WO2017125406A1 - Méthodes de prédiction de remodelage ventriculaire gauche chez des sujets souffrant d'hypertension - Google Patents

Méthodes de prédiction de remodelage ventriculaire gauche chez des sujets souffrant d'hypertension Download PDF

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WO2017125406A1
WO2017125406A1 PCT/EP2017/050932 EP2017050932W WO2017125406A1 WO 2017125406 A1 WO2017125406 A1 WO 2017125406A1 EP 2017050932 W EP2017050932 W EP 2017050932W WO 2017125406 A1 WO2017125406 A1 WO 2017125406A1
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left ventricular
hypertension
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hypertensive
ventricular remodeling
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Philippe Rouet
Fatima SMIH ROUET
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paul Sabatier Toulouse Iii
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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
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • 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
    • G01N2560/00—Chemical aspects of mass spectrometric analysis of biological material
    • 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

Definitions

  • the present invention relates to methods of predicting left ventricular remodelling in subjects suffering from hypertension.
  • Hypertension is the principal etiology of pathologic left ventricular hypertrophy
  • LVH left ventricular remodeling 1 .
  • Pressure-dependent hemodynamic overload induces left ventricular remodeling as an adaptive response to minimize wall stress.
  • LVH becomes maladaptive and emerges as a strong and independent risk factor for cardiovascular morbidity (heart failure, coronary artery disease, cerebrovascular accidents, ventricular arrhythmia) and mortality.
  • cardiovascular morbidity heart failure, coronary artery disease, cerebrovascular accidents, ventricular arrhythmia
  • mortality 2 ' 3 ' 4 ' 5,6
  • studies indicate that in 20 7 to 36 8 of chronic hypertensive patients, the myocardium undergoes profound structural remodeling, characterized by enhanced cardiomyocyte growth, increased rate of cardiomyocyte apoptosis, accumulation of fibrosis and microcirculatory changes. This structural remodeling disrupts myocardial excitation- contraction coupling and eventually leads to heart failure.
  • LVH left ventricular
  • Echocardiography and electrocardiography are presently the prominent tools for LVH diagnosis, though these techniques prove to be time consuming and costly.
  • PET positron electron tomography
  • PET cannot be used for routine detection of LVH because it exposes the patients to ionizing radiation and to radioactive substances and it is an expensive procedure, only available in a minority of medical centers.
  • Circulating biomarkers have also been investigated in hypertensive heart disease (i.e. left ventricular hypertrophy secondary to hypertension): cardiotrophin-1 19 , annexin A5 20 , propeptide of procollagen type I 21 have been discovered but none of these biomarkers is currently used in clinical practice due to their low sensitivity or lack of specificity.
  • the present invention relates to methods of predicting left ventricular remodelling in subjects suffering from hypertension.
  • the present invention is defined by the claims.
  • LVH left ventricular hypertrophy
  • Previous studies have shown an altered metabolic profile in hypertensive patients with LVH.
  • the goal of the inventors was to search for blood metabolomic biomarkers of LVH to provide diagnostic utility in the rapid detection of LVH in large populations of hypertensive individuals.
  • the inventors analyzed plasma X H NMR-based metabolomic profiling in 48 hypertensive patients with LVH, 48 hypertensive patients with normal LV size and 24 healthy controls.
  • a multivariate analysis of the spectral data set was performed by using the Partial Least Squares Discriminant Analysis (PLS-DA).
  • PLS-DA Partial Least Squares Discriminant Analysis
  • transcriptomics the inventors demonstrated metabolic pathway regulation in leukocytes in a subset of the IBLOMAVED cohort (14 hypertensive patients with LVH compared to 14 hypertensive patients without LVH and 8 controls): genes encoding for glycolytic enzymes were found to be overexpressed in hypertensive patients with LVH.
  • discriminant variables were identified as signals coming from methylene (-CH2-) and methyl (-CH3) moieties of aliphatic chains from plasma lipids.
  • the -CH2-/-CH3 ratio which is an indicator of the mean length of the aliphatic lipid chains was significantly higher in the LVH group.
  • the inventors propose the -CH2-/-CH3 ratio from plasma aliphatic lipid chains as a biomarker for left ventricular remodeling in hypertension.
  • the present invention relates to a method of predicting left ventricular remodeling in a subject suffering from hypertension comprising i) determining the mean length of the aliphatic chains of the plasma lipids present in the blood sample obtained from the subject, ii) comparing the mean length determined at step i) with a predetermined reference value and iii) concluding that the subject has or is at risk of having left ventricular remodeling when the mean length determined at step i) is higher than the predetermined reference value or concluding that the subject has not or is not at risk of having left ventricular remodeling when the mean length determined at step i) is lower than the predetermined reference value.
  • hypotension or "high blood pressure” refers to a resting blood pressure, as measured with a sphygmomanometer, of greater than 120 mmHg (systolic)/80 mmHg (diastolic). Blood pressure between 121-139/81-89 is considered prehypertension and above this level (140/90 mm Hg or higher) is considered high (hypertension). Both prehypertension and hypertension blood pressure are included in the meaning of "hypertension” as used herein.
  • resting blood pressures of 135 mmHg/87 or of 140 mmHg/90 mmHg are intended to be within the scope of the term "hypertension" even though the 135/87 is within a prehypertensive category.
  • Blood pressures of 145 mm Hg/90 mmHg, 140 mmHg/95 mmHg, and 142 mmHg/93 mmHg are further examples of high blood pressures. It will be appreciated that blood pressure normally varies throughout the day. It can even vary slightly with each heartbeat. Normally, it increases during activity and decreases at rest. It's often higher in cold weather and can rise when under stress. More accurate blood pressure readings can be obtained by daily monitoring blood pressure, where the blood pressure reading is taken at the same time each day to minimize the effect that external factors. Several readings over time may be needed to determine whether blood pressure is high.
  • left ventricular remodeling has its general meaning in the art and it is used to describe the multiple of changes that occur in cardiac shape, size and composition in response to hypertension.
  • left ventricular remodeling involves profound structural remodeling, characterized by enhanced cardiomyocyte growth, increased rate of cardiomyocyte apoptosis, accumulation of fibrosis and microcirculatory changes.
  • Left ventricular remodeling leads to left ventricular dysfunction.
  • left ventricular dysfunction refers to a condition in which the left ventricle of the heart is functionally impaired. This impairment of the left ventricular causes the heart to become less efficient in pumping blood throughout the body. Left ventricular dysfunction usually leads to heart failure as well as to other cardiovascular complications.
  • a diagnostic of left ventricular dysfunction can be made by measuring the diminished ejection fraction, mitral valve inflow pattern, pulmonary venous inflow pattern or mitral annular velocity using 2-dimensional echocardiogram coupled with Doppler flow or by performing radionuclide ventriculography, a MRI or a computed tomography using routine techniques known to those skilled the art.
  • the term "Risk” in the context of the present invention relates to the probability that an event will occur over a specific time period, as in the conversion to left ventricular remodeling, and can mean a subject's "absolute” risk or “relative” risk.
  • Absolute risk can be measured with reference to either actual observation post- measurement for the relevant time cohort, or with reference to index values developed from statistically valid historical cohorts that have been followed for the relevant time period.
  • Relative risk refers to the ratio of absolute risks of a subject compared either to the absolute risks of low risk cohorts or an average population risk, which can vary by how clinical risk factors are assessed.
  • Odds ratios the proportion of positive events to negative events for a given test result, are also commonly used (odds are according to the formula p/(l-p) where p is the probability of event and (1- p) is the probability of no event) to no- conversion.
  • "Risk evaluation,” or “evaluation of risk” in the context of the present invention encompasses making a prediction of the probability, odds, or likelihood that an event or disease state may occur, the rate of occurrence of the event or conversion from one disease state to another, i.e., from a normal condition to left ventricular remodeling or to one at risk of developing left ventricular remodeling.
  • Risk evaluation can also comprise prediction of future clinical parameters, traditional laboratory risk factor values, or other indices of left ventricular remodeling, either in absolute or relative terms in reference to a previously measured population.
  • the methods of the present invention may be used to make continuous or categorical measurements of the risk of conversion to left ventricular remodeling, thus diagnosing and defining the risk spectrum of a category of subjects defined as being at risk of having left ventricular remodeling.
  • the invention can be used to discriminate between normal and other subject cohorts at higher risk of having left ventricular remodeling.
  • the present invention may be used so as to discriminate those at risk of having left ventricular remodeling from normal, or those having left ventricular remodeling disease from normal.
  • the term "plasma lipid” designates a lipid present in plasma, including cholesterol and triglycerides carried in the blood.
  • the term "aliphatic chain” has its general meaning in the art and denotes saturated or non-saturated chains, i.e. chains comprising at least one ethylenic unsaturation and/or optionally at least one acetylenic unsaturation.
  • an aliphatic chain comprises methylene (-CH2-) and methyl (-CH3) moieties and the -CH2-/-CH3 ratio is typically an indicator of the mean length of the aliphatic lipid chains.
  • MS mass spectrometry
  • MS refers to an analytical technique to identify compounds by their mass.
  • MS refers to methods of filtering, detecting, and measuring ions based on their m/z.
  • MS technology generally includes (1) ionizing the compounds to form charged species (e.g., ions); and (2) detecting the molecular weight of the ions and calculating their m/z. The compounds may be ionized and detected by any suitable means.
  • a “mass spectrometer” generally includes an ionizer and an ion detector.
  • one or more molecules of interest are ionized, and the ions are subsequently introduced into a mass spectrographic instrument where, due to a combination of magnetic and electric fields, the ions follow a path in space that is dependent upon mass (“m") and charge (“z”).
  • m mass
  • z charge
  • sample is subjected to liquid chromatography before subjected to mass spectrometry.
  • HPLC high performance liquid chromatography
  • HPLC columns include, but are not limited to, polar, ion exchange (both cation and anion), hydrophobic interaction, phenyl, C-2, C-8, C-18, and polar coating on porous polymer columns.
  • eluent also known as a "mobile phase”
  • gradient elution the gradient conditions, temperature, etc.
  • the predetermined reference value is a threshold value or a cut-off value.
  • a “threshold value” or “cut-off value” can be determined experimentally, empirically, or theoretically.
  • a threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by a person of ordinary skilled in the art. For example, retrospective measurement of the mean length of aliphatic chains of plama lipids in properly banked historical subject samples may be used in establishing the predetermined reference value.
  • the threshold value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative).
  • the optimal sensitivity and specificity can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
  • ROC Receiver Operating Characteristic
  • the full name of ROC curve is receiver operator characteristic curve, which is also known as receiver operation characteristic curve. It is mainly used for clinical biochemical diagnostic tests.
  • ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate (1 -specificity). It reveals the relationship between sensitivity and specificity with the image composition method.
  • a series of different cut-off values are set as continuous variables to calculate a series of sensitivity and specificity values. Then sensitivity is used as the vertical coordinate and specificity is used as the horizontal coordinate to draw a curve. The higher the area under the curve (AUC), the higher the accuracy of diagnosis.
  • AUC area under the curve
  • the point closest to the far upper left of the coordinate diagram is a critical point having both high sensitivity and high specificity values.
  • the AUC value of the ROC curve is between 1.0 and 0.5. When AUC>0.5, the diagnostic result gets better and better as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low.
  • the subject when it is concluded that the subject has or is at risk of having left ventricular remodeling, the subject is subsequently administered with a therapeutically effective amount of a drug suitable for the treatment and prevention of left ventricular remodeling.
  • a drug suitable for the treatment and prevention of left ventricular remodeling.
  • said drug is selected from the group consisting of diuretics, angiotensin converting enzyme (ACE) inhibitors, digoxin (also called digitalis), calcium channel blockers, and beta-blockers.
  • ACE angiotensin converting enzyme
  • digoxin also called digitalis
  • calcium channel blockers calcium channel blockers
  • beta-blockers beta-blockers.
  • thiazide diuretics such as hydrochlorothiazide at 25-50 mg/day or chlorothiazide at 250-500 mg/day, are useful.
  • supplemental potassium chloride may be needed, since chronic diuresis causes hypokalemis alkalosis.
  • Typical doses of ACE inhibitors include captopril at 25-50 mg/day and quinapril at 10 mg/day.
  • the subject is administered with an adrenergic beta-2 agonist.
  • adrenergic beta-2 agonist refers to adrenergic beta-2 agonists and analogues and derivatives thereof, including, for example, natural or synthetic functional variants which have adrenergic beta-2 agonist biological activity, as well as fragments of an adrenergic beta-2 agonist having adrenergic beta-2 agonist biological activity.
  • adrenergic beta-2 agonists include, but are not limited to, clenbuterol, albuterol, formeoterol, levalbuterol, metaproterenol, pirbuterol, salmeterol, and terbutaline.
  • the subject is administered with an adrenergic beta-1 antagonist.
  • Adrenergic beta-1 antagonists and adrenergic beta-1 blockers refer to adrenergic beta-1 antagonists and analogues and derivatives thereof, including, for example, natural or synthetic functional variants which have adrenergic beta-1 antagonist biological activity, as well as fragments of an adrenergic beta-1 antagonist having adrenergic beta-1 antagonist biological activity.
  • adrenergic beta-1 antagonists include, but are not limited to, acebutolol, atenolol, betaxolol, bisoprolol, esmolol, and metoprolol.
  • acebutolol atenolol
  • betaxolol bisoprolol
  • esmolol esmolol
  • metoprolol metoprolol
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 Methylene (-CH2-) and methyl (-CH3) moieties of aliphatic chains from plasma lipids ratio (R).
  • R plasma lipids ratio
  • Formulae illustrate -CH2-/-CH3 ratios according to the fatty acid chain length.
  • Single line inflexions points represent methylene (-CH2-).
  • FIG. 1 Methylene/methyl ratio in aliphatic lipid chains from plasma lipids of control, hypertensive patients with normal LV size (HTN normal LV size) and hypertensive patients with LV hypertrophy (HTN LVH). The methylene/methyl ratio is significantly higher in the HTN LVH group compared to HTN normal LV size group and control.
  • B Plasma cholesterol concentration in control, hypertensive patients with normal LV size (HTN normal LV size) and hypertensive patients with LV hypertrophy (HTN LVH). No difference was found among groups.
  • FIG. 3 Receiver Operating Characteristic (ROC) curve analysis of methylene/methyl ratio in relation to hypertensive group with LVH compared to hypertensive group with normal LV size.
  • the AUC area under the curve
  • the study population was enrolled from 2007 to 2009 in the cardiology department of Rangueil Hospital, Toulouse, France, consisted of 2 groups of patients: (1) 48 patients with hypertension and normal LV size and (2) 48 patients with hypertension and LV hypertrophy; 24 healthy controls were also included in the study.
  • For transcriptomic analysis we selected 14 patients from the first group (patients with hypertension and normal LV size) and 14 patients from the second group (patients with hypertension and LVH), matched for age and cardiovascular risk factors; these were compared to 8 controls from the healthy control group.
  • ⁇ ⁇ NMR analysis the entire population was considered.
  • Exclusion criteria included presence of chronic and acute heart failure, others form of cardiomyopathy such as familial obstructive hypertrophic cardiomyopathy, dilated cardiomyopathy, toxic cardiomyopathy, myocardial necrosis, heart rhythm problems, active smoking or smoking cessation less than three years previously, hemopathies, septicemia, hepathopathies and kidney failure requiring dialysis. All hypertensive patients of the study had been receiving pharmacological treatments to lower blood pressure. All subjects underwent a complete cardiac evaluation, including medical history, physical examination, blood pressure measurement and an echocardiography. This research protocol was registered in a clinical database (ClinicalTrials.gov NCTO 1024049) and conforms to the ethical guidelines of the 1975 Declaration of Helsinki. The protocol was approved by the institution's human research (COSSEC) and regional ethics committee (Comite de Protection des Personnes (CPP) # DC2008-452). Written informed consent was obtained from all participants.
  • COSSEC COSSEC
  • CPP Complement de Protection des Personnes
  • LVEF left ventricular ejection fraction
  • LMM left ventricular mass
  • valve function valve function
  • the LVEF was calculated according to the modified Simpson's rule.
  • the LV mass was indexed to the body surface area to derive the LV mass index (LVMI, g/m 2 ).
  • Left ventricular hypertrophy (LVH) was defined according to the previously established criterion (LVMI >125 g/m 2 for men and LVMI >110 g/m 2 for women) 29 .
  • Venous blood samples were collected after overnight fasting in Becton Dickinson Vacutainer CPT tubes with sodium heparin. The blood plasma was immediately separated by centrifugation (3000 RCF/4°C/ 10 min) and aliquots were stored at -80°C. For white blood cell separation, blood samples were collected in 8 ml BD CPT vacutainer tubes and processed immediately according to the manufacturer's protocol. Microarray analysis
  • Total plasma cholesterol was measured by the CHOD-PAP method with kit Al 1A01634 (HORIBA ABX diagnostic, adjoin, France).
  • the patients' characteristics including age, sex, body mass index (BMI), presence of diabetes, dyslipidemia, obesity and echocardiographic parameters are shown in Table 1.
  • the hypertensive population had a systolic blood pressure of 149 + 20 mmHg versus 125 + 13 mmHg for the control group.
  • Patients with LV Hypertrophy displayed a LV mass index of 115 + 33 g/m 2 and an LV thickness/radius ratio (h/r) of 52 + 8, both significantly greater (p ⁇ 0.001) when compared to hypertensive patients with no LV remodeling (81 + 18 g/m 2 and 37 + 4, respectively) and to healthy controls (74 + 18 g/m 2 and 36+ 5, respectively).
  • the transcriptomic study compared gene expression in leukocytes from 14 hypertensive patients with LVH, 14 hypertensive patients with normal LV size, and 8 controls.
  • the total number of probes tested on the microarray was 25,000.
  • Four genes encoding glycolytic enzymes were found overexpressed in patients with LV remodeling: hexokinase 1 (HK1), glucose-6-phosphate-isomerase (GPI), glyceraldehydes-3-phosphate dehydrogenase (GAPDH) and phosphoglycerate kinase (PGK1).
  • PLS-DA partial least squares discriminant analysis
  • Prolonged hypertension may result in LV structural remodeling, alteration of cardiac function and chronic heart failure. 2
  • Early detection and treatment of LV hypertrophy in hypertensive patients is important in order to prevent the progression towards advanced cardiac disease. While the microarray technique has already been used to report large-scale gene expression changes in leukocytes of patients with essential hypertension 24 , such study had not been performed yet in hypertensive patients with LVH.
  • hexokinase 1 HK1
  • GPI glucose-6-phosphate isomerase
  • GPDH glyceraldehydes-3-phosphate dehydrogenase
  • PGK1 phosphoglycerate kinase
  • Glyceraldehydes-3-phosphate dehydrogenase (GAPDH) and PGK1 are major regulatory enzymes in the glycolytic pathway catalyzing the generation of NADH from NAD + in the sixth step of glycolysis and the first ATP-generating step of the glycolytic pathway, respectively.
  • GAPDH has been shown to be higher in the fetal heart and increased with cardiac hypertrophy.
  • the gene expression pattern observed in white blood cells from hypertensive patients with LVH included genes previously involved in cardiac remodeling such as TEVIP metallopeptidase 1 and 2 45 and methionine sulfoxide reductase Bl (MSRB1). 46 This observation further supports the notion that the transcriptome of white blood cells remodels in parallel to the cardiac transcriptome. In accordance with another study, we found no differences in the transcriptomes of white blood cells between the hypertensive and control groups 24 . On the other hand, hypertensive patients with LVH displayed a specific pattern of gene expression different from both control and hypertensive patients.
  • VLCAD very long- chain acyl-CoA dehydrogenase
  • Increased expression of the truncated PPARa is associated with decreased expression of the PPARa target genes involved in fatty acid transport and oxidation. 13 Moreover, decreased PPARa expression and/or activity in the heart could be linked to the development of local inflammation and fibrosis. 51 The inhibition of myocardial fatty acid metabolism has been proposed as an independent predictor of the cardiac hypertrophic response in hypertensive patients. 17 In leukocytes, we did not find a decrease in the expression of genes encoding for fatty acid oxidation enzymes, suggesting that their downregulation occurs in a later phase of hypertensive heart disease (i.e.
  • LVH is present in about 35 % of hypertensive individuals.
  • Gene expression profiling allows a better understanding of pathophysiological processes and may thereby contribute to a better prediction of clinical outcome.
  • Gene expression fingerprinting is still a challenge in the field of cardiology, even though it is becoming a standard procedure in cancerology. 52 This is due to the difficulty in obtaining heart tissue samples, and because RNA extractions and microarray analyses are difficult to implement for high-throughput screening of patients in clinic.
  • Our study proposes a new circulating biomarker as an alternative to molecular gene expression analysis for the detection of LV remodeling in hypertensive patients.
  • Verdecchia P Porcellati C, Reboldi G, et al. Left Ventricular Hypertrophy as an Independent Predictor of Acute Cerebrovascular Events in Essential Hypertension. Circulation. 2001;104(17):2039-2044.
  • Van Bilsen M van Nieuwenhoven F a, van der Vusse GJ. Metabolic remodelling of the failing heart: beneficial or detrimental? Cardiovasc Res. 2009;81(3):420-428.
  • Depre C Shipley GL, Chen W, et al. Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nat Med. 1998;4(11): 1269-1275.
  • Schillaci G Verdecchia P, Porcellati C, Cuccurullo O, Cosco C, Perticone F.

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Abstract

La présente invention concerne des méthodes de prédiction de remodelage ventriculaire gauche chez des sujets souffrant d'hypertension. La présente invention concerne plus particulièrement une méthode de prédiction de remodelage ventriculaire gauche chez un sujet souffrant d'hypertension consistant i) à déterminer la longueur moyenne des chaînes aliphatiques des lipides plasmatiques présents dans l'échantillon sanguin prélevé auprès du sujet, ii) à comparer la longueur moyenne déterminée à l'étape i) avec une valeur de référence prédéfinie, et iii) à conclure que le sujet a ou présente un risque d'avoir un remodelage du ventricule gauche lorsque la longueur moyenne déterminée à l'étape i) est supérieure à la valeur de référence prédéfinie ou à conclure que le sujet n'a pas ou ne risque pas d'avoir un remodelage du ventricule gauche lorsque la longueur moyenne déterminée à l'étape i) est inférieure à la valeur de référence prédéfinie.
PCT/EP2017/050932 2016-01-19 2017-01-18 Méthodes de prédiction de remodelage ventriculaire gauche chez des sujets souffrant d'hypertension WO2017125406A1 (fr)

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CN117054652B (zh) * 2023-08-04 2024-05-17 南京医科大学 一种用于辅助检测心肌肥厚的生物标志物及其应用

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