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WO2006117410A1 - Utilisation d'un fragment c-terminal comme marqueur de la cardiotrophine-1 - Google Patents

Utilisation d'un fragment c-terminal comme marqueur de la cardiotrophine-1 Download PDF

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WO2006117410A1
WO2006117410A1 PCT/ES2005/000227 ES2005000227W WO2006117410A1 WO 2006117410 A1 WO2006117410 A1 WO 2006117410A1 ES 2005000227 W ES2005000227 W ES 2005000227W WO 2006117410 A1 WO2006117410 A1 WO 2006117410A1
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probnp
human
amino acids
concentration
picp
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Javier DÍEZ MARTÍNEZ
Begoña LÓPEZ SALAZAR
Aránzazu GONZÁLEZ MIQUEO
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Proyecto de Biomedicina CIMA SL
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5412—IL-6
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/321—Arterial hypertension
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • Field of the invention Markers for detection of heart disease.
  • the essential criterion for determining hypertensive heart disease is the presence of left ventricular hypertrophy (LVH) in the absence of a cause other than arterial hypertension. It is currently accepted that apart from the growth of cardiomyocytes, an exaggerated deposition of collagen fibers that leads to myocardial fibrosis also contributes to LVH in arterial hypertension. Hypertensive LVH develops in response to stress pathways activated by mechanical overload imposed by systemic hypertension on the left ventricle. It has been proposed that some of these routes involve the participation of ligands dependent on gp 130.
  • Cardiotrophin-1 a cytokine that induces cardiomyocyte hypertrophy and stimulates cardiac fibroblasts
  • CT-1 is a 201 amino acid member of the interleukin-6 superfamily, which binds to glycoprotein 130 (gp 130) and to the leukemia inhibitor factor (LIF) receptor [1].
  • LIF leukemia inhibitor factor
  • CT-I ventricular CT-I gene
  • SHR spontaneous hypertension
  • the cardiac levels of the mRNA of CT-I and protein are increased in hypertensive, salt-sensitive Dahl rats, with LVH, compared to normotensive and salt-resistant Dahl rats.
  • CT-I its receptors and signaling pathways at the gene level and of proteins in cardiac fibroblasts has been demonstrated.
  • CT-I directly stimulates the proliferation and synthesis of type I collagen in this type of cells [2-3].
  • CT-I research As a marker.
  • application WO-0103753, [4] describes an assay for the diagnosis or detection of a predisposition to cardiac hypertrophy by means of a competitive ELISA; said ELISA can be performed on a compound that specifically binds to CT-I, such as a CT-I receptor or an antibody against CT-I.
  • Said immunoassay can be performed on any type of sample; blood, urine, serum and others. However, it does not describe the use of a CT-I fragment.
  • [5] describes a competitive radioimmunoassay for human CT-I, the rabbit antiserum recognizing the N-terminal region of human CT-I (amino acids 46-70) and using recombinant human CT-I as a calibrator, according to which found that the lower limit of detection in buffer was 42 fmol / ml; and [6] describes an immunochemiluminometric assay to detect high levels of plasma CT-I in case of heart failure.
  • the method described in [6] is a non-competitive assay where two antibodies are used. Said antibodies were developed against specific fragments of CT-I, one of them being an antibody developed against the fragment comprising amino acids 186-199 and the second being an antibody developed against the fragment comprising amino acids 105-120 of CT -I.
  • [7] describes a competitive, non-radioactive immunoluminometric assay to detect fragment 105-120 of CT-I using as essential components an antibody developed against said peptide and the peptide itself.
  • CT-I and PICP in patients with hypertensive heart disease.
  • the present invention intends to test two hypotheses, firstly, that this CT-I may be positively regulated in an abnormal way in hypertensive patients, and secondly that this cytokine may be a marker of hypertensive heart failure.
  • CT-I plasma levels of CT-I in normotensive subjects and in hypertensive patients with and without LVH.
  • NT-proBNP amino-terminal cerebral natriuretic pro-peptide
  • PICP carboxy-terminal propeptide of type I procollagen
  • the present invention was developed to investigate whether the plasma or serum concentration of cardiotrophin-1 is related to hypertensive heart disease, as defined by the presence of left ventricular hypertrophy (LVH) echocardiographically evaluated. It was investigated whether plasma or serum cardiotrophin-1 (CT-I) is related to left ventricular hypertrophy (LVH) in patients with essential hypertension. Description of the invention The present invention relates to the use of the C-terminal fragment of human CT-I comprising amino acids 186-200, as a marker for the evaluation of the concentration of CT-I in plasma or serum in early detection of hypertensive heart disease.
  • the evaluation of the plasma or serum concentration of CT-I can be carried out by means of a test preferably selected from an immunoassay, a chromatographic test and a spectrophotometric test.
  • the assay is an immunoassay and more preferably it is an ELISA.
  • at least one additional marker is used in addition to the fragment comprising amino acids 186-200 of human CT-I.
  • said additional marker is selected from the cerebral natriuretic propeptide, NT-proBNP, and the carboxy-terminal propeptide of type I procollagen, PICP.
  • two additional markers are used being said NT-proBNP markers and the carboxy-terminal propeptide of type I procollagen , PICP.
  • CT-I evaluation is performed by an ELISA
  • NT-proBNP evaluation is performed by an ELISA
  • PICP evaluation is performed by a radioimmunoassay.
  • Another object of the invention is the use of the C-terminal fragment of human CT-I comprising amino acids 186-200 in a method comprising: a) measuring serum or plasma concentration
  • NT-proBNP and PICP therefore being a further object of the invention is the use of the C-terminal fragment of human CT-I comprising amino acids 186-200 in a method comprising: a) measuring serum concentration or plasma
  • said additional markers are both NT-proBNP and PICP, therefore being a further object of the invention is the use of the C-terminal fragment of human CT-I comprising amino acids 186-200 in a method comprising: a) measuring serum or plasma concentration
  • said method comprises: a) measuring the concentration in serum or plasma - of the fragment comprising amino acids 186-200 of human CT-I,
  • said method comprises: a) measuring serum or plasma concentration - of the fragment comprising amino acids 186-200 of human CT-I,
  • the concentration of CT-I can be correlated with systolic blood pressure, LVMI and PICP.
  • ROC curves are obtained to predict LVH.
  • the area under the ROC curves can be correlated with the CT-I and the NT-proBNP.
  • Another object of the invention is the use of the ' C-terminal fragment of human CT-I comprising amino acids 186-200, for the manufacture of a kit for the early detection of hypertensive heart disease by means of the determination of CT -I in plasma or serum.
  • the evaluation of the concentration of CT-I in plasma or serum is carried out by means of an assay selected from an immunoassay, a chromatographic assay and a spectrophotometric assay, more preferably, the immunoassay is an ELISA.
  • At least one additional marker selected from the brain natriuretic pro-peptide, NT-proBNP, and the propeptide is used in the kit carboxy-terminal of type I procollagen, PICP. More preferably, two additional markers are used, said NT-proBNP markers and the carboxy-terminal propeptide of type I procollagen, PICP.
  • the CT-I evaluation is preferably carried out by means of an ELISA
  • the NT-proBNP evaluation is preferably carried out by means of an ELISA
  • the PICP evaluation is preferably carried out by means of a radioimmunoassay.
  • Another object of the invention is a method for the early detection of hypertensive heart disease characterized in that it comprises the determination of CT-1 in plasma or serum by means of an assay in which the C-terminal fragment of CT- is used as a marker.
  • Human I comprising amino acids 186-200.
  • the method in addition to the fragment comprising amino acids 186-200 of human CT-I, the method comprises determining the concentration of at least one additional marker.
  • Said marker is preferably selected from NT-proBNP and the PICP. More preferably, the method comprises determining the concentration of two additional markers, said markers being NT-proBNP and PICP.
  • the method defined above preferably comprises: a) measuring serum or plasma concentration
  • the method defined above preferably comprises: a) measuring the concentration in serum or plasma
  • the method comprises: a) measuring the concentration in serum or plasma - of the fragment comprising amino acids 186-200 of human CT-I,
  • the method comprises: a) measure the serum or plasma concentration of
  • the method comprises correlating CT-I with systolic blood pressure, LVMI and PICP.
  • the method comprises obtaining ROC curves to predict LVH.
  • Low area ROC curves can be correlated with CT-I and NT-proBNP.
  • reference limit values for CT-I and NT-proBNP can be calculated, thus determining the risk of presenting LVH.
  • Another object of the present invention is a kit for the early detection of hypertensive heart disease, characterized in that it comprises the C-terminal fragment comprising amino acids 186-200 of human CT-I as a marker, together with appropriate reagents. Said kit preferably comprises at least one additional marker.
  • Said additional marker is preferably selected from NT-proBNP and PICP, more preferably it comprises two additional markers that are NT-proBNP and PICP.
  • Another object of the present invention is a monoclonal antibody against the C-terminal fragment of human CT-I comprising amino acids 186-200. Brief description of the figures Figure 1. ELISA calibration curve for different added amounts of human cardiotrophin-1 (CT-I). Absorbance values were adjusted to the HiIl (interior) equation.
  • FIG. 1 Plasma concentration of cardiotrophin-1 (CT-I) (left panel), serum concentration of carboxy-terminal propeptide of type I procollagen
  • PICP serum amino-terminal cerebral natriuretic propeptide
  • NT-proBNP serum amino-terminal cerebral natriuretic propeptide
  • Figure 6. Characteristic operating curves of the receptor for cardiotrophin-1 (CT-I) and amino-terminal cerebral natriuretic propeptide (NT-proBNP), represented for various limit values, to determine left ventricular hypertrophy as defined in the text .
  • the study population consisted of 31 normotensive subjects and 111 hypertensive patients with resting systolic blood pressure and resting diastolic blood pressure of more than 139 and 89 mm Hg, respectively. Blood pressure was measured 3 times using a mercury sphygmomanometer and the average of these 3 readings was recorded. All patients had an appropriate clinical and laboratory evaluation to exclude secondary hypertension and none of them had received prior treatment with antihypertensive drugs. The hypertensive patients were divided into two subgroups according to the presence or absence of LVH on the echocardiogram. Although in 54 patients no LVH was detected, it was present in 57 patients.
  • Echocardiography excluded other heart diseases associated with LVH (for example, hypertrophic cardiomyopathy and aortic stenosis). No patient showed clinical manifestations of ischemic heart disease or heart failure, and systolic dysfunction was excluded by an echocardiographic evaluation.
  • LVH hypertrophic cardiomyopathy and aortic stenosis
  • LVMI mass index of the left ventricle
  • the endocardial fractional shortening of the left ventricle and ejection fraction (EF) were calculated according to Qui ⁇ ones et al. [13].
  • the left ventricular mesocardial shortening fraction (MWFS) was calculated according to de Simone et al. [14]. Systolic dysfunction was diagnosed when the EF and MWFS values were below 45% and / or 12% respectively. Measurement of CT-I in plasma
  • a new enzyme-linked immunoabsorbent assay was developed to measure CT-I in plasma.
  • An oligopeptide corresponding to amino acids 186-200, described in [9], of human CT-I was synthesized according to the Merrifield solid phase method using the Fmoc alternative. There is no homology between this peptide and other cytokines of the interleukin-6 family.
  • the peptide was further purified by high performance liquid chromatography. The pure molecular mass was confirmed using matrix assisted laser desorption mass spectrometry.
  • Two rabbits were immunized by intradermal injection of 1 ml of a 1: 1 emulsion of Freund's complete adjuvant and saline solution containing 0.5 mg of the antigenic peptide and 0.5 mg of the FIS adjuvant T-cell determinant.
  • the rabbits were reinforced on days 30 and 45 with the same mixture of peptides but emulsified in incomplete Freund's adjuvant by subcutaneous and intramuscular injections, respectively.
  • On day 65 it sera were extracted and antibodies were tested against the peptide containing residues 186-200 of human CT-I, and against recombinant human CT-I, by ELISA and Western blotting.
  • the samples were then incubated with a polyclonal anti-CT-1 antibody at a dilution of 1: 500 in PBS at room temperature for one hour (100 ⁇ l / well).
  • the level of PICP was determined in serum samples by radioimmunoassay according to a previously described method [15]. Inter-trial and intra-trial variation coefficients were 7% and 3%, respectively. The sensitivity was 5 ⁇ g of PICP / 1 (or 50 pmol of PICP / 1).
  • NT-proBNP was measured in serum samples by ELISA according to Karl et al. [16]. The inter-trial and intra-trial variation coefficients were less than 2%. The sensitivity was 5 pg of NT-proBNP / ml (or 0.590 pmol of NT-proBNP / ml).
  • Statistical Analysis Once normality was demonstrated (Shapiro-Wilks test), a Student's t-test was used to compare the normotensive group and the entire group of hypertensives, and the subgroup of hypertensive without LVH and the subgroup of hypertensive with LVH; in the other cases, the non-parametric Mann-Whitney U test was used.
  • ROC characteristic receiver operation curves
  • Table 1 shows clinical and echocardiographic parameters evaluated in normotensive and hypertensive patients.
  • BMI indicates body mass index; PAS systolic blood pressure; PAD diastolic blood pressure; PAM mean blood pressure; PP pulse pressure; IMVI left ventricular mass index; TRIV isovolumetric relaxation time; V E maximum transmitral flow in the initial diastole; V A maximum transmitral flow in late diastole; TD deceleration time; FE ejection fraction; ; FAM mesocardial shortening fraction; CT-I cardiotrophin-1; PICP carboxy-terminal propeptide of procollagen type I; NT-proBNP amino-terminal cerebral natriuretic propeptide. NS not significant. * Mann Whitney U test; ** Test of the
  • Table 2 shows the clinical and echocardiographic parameters evaluated in the two subgroups of hypertensive patients.
  • V E V A 0.96 ⁇ 0.03 0.88 ⁇ 0.02 NS ***
  • LVH indicates left ventricular hypertrophy; IM C body mass index; PAS systolic blood pressure; PAD diastolic blood pressure; PAM mean blood pressure; PP pulse pressure; IMVI left ventricular mass index; TRIV relaxation time isovolum é trie a; V E maximum transverse flow in the initial diastole; V A maximum transverse flow in late diastole; TD deceleration time; FE ejection fraction; ; FAM mesocardial shortening fraction.
  • CT-I immunoreactivity was detected in the plasma of all subjects studied. Plasma CT-I was significantly higher in hypertensive patients compared to normotensive patients (Table 1). In addition, CT-I was increased in hypertensive patients with LVH compared to hypertensive patients without LVH (68.87 + 7.59 versus 37.67 + 2.27 fmol / ml, P ⁇ 0.001) ( Figure 2). 31% and 68% of hypertensive patients without and with LVH, respectively, showed CT-I values above the upper limit in the controls (41 fmol / ml), this difference being statistically significant (P ⁇ 0.001). Serum concentrations of PICP and NT-proBNP
  • Serum PICP was significantly higher in hypertensive patients than in normotensive patients (Table 1). In addition, PICP was increased in hypertensive patients with LVH compared to hypertensive patients without LVH (119.30 + 4.22 versus 99.87 ⁇ 3.98 ⁇ g / 1) ( Figure 2).
  • NT-proBNP values were similar in hypertensive compared to normotensive (Table 1). In addition, no difference was found in NT-proBNP between hypertensive with and without LVH (49.42 ⁇ 4.58 versus 49.63 ⁇
  • systolic blood pressure 0.453, P ⁇ 0.001
  • LVMI 0.319, P ⁇ 0.001
  • PICP 0.573, P ⁇ 0.001 in all subjects
  • ROC curves show the overall behavior of CT-I and NT-proBNP to predict LVH (Figure 6).
  • the area under the ROC curve was larger (P ⁇ 0.05) for CT-I (0.78 ⁇ 0.04) than for NT-proBNP (0.50 ⁇ 0.05). Only the area under the ROC curve for CT-I was greater (P ⁇ 0.001) than 0.50.
  • reference limit values were calculated for CT-I and NT-proBNP. The sensitivity and specificity of each of these two values to predict LVH are presented in Table 3. In general, the CT-I limit value showed better sensitivity and specificity.
  • CT-I increased (P ⁇ 0.001) in hypertensive patients compared to normotensive patients.
  • the value of CT-I was higher (P ⁇ 0.001) in hypertensive patients with LVH than in hypertensive patients without LVH. 31% of patients without LVH showed CT-I values above the upper normal limit in normotensive patients.
  • the characteristic operating curves of the receiver showed that a limit of 39 fmol / ml for CT-I provided a specificity of 75% and a sensitivity of 70% to predict LVH with a relative risk of 6.21 (95% CI, 2 , 95 to 13.09). These results show an association between LVH and the plasma concentration of CT-I in essential hypertension. Although preliminary, these findings suggest that the determination of CT-I may be an easy and reliable method for the selection and initial diagnosis of hypertensive heart disease. Pathophysiological Meaning Several mechanisms may participate in the observed increase in CT-I in hypertension. Talwar et al.
  • CT-I cardiovascular disease
  • the 100 kDA PICP is cleaved during the extracellular processing of type I procollagen into fibril-forming type I collagen molecules.
  • the released peptide is found in an immunochemically intact form in the blood.
  • Several studies conducted in SHR and in hypertensive patients demonstrate that the circulating level of PICP is associated with the degree of myocardial deposition of type I collagen fibers in hypertensive heart disease [18, 19].
  • the findings indicated in this document suggest that an excess of CT-I may be related to an exaggerated synthesis and deposition of type I collagen in the myocardium of hypertensive patients. Two observations confirm this possibility.
  • CT-I initiates and maintains the fibrotic process that leads to the formation of scars in the infarcted areas of the rat heart.
  • the LVH detected by electrocardiogram or echocardiogram is an established substitute assessment criterion of cardiovascular prognosis, because there is currently evidence of a continuous risk prediction, as well as the documentation of effects beneficial investment of LVH.
  • the sensitivity of echocardiography to detect LVH has been high (85-100%), while that of electrocardiography has varied from as high as 50% in necropsy populations with serious diseases to a value. as low as 6-17% in studies at Cornell and Framingham.
  • the accuracy and reproducibility of echocardiographic measurements depend on the experience of the operator.
  • the availability of additional methods to detect the presence of LVH can play a role in the initial clinical evaluation of hypertensive patients.
  • the present invention shows how it is observed by the analysis of the ROC curve, that plasma CT-I is a sensitive and specific parameter in the identification of echocardiographic LVH. Secondly, the present invention shows that subjects with plasma concentrations of CT-I> 39 fmol / ml are 6 times more likely to have echocardiographic LVH than subjects with a plasma level of CT-I below this value. Third, the present invention shows that plasma CT-I has a higher yield for estimating echocardiographic LVH than MT-proBNP.
  • CT-I secret heart through the coronary sinus in the peripheral circulation, given the previous evidence that demonstrates that the CT-I mRNA is expressed in other organs, there may be additional potential sources of Circulating CT-I
  • the main advantages of this invention are: (1) it was found that plasma concentrations of CT-I are abnormally high at. patients with essential hypertension, (2) it was found that there is an association between the plasma levels of CT-I and LMVI and PICP in hypertensive patients, and (3) it was found that CT-I is more accurate than NT-proBNP in the discrimination of LVH in these patients. In addition, for the first time it was shown that plasma levels of CT-I are abnormally increased in essential hypertension. In addition, it was discovered that plasma levels of this cytokine are associated with the magnitude of the growth of the left ventricle in hypertensive patients. In this way, the measurement of plasma or serum CT-I could be a practical and useful tool in the initial evaluation of hypertensive heart disease. In particular, it could have clinical relevance in the identification of hypertensive patients susceptible to undergoing additional studies to identify LVH (ie, echocardiography).
  • Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 2000; 101: 1729-
  • Plasma M- terminal pro BNP and cardiotrophin-1 are elevated in aortic stenosis. Eur J Heart Fail 2001; 3: 15-19.

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Abstract

La présente invention concerne l'utilisation du fragment C-terminal de la CT-1 humaine, comprenant les acides aminés 186-200, comme marqueur de l'évolution de la CT-1 dans le plasma ou le sérum, à des fins de détection précoce de la maladie cardiaque hypertensive. La présente invention concerne également une méthode destinée à la détection précoce d'une maladie cardiaque, consistant à déterminer la concentration de la CT-1 dans le plasma ou le sérum, seule ou de façon combinée avec d'autres marqueurs, ainsi qu'une trousse destinée à la détection précoce de la maladie cardiaque hypertensive, dans laquelle est utilisé ledit fragment C-terminal de la CT-1 humaine comprenant les acides aminés 186-200.
PCT/ES2005/000227 2005-04-28 2005-04-28 Utilisation d'un fragment c-terminal comme marqueur de la cardiotrophine-1 Ceased WO2006117410A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001003573A2 (fr) * 1999-07-08 2001-01-18 Matrix Therapeutics Limited Procede diagnostique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001003573A2 (fr) * 1999-07-08 2001-01-18 Matrix Therapeutics Limited Procede diagnostique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
GONZALEZ A. ET AL.: "Plasma cardiotrophin-1, a myocardial stress marker in hypertensive heart disease?", AMERICAN JOURNAL OF HYPERTENSION, vol. 16, no. 5, 2ND PART, May 2003 (2003-05-01), pages 85A, XP008071910 *
LOPEZ B. ET AL.: "Is plasma cardiotrophin-1 a marker of hypertensive heart disease?", JOURNAL OF HYPERTENSION, vol. 23, no. 3, March 2005 (2005-03-01), pages 625 - 632, XP008071917 *
NG L.L. ET AL.: "Non-competitive immunochemiluminometric assay for cardiotrophin-1 detects elevated plasma levels in human heart failure", CLINICAL SCIENCE, vol. 102, no. 4, April 2002 (2002-04-01), pages 411 - 416, XP003002474 *
UUSIMAA P. ET AL.: "Plasma B-type natriuretic peptide reflects left ventricular hypertrophy and diastolic function in hypertension", INTERNATIONAL JOURNAL OF CARDIOLOGY, vol. 97, no. 2, November 2004 (2004-11-01), pages 251 - 256, XP004581179 *

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