Modest elevation in BNP in asymptomatic hypertensive patients reflects sub-clinical cardiac remodeling, inflammation and extracellular matrix changes

Dermot Phelan, Chris Watson, Ramon Martos, Patrick Collier, Anil Patle, Seamas Donnelly, Mark Ledwidge, John Baugh, Ken McDonald, Dermot Phelan, Chris Watson, Ramon Martos, Patrick Collier, Anil Patle, Seamas Donnelly, Mark Ledwidge, John Baugh, Ken McDonald

Abstract

In asymptomatic subjects B-type natriuretic peptide (BNP) is associated with adverse cardiovascular outcomes even at levels well below contemporary thresholds used for the diagnosis of heart failure. The mechanisms behind these observations are unclear. We examined the hypothesis that in an asymptomatic hypertensive population BNP would be associated with sub-clinical evidence of cardiac remodeling, inflammation and extracellular matrix (ECM) alterations. We performed transthoracic echocardiography and sampled coronary sinus (CS) and peripheral serum from patients with low (n = 14) and high BNP (n = 27). Peripheral BNP was closely associated with CS levels (r = 0.92, p<0.001). CS BNP correlated significantly with CS levels of markers of collagen type I and III turnover including: PINP (r = 0.44, p = 0.008), CITP (r = 0.35, p = 0.03) and PIIINP (r = 0.35, p = 0.001), and with CS levels of inflammatory cytokines including: TNF-α (r = 0.49, p = 0.002), IL-6 (r = 0.35, p = 0.04), and IL-8 (r = 0.54, p<0.001). The high BNP group had greater CS expression of fibro-inflammatory biomarkers including: CITP (3.8±0.7 versus 5.1±1.9, p = 0.007), TNF-α (3.2±0.5 versus 3.7±1.1, p = 003), IL-6 (1.9±1.3 versus 3.4±2.7, p = 0.02) and hsCRP (1.2±1.1 versus 2.4±1.1, p = 0.04), and greater left ventricular mass index (97±20 versus 118±26 g/m(2), p = 0.03) and left atrial volume index (18±2 versus 21±4, p = 0.008). Our data provide insight into the mechanisms behind the observed negative prognostic impact of modest elevations in BNP and suggest that in an asymptomatic hypertensive cohort a peripheral BNP measurement may be a useful marker of an early, sub-clinical pathological process characterized by cardiac remodeling, inflammation and ECM alterations.

Conflict of interest statement

Competing Interests: This research was in part funded by a research bursary allocated by the Irish Heart Foundation which was funded by Pfizer. Pfizer had no input into the allocation of the bursary. The research was preformed completely independently of Pfizer. Pfizer had no input into the design or execution of the study or in the data analysis or manuscript preparation. No additional external funding was received for this study. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. There are no other relevant declarations relating to employment, consultancy, patents and products in development or marketed products.

Figures

Figure 1. Scatter plots showing significant correlations…
Figure 1. Scatter plots showing significant correlations between levels of BNP (log transformed) in serum from both the coronary sinus and periphery and levels of markers of collagen type I and type III turnover including PINP, CITP and PIIINP in serum from the coronary sinus.
Figure 2. Scatter plots showing significant correlations…
Figure 2. Scatter plots showing significant correlations between levels of BNP (log transformed) in serum from both the coronary sinus and periphery and the inflammatory cytokines TNF-α, IL-6 and IL-8 in serum from the coronary sinus.
Figure 3. Scatter plots showing significant correlations…
Figure 3. Scatter plots showing significant correlations between CS levels of BNP (log transformed) and structural changes in the heart including LAVI and LVMI.

References

    1. Nishikimi T, Maeda N, Matsuoka H (2006) The role of natriuretic peptides in cardioprotection. Cardiovasc Res 69: 318–328.
    1. Levin ER, Gardner DG, Samson WK (1998) Natriuretic peptides. N Engl J Med 339: 321–328.
    1. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, et al. (2002) Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 347: 161–167.
    1. Cheng V, Kazanagra R, Garcia A, Lenert L, Krishnaswamy P, et al. (2001) A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 37: 386–391.
    1. Omland T, Sabatine MS, Jablonski KA, Rice MM, Hsia J, et al. (2007) Prognostic value of B-Type natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 50: 205–214.
    1. Paget V, Legedz L, Gaudebout N, Girerd N, Bricca G, et al. (2011) N-terminal pro-brain natriuretic peptide: a powerful predictor of mortality in hypertension. Hypertension 57: 702–709.
    1. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, et al. (2004) Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 350: 655–663.
    1. Tsuchida K, Tanabe K (2008) Plasma brain natriuretic peptide concentrations and the risk of cardiovascular events and death in general practice. J Cardiol 52: 212–223.
    1. Whitworth JA (2003) 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 21: 1983–1992.
    1. Diez J, Laviades C, Mayor G, Gil MJ, Monreal I (1995) Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation 91: 1450–1456.
    1. Lopez B, Gonzalez A, Varo N, Laviades C, Querejeta R, et al. (2001) Biochemical assessment of myocardial fibrosis in hypertensive heart disease. Hypertension 38: 1222–1226.
    1. Kuwahara F, Kai H, Tokuda K, Takeya M, Takeshita A, et al. (2004) Hypertensive myocardial fibrosis and diastolic dysfunction: another model of inflammation? Hypertension 43: 739–745.
    1. Kai H, Kuwahara F, Tokuda K, Imaizumi T (2005) Diastolic dysfunction in hypertensive hearts: roles of perivascular inflammation and reactive myocardial fibrosis. Hypertens Res 28: 483–490.
    1. Watanabe S, Shite J, Takaoka H, Shinke T, Imuro Y, et al. (2006) Myocardial stiffness is an important determinant of the plasma brain natriuretic peptide concentration in patients with both diastolic and systolic heart failure. Eur Heart J 27: 832–838.
    1. Chatzis D, Tsioufis C, Tsiachris D, Taxiarchou E, Lalos S, et al.. (2009) Brain natriuretic peptide as an integrator of cardiovascular stiffening in hypertension. Int J Cardiol.
    1. Kapoun AM, Liang F, O’Young G, Damm DL, Quon D, et al. (2004) B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. Circ Res 94: 453–461.
    1. Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, et al. (2000) Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci U S A 97: 4239–4244.
    1. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, et al. (2005) Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18: 1440–1463.
    1. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, et al. (2009) Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 22: 107–133.
    1. Martos R, Baugh J, Ledwidge M, O’Loughlin C, Conlon C, et al. (2007) Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 115: 888–895.
    1. Hajjar I, Kotchen TA (2003) Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. Jama 290: 199–206.
    1. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK (1996) The progression from hypertension to congestive heart failure. Jama 275: 1557–1562.
    1. Tanaka M, Fujiwara H, Onodera T, Wu DJ, Hamashima Y, et al. (1986) Quantitative analysis of myocardial fibrosis in normals, hypertensive hearts, and hypertrophic cardiomyopathy. Br Heart J 55: 575–581.
    1. Rossi MA (1998) Pathologic fibrosis and connective tissue matrix in left ventricular hypertrophy due to chronic arterial hypertension in humans. J Hypertens 16: 1031–1041.
    1. Querejeta R, Lopez B, Gonzalez A, Sanchez E, Larman M, et al. (2004) Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation 110: 1263–1268.
    1. Ciulla M, Paliotti R, Hess DB, Tjahja E, Campbell SE, et al. (1997) Echocardiographic patterns of myocardial fibrosis in hypertensive patients: endomyocardial biopsy versus ultrasonic tissue characterization. J Am Soc Echocardiogr 10: 657–664.
    1. Plaksej R, Kosmala W, Frantz S, Herrmann S, Niemann M, et al. (2009) Relation of circulating markers of fibrosis and progression of left and right ventricular dysfunction in hypertensive patients with heart failure. J Hypertens 27: 2483–2491.
    1. Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, et al. (2002) Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105: 2512–2517.
    1. Brilla CG, Funck RC, Rupp H (2000) Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 102: 1388–1393.
    1. Grodecki PV, Klein AL (1993) Pitfalls in the echo-Doppler assessment of diastolic dysfunction. Echocardiography 10: 213–234.
    1. Oguzhan A, Arinc H, Abaci A, Topsakal R, Kemal Eryol N, et al. (2005) Preload dependence of Doppler tissue imaging derived indexes of left ventricular diastolic function. Echocardiography 22: 320–325.
    1. Querejeta R, Varo N, Lopez B, Larman M, Artinano E, et al. (2000) Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 101: 1729–1735.
    1. Collier P, Watson CJ, Voon V, Phelan D, Jan A, et al.. (2011) Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure? Eur J Heart Fail.
    1. Berk BC, Fujiwara K, Lehoux S (2007) ECM remodeling in hypertensive heart disease. J Clin Invest 117: 568–575.
    1. Barasch E, Gottdiener JS, Aurigemma G, Kitzman DW, Han J, et al. (2011) The relationship between serum markers of collagen turnover and cardiovascular outcome in the elderly: the Cardiovascular Health Study. Circ Heart Fail 4: 733–739.
    1. Montecucco F, Pende A, Quercioli A, Mach F (2011) (2011) Inflammation in the pathophysiology of essential hypertension. J Nephrol. 24(1): 23–34.
    1. Melendez GC, McLarty JL, Levick SP, Du Y, Janicki JS, et al. (2010) Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension 56: 225–231.
    1. Sun M, Chen M, Dawood F, Zurawska U, Li JY, et al. (2007) Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation 115: 1398–1407.
    1. Sivasubramanian N, Coker ML, Kurrelmeyer KM, MacLellan WR, DeMayo FJ, et al. (2001) Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation 104: 826–831.
    1. Frangogiannis NG (2004) Chemokines in the ischemic myocardium: from inflammation to fibrosis. Inflamm Res 53: 585–595.
    1. Chiurchiu V, Izzi V, D’Aquilio F, Carotenuto F, Di Nardo P, et al. (2008) Brain Natriuretic Peptide (BNP) regulates the production of inflammatory mediators in human THP-1 macrophages. Regul Pept 148: 26–32.
    1. de Bold AJ (2009) Cardiac natriuretic peptides gene expression and secretion in inflammation. J Investig Med 57: 29–32.
    1. Shor R, Rozenman Y, Bolshinsky A, Harpaz D, Tilis Y, et al. (2006) BNP in septic patients without systolic myocardial dysfunction. Eur J Intern Med 17: 536–540.
    1. Nakatsu T, Shinohata R, Mashima K, Yuki Y, Nishitani A, et al. (2007) Use of plasma B-type natriuretic peptide level to identify asymptomatic hypertensive patients with abnormal diurnal blood pressure variation profiles: nondippers, extreme dippers, and risers. Hypertens Res 30: 651–658.
    1. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, et al. (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359: 2195–2207.
    1. Troughton RW, Richards AM, Yandle TG, Frampton CM, Nicholls MG (2007) The effects of medications on circulating levels of cardiac natriuretic peptides. Ann Med 39: 242–260.
    1. Rosenberg J, Gustafsson F, Remme WJ, Riegger GA, Hildebrandt PR (2008) Effect of beta-blockade and ACE inhibition on B-type natriuretic peptides in stable patients with systolic heart failure. Cardiovasc Drugs Ther 22: 305–311.
    1. Ohtsuka T, Hamada M, Hiasa G, Sasaki O, Suzuki M, et al. (2001) Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy. J Am Coll Cardiol 37: 412–417.
    1. Nishio M, Sakata Y, Mano T, Ohtani T, Takeda Y, et al. (2008) Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats. Eur J Heart Fail 10: 446–453.
    1. Bartholomeu JB, Vanzelli AS, Rolim NP, Ferreira JC, Bechara LR, et al. (2008) Intracellular mechanisms of specific beta-adrenoceptor antagonists involved in improved cardiac function and survival in a genetic model of heart failure. J Mol Cell Cardiol 45: 240–249.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere