Protein, and Traditional Cardiovascular Risk Factors in Women , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[31]  Sridevi Devaraj,et al.  Demonstration That C-Reactive Protein Decreases eNOS Expression and Bioactivity in Human Aortic Endothelial Cells , 2002, Circulation.

[32]  Ren-Ke Li,et al.  A Self-Fulfilling Prophecy: C-Reactive Protein Attenuates Nitric Oxide Production and Inhibits Angiogenesis , 2002, Circulation.

[33]  S. Hunt,et al.  PAI-1 in human hypertension: relation to hypertensive groups. , 2002, American journal of hypertension.

[34]  D. Levy,et al.  Impact of age and sex on plasma natriuretic peptide levels in healthy adults. , 2002, The American journal of cardiology.

[35]  A. Brasier,et al.  Vascular inflammation and the renin-angiotensin system. , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[36]  H. Dige-Petersen,et al.  Vasodilatory capacity and vascular structure in long-standing hypertension: a LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension. , 2002, American journal of hypertension.

[37]  D. Vaughan,et al.  Aldosterone and PAI-1: implications for renal injury. , 2002, Journal of nephrology.

[38]  J. Hensen,et al.  Ratio of serum aldosterone to plasma renin concentration in essential hypertension and primary aldosteronism. , 2002, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[39]  Daniel Levy,et al.  Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study , 2001, The Lancet.

[40]  D. Vaughan,et al.  Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition , 2001, Circulation.

[41]  D. Singer,et al.  Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham offspring study. , 2001, Diabetes care.

[42]  P. López-Jaramillo,et al.  Is C-reactive protein an independent risk factor for essential hypertension? , 2001, Journal of hypertension.

[43]  K. Borch-Johnsen,et al.  Elevated Urinary Albumin Excretion Is Associated With Impaired Arterial Dilatory Capacity in Clinically Healthy Subjects , 2001, Circulation.

[44]  D. Gaudet,et al.  Arterial Pressure, Left Ventricular Mass, and Aldosterone in Essential Hypertension , 2001, Hypertension.

[45]  S. Vollset,et al.  The Hordaland Homocysteine Studies , 2001, Lipids.

[46]  D. Vaughan,et al.  Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. , 2000, Kidney international.

[47]  G. Lip,et al.  Does hypertension confer a prothrombotic state? Virchow's triad revisited. , 2000, Circulation.

[48]  D. Levy,et al.  Association of blood pressure with fibrinolytic potential in the Framingham offspring population. , 2000, Circulation.

[49]  P. Ridker,et al.  Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men. , 1999, The American journal of cardiology.

[50]  G. Desideri,et al.  High plasma renin activity is combined with elevated urinary albumin excretion in essential hypertensive patients. , 1999, Kidney international.

[51]  H. Schouten,et al.  Endothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type 1 diabetes under near-normoglycemic conditions. , 1999, Diabetes.

[52]  M. Mulvany,et al.  Vascular remodelling of resistance vessels: can we define this? , 1999, Cardiovascular research.

[53]  D. Vaughan,et al.  Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. , 1998, Hypertension.

[54]  M. Cirillo,et al.  Microalbuminuria in nondiabetic adults: relation of blood pressure, body mass index, plasma cholesterol levels, and smoking: The Gubbio Population Study. , 1998, Archives of internal medicine.

[55]  D. O'Connor,et al.  Plasma hydrogen peroxide production in hypertensives and normotensive subjects at genetic risk of hypertension , 1998, Journal of hypertension.

[56]  Detection.  The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) , 1997 .

[57]  R. Weinshilboum,et al.  The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. , 1997, Archives of internal medicine.

[58]  A. Mark,et al.  The sympathetic nervous system in hypertension: a potential long-term regulator of arterial pressure. , 1996, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[59]  T. Ogihara,et al.  Impaired endothelial function with essential hypertension assessed by ultrasonography. , 1996, American heart journal.

[60]  T. Ishimitsu,et al.  Relationship between left ventricular geometry and natriuretic peptide levels in essential hypertension. , 1996, Hypertension.

[61]  S. Vollset,et al.  Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. , 1995, JAMA.

[62]  C. Jern,et al.  Enhanced levels of tissue-type plasminogen activator in borderline hypertension. , 1995, Hypertension.

[63]  P. Wilson,et al.  Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. , 1993, JAMA.

[64]  N. Markandu,et al.  Plasma concentrations and comparisons of brain and atrial natriuretic peptide in normal subjects and in patients with essential hypertension. , 1993, Journal of human hypertension.

[65]  A. Donker,et al.  Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus , 1992, The Lancet.

[66]  D. Hosmer,et al.  Applied Logistic Regression , 1991 .

[67]  David W. Hosmer,et al.  Best subsets logistic regression , 1989 .

[68]  B. Brenner,et al.  Glomeruli and blood pressure. Less of one, more the other? , 1988, American journal of hypertension.

[69]  M. Alessi,et al.  Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. , 1988, Blood.

[70]  Y. Sako,et al.  Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. , 1987, Journal of chromatography.

[71]  M. Hartford,et al.  Blood pressure in relation to the renin-angiotensin-aldosterone system. , 2009, Acta medica Scandinavica.

[72]  W. Kannel,et al.  An investigation of coronary heart disease in families. The Framingham offspring study. , 1979, American journal of epidemiology.

[73]  P. Whelton,et al.  Relation Between Blood Pressure and Renin, Renin Substrate, Angiotensin II, Aldosterone and Urinary Sodium and Potassium in 574 Ambulatory Subjects , 1979, Hypertension.

[74]  V. Parin.  [On the pathogenesis of hypertension]. , 1961, Sovetskaia meditsina.

[75]  A. Clauss,et al.  Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens , 1957 .