当前位置:Home > 医源资料库 > 在线期刊 > 中风学杂志 > 2005年第36卷第5期 > Natriuretic Peptides and Mortality After Stroke

Natriuretic Peptides and Mortality After Stroke

来源:中风学杂志 作者:A.M. Mkikallio, MD; T.H. Mkikallio, MD, PhD; J.T. 2007-5-14
336*280 ads

摘要: After the exclusions, the eligible stroke population comprised 51 (mean age, 67±10 years) first-ever brain infarction patients。 After the follow-up, their clinical outcome was assessed by reviewing their medical records supplemented by an interview of the patient or a family member to make sure......


    the Graduate School of Circumpolar Wellbeing, Health, and Adaptation (A.M.M.), Centre for Arctic Medicine, University of Oulu, Finland Biocenter (O.V.), Oulu, Finland
    the Departments of Neurology (A.M.M., J.T.K., K.A.S., V.V.M.) and Physiology (O.V.) and the Department of Medicine (T.H.M., J.M.T., K.Y., H.V.H.), Division of Cardiology, University of Oulu, Oulu, Finland.

    Abstract

    Background and Purpose— Measurement of natriuretic peptides provides prognostic information in various patient populations. The prognostic value of natriuretic peptides among patients with acute stroke is not known, although elevated peptide levels have been observed.

    Methods— A series of 51 patients (mean age, 68±11years) with first-ever ischemic stroke underwent a comprehensive clinical examination and measurements of plasma atrial natriuretic peptides (N-ANP) and brain natriuretic peptides (N-BNP) in the acute phase of stroke. The patients were followed-up for 44±21 months. Risk factors for all-cause mortality were assessed. Control populations, matched for gender and age, consisted of 51 patients with acute myocardial infarction (AMI) and 25 healthy subjects.

    Results— Plasma concentrations of N-ANP (mean±SD, 988±993 pmol/L) and N-BNP (751±1608 pmol/L) in the stroke patients were at the same level as those in the AMI patients (NS for both), but significantly higher than those of the healthy subjects (358±103 pmol/L, P<0.001 and 54±26 pmol/L, P<0.01, respectively). Elevated levels of N-ANP and N-BNP predicted mortality after stroke (risk ratio [RR] 4.3, P<0.01 and RR 3.9, P<0.01, respectively) and after AMI (P<0.05), and remained independent predictors of death after stroke even after adjustment for age, diabetes, coronary artery disease, and medication (RR 3.9, P<0.05 and RR 3.7, P<0.05, respectively).

    Conclusion— Plasma levels of natriuretic peptides are elevated in the acute phase of stroke and predict poststroke mortality.

    Key Words: natriuretic peptides  outcome  stroke

    Introduction

    Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are vasoactive peptide hormones with natriuretic, diuretic, and vasodilator activity.1–3 They have emerged as important candidates in the development of diagnostic and prognostic tools for cardiovascular diseases.3,4 An association between elevated levels of natriuretic peptides (NPs) and increased mortality has been established in patients with heart failure,5,6 as well as in patients with acute coronary syndromes.7,8 Moreover, previous studies have further extended the role of BNP measurements to risk stratification of the general population.9–11

    The current information concerning the role of NPs in cerebrovascular diseases is limited. Polymorphisms of the gene for ANP12 and elevated plasma levels of ANP were recently reported to predict the risk of stroke.11 In the acute phase of stroke, the plasma levels of ANP have been reported to be elevated,13 and the levels of BNP have been shown to correlate with blood pressure levels.14 Immunohistochemical studies suggest that cerebral ischemia induces ANP secretion in brain tissue.15,16 A similar association of NPs with the progression of cerebral ischemia was also reported in a study on the development of delayed neurological deficits in patients with gradually increasing BNP levels after subarachnoid hemorrhage.17

    The origin of NP secretion in acute cerebrovascular diseases is still unsettled, although some evidence exists to suggest both a cerebral15,16 and a cardiac origin. We compared the levels of NPs in the acute phase of acute myocardial and brain infarctions and designed this prospective case-control follow-up study to evaluate the prognostic role of NPs after ischemic stroke.

    Patients and Methods

    Study Population

    The study population consisted of 237 stroke patients treated in the stroke unit of our hospital between December 1997 and May 1999. Ischemic stroke patients admitted within the first 24 hours of symptom onset were recruited into the study. We excluded patients older than age 80 years and patients with previous strokes, transient ischemic attacks, head trauma, other cerebral disease, severe psychiatric illness, alcoholism, or malignancy in their medical history. Patients with unstable angina at recruitment or nonsinus rhythm on ECG, as well as patients unable or unwilling to give informed consent, for whom a family member was not available to give consent, were excluded. After the exclusions, the eligible stroke population comprised 51 (mean age, 67±10 years) first-ever brain infarction patients. Two control populations were used. Acute myocardial infarction (AMI) control patients were randomly selected from a larger population and matched in a 1-to-1 fashion for age and gender with the stroke patients. The control patients were selected from a population of 521 patients with AMI. The persons involved in the control group selection were blinded to the patients’ clinical and survival data. The results of the entire AMI population have been published earlier.18 The other control group consisted of 25 healthy subjects.

    Procedures

    Past and present clinical history, including medication, was obtained by interviewing the patient or a family member in case the patient was aphasic or unconscious. The hospital records were also reviewed for the medical history. All patients underwent a comprehensive clinical evaluation, standard ECG, chest x-ray, blood pressure measurement, and biochemical analyses. The stroke patients underwent computed tomography of the brain and scoring of the neurological deficits on the Scandinavian Stroke Scale (SSS), modified Rankin Scale (MRS), Barthel Index (BI), and Glasgow Coma Scale (GCS) within the first 12 hours after admission. Thirty-nine percent of the stroke patients had a stroke in the right cerebral hemisphere, 53% in the left hemisphere, and 8% in the brain stem. Acute coronary event and heart failure were ruled out based on the aforementioned procedures. The diagnosis of AMI was confirmed with 2 of the following 3 criteria: (1) chest pain or dyspnea lasting for at least 30 minutes; (2) elevation of myocardial enzymes up to >2-times the upper limit of the reference value, which could not be attributed to any other condition; and (3) ischemic ECG changes on admission or any later change in ECG caused by AMI. The healthy control population consisted of subjects with normal echocardiography, no medication, and no symptoms of cardiac or neurological diseases in the interview.

    The blood samples for the analysis of NPs were taken on day 2 after admission through an intravenous cannula into EDTA vacuum tubes. The samples were placed on ice and centrifuged at 4°C for 10 minutes, and the plasma was stored at –70°C. The amino-terminal fragments of natriuretic peptides (N-ANP and N-BNP) were analyzed. The assay was performed as described previously.19

    The patients were followed-up for nearly 4 years (mean, 44±21 months). After the follow-up, their clinical outcome was assessed by reviewing their medical records supplemented by an interview of the patient or a family member to make sure that the patient was alive. In the case of death, the hospital records and death certificates were reviewed to verify death. The local ethics committee approved the study protocol, and informed consent was obtained from each patient or family member.

    Statistical Analysis

    The end-point of this study was all-cause mortality. A sample size of 50 patients with an average follow-up of 3.5 years was based on the assumption that the annual incidence of death in this type of population is 10% in the current treatment era. A minimal number of 15 end-points was evaluated to be needed to accomplish a valid analysis for 1 powerful risk predictor.20

    The data were analyzed using the SPSS software (SPSS 11.0; SPSS Inc). Univariate comparisons of the baseline characteristics between the different study groups as well as between the stroke patients who died and those who survived were performed with the 2 test for the categorical variables and with the 2-sample t test for the continuous variables. To find the best cutoff points for all predictive variables, the dichotomous cutoff points that maximized the risk ratio obtained from the Cox regression model were sought, with all-cause mortality as the end-point. Risk ratio (RR) and 95% confidence intervals (CI) were calculated for each variable. After adjustment for age, clinical variables, and medication, the risk variables were included in a Cox proportional hazards regression analysis to estimate their independent predictive powers. Kaplan–Meier estimates of the distribution of times from baseline to death were computed, and log-rank analysis was performed to compare the survival curves between the groups. P<0.05 was considered significant.

    Results

    The baseline clinical characteristics of the patient and control populations are presented in Table 1. Twenty-two (43%) stroke and 6 (12%) AMI patients died during the follow-up. Among the stroke patients, 9 (41%) cerebrovascular deaths, 7 (32%) cardiac deaths, and 6 (27%) other causes of death were observed. During the follow-up, 4 (7.8%) of the stroke patients experienced a transient ischemic attack and 8 (15.7%) had a recurrent nonfatal stroke.

    The plasma concentration of N-ANP averaged (mean ±SD) 988±993 pmol/L and that of N-BNP averaged 751±1608 pmol/L in the stroke patients. The values were equally high as the values in the AMI patients (706±418 pmol/L for N-ANP and 502±468 pmol/L for N-BNP), with a tendency toward higher N-ANP values in the stroke patients (P=0.07). The healthy controls had significantly lower N-ANP (358±103 pmol/L, P<0.001) and N-BNP (54±26 pmol/L, P<0.01) values than the stroke or AMI patients.

    The N-ANP and N-BNP plasma concentrations were significantly higher among the stroke patients who died during the follow-up than among the survivors (1501.4±1287.2 versus 592.5±376.2, P<0.001 and 1408.2±2288.3 versus 244.8±246.3, P<0.05, respectively). Similarly, the plasma concentrations were higher among the AMI patients who died during the follow-up than among the survivors (1304±665 versus 667±418, P<0.05 and 1098±1095 versus 465±450, P<0.05, respectively). Blood pressure values and laboratory tests other than NP levels did not show significant differences between the stroke survivors and those who died. The patients who died during follow-up had significantly lower baseline SSS scores (25.1±15.7 versus 34.2±11.8, P<0.05). The GCS, MRS, and BI scores were also poorer in the patients who died, but the differences did not reach statistical significance. Significant correlations were found between the N-ANP and N-BNP concentrations and the neurological deficit based on the SSS (r=–0.352, P<0.05 and r=–0.324, P<0.05), MRS (r=0.372, P<0.05 and r=0.329, P<0.05), and BI (r=–0.408, P<0.01 and r=–0.361, P<0.05) scores. No significant correlation was seen between the NP concentration and the GCS score. The baseline clinical characteristics and the assessed risk variables of the stroke patients who died and those who were still alive after the follow-up are listed in the Tables 2 and 3 .

    Univariate and Multivariate Predictors of Mortality

    Among the patients with stroke, both N-ANP (RR, 4.3; CI, 1.6 to 11.2; P<0.01) and N-BNP (RR, 3.9; CI, 1.6 to 9.4; P<0.01) had significant prognostic value. A low SSS score (RR, 2.5; CI, 1.1 to 6.1; P<0.05) and older age (RR, 7.5; CI, 1.0 to 56.3; P<0.05) also predicted death. In multivariate analysis, after adjustment for age, diabetes, coronary artery disease, and usage of angiotensin-converting enzyme inhibitors and -blockers, N-ANP and N-BNP showed independent prognostic values for mortality (RR, 3.9; CI, 1.2 to 12.6; P<0.05 and RR, 3.7; CI, 1.4 to 10.0; P<0.05, respectively), whereas SSS did not (Table 4). Among the AMI patients, N-ANP (RR, 5.2; CI, 1.0 to 31.0; P<0.05) was also significantly prognostic, whereas N-BNP did not reach statistical significance (RR, 3.5; CI, 0.7 to 19.2; P<0.1) because of the small sample size. The Kaplan–Meier survival curves showed poor survival for the stroke and AMI patients with N-ANP >850 pmol/L. The cumulative survival rate was 80% for the stroke patients with N-ANP <850 pmol/L and 20% for those with higher values, estimated over the 4-year follow-up period. Similarly, the AMI patients with high N-ANP values had poorer survival than those with lower N-ANP levels (Figure).

    Upper panels, Kaplan–Meier survival curves for stroke and acute myocardial infarction patients with N-ANP plasma concentrations less than or more than 850 pmol/L. The estimated cumulative survival rate over a 4-year period was 80% for the stroke patients with N-ANP <850 pmol/L and 20% for those with N-ANP >850 pmol/L. Lower panels, Kaplan–Meier survival curves for stroke and acute myocardial infarction patients with N-BNP plasma concentrations less than or more than 500 pmol/L.

    Discussion

    The present findings demonstrate that elevated values of plasma NPs in the acute phase of stroke indicate an increased risk of future mortality. High plasma levels of NPs predicted mortality after stroke better than any other risk variable, with the risk of death being 4-fold among the patients with high NP values. This is the first study to our knowledge to report an association between elevated NP values and an increased risk of death after acute ischemic stroke.

    NPs in Stroke

    NPs are synthesized mainly in the atrial (ANP) and ventricular (BNP) myocardium.1,21 They are also known to be released from brain tissue, mainly from the hypothalamus,22 and their release is suggested to be induced by cerebral ischemia.15,16 Our findings are in concordance with a previous study13 reporting markedly elevated levels of ANP in the acute phase of stroke. We also found high BNP levels in stroke patients. When the NP values in the acute phases of stroke and AMI were compared, we found the stroke patients to have equally high or even higher NP plasma values than the AMI patients, although an acute cardiac event was ruled out. This suggests that the secretion of NPs from the myocardium or various extracardiac sites, such as the brain and the vascular wall, is increased in ischemic stroke.

    NP release has been claimed to be associated with the intensity of brain ischemia, reflecting increased biosynthesis and secretion from ischemic brain tissue.15,16 High concentrations of plasma BNP have been associated with the development of cerebral ischemia and neurological deficits.17 A similar association between NP levels and the clinical manifestations of cerebral ischemia was also found in this population, because the concentrations of NPs correlated significantly with the measures of neurological deficits (SSS, BI, MRS). However, as predictors of poor outcome, NPs surpassed the measures of neurological deficits, indicating that NPs provide prognostic information incremental to that obtained from the measures assessing merely the clinical severity of brain injury.

    NPs and Mechanisms of Stroke Mortality

    The prognostic value of NPs has previously been demonstrated in patients with heart failure,5,6 patients with acute coronary syndromes,7,8,23 and the general population.9–11 This study suggests a further application of NP measurement to the risk stratification of stroke patients.

    It is generally assumed that elevated NP concentrations indicate activation of the neuroendocrine system, and that higher NP levels hence reflect a greater degree of hemodynamic dysfunction and explain the increased mortality in patients with acute cardiac disease. The mechanisms underlying the association of elevated NPs with increased mortality after stroke in patients with no obvious heart diseases are less obvious. The most probable reason for the high NP levels in acute stroke is the severity of brain injury. It is plausible to speculate that the elevated NP levels in the acute phase of stroke reflect the magnitude of brain injury and, by this mechanism, increase the risk of dying after stroke. This assumption is also supported by the association between the clinical deficits and NP values.

    In addition, these peptides have a role in the modulation of the autonomic control of the heart.24,25 BNP is known to augment parasympathetic vagal neurotransmission, but high concentrations of NPs can directly stimulate cardiac pacemaking,24 suggesting that the disturbances in autonomic cardiovascular control might be one explanation for the increased risk of death in patients with elevated NP values. Further evidence for this interpretation was obtained in our recent study reporting that autonomic dysfunction in the acute phase of stroke also predicts long-term mortality.26

    The NP system is suggested to be involved in atherosclerotic plaque formation in coronary arteries.27 The severity of coronary artery disease is reported to correlate with NP values28 and with changes in the ANP gene.29 These findings imply that the severity of atherosclerosis underlying the pathologically high plasma values of NPs might also account for the poor long-term survival of stroke patients.

    Limitations

    The small sample size is an obvious limitation of the present preliminary study and obliges us to be cautious in the generalization of the results. More research with larger populations will be needed to establish the role of NPs in risk stratification after stroke. The long follow-up time ensured the accumulation of sufficient number of deaths for reliable statistical analyses, however. Moreover, several clinical variables were added in the multivariate analysis to reveal the independent prognostic power of NPs. They proved to be the most powerful predictors of mortality in this limited-size population, indicating their strong predictive power. This study was designed to reveal the predictive power of NPs in total mortality, but not in different subgroups. To assess survival in different mortality categories, a larger prospective observational study will be needed.

    Clinical Implications

    The results of this study show that elevated plasma levels of NPs are not a specific feature of acute cardiac events but are also seen after acute stroke. Furthermore, measurements of NP values seem to be useful in the risk stratification of patients with acute stroke. Preliminary findings on heart failure patients suggest that BNP-guided treatment leads to a better outcome.30 Application of similar procedures to stroke populations would seem tempting.

    Acknowledgments

    This study was supported by The Graduate School of Circumpolar Wellbeing, Health, and Adaptation, Centre for Arctic Medicine, University of Oulu, Finland, and by grants from The Foundation for Cardiovascular Research, The Paulo Foundation, The Paavo Nurmi Foundation, and The Neurology Foundation, Helsinki, Finland.

    References

    Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med. 1998; 339: 321–328.

    Richards AM, McDonald D, Fitzpatrick MA, Nicholls MG, Espiner EA, Ikram H, Jans S, Grant S, Yandle T. Atrial natriuretic hormone has biological effects in man at physiological plasma concentrations. J Clin Endocrinol Metab. 1988; 67: 1134–1139.

    DeLemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet. 2003; 362: 316–322.

    Ruskoaho H. Cardiac hormones as diagnostic tools in heart failure. Endocrinol Rev. 2003; 24: 341–356.

    Cowie MR, Mendez GF. BNP and congestive heart failure. Prog Cardiovasc Dis. 2002; 44: 293–321.

    Anand IS, Fisher LD, Chiang YT, Latini R, Masson S, Maggioni AP, Glazer RD, Tognoni G, Cohn JN; Val-HeFT Investigators. Val-HeFT Investigators. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003; 107: 1278–1283.

    Jernberg T, Stridsberg M, Venge P, Lindahl B. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Card. 2002; 40: 437–445.

    Morrow DA, de Lemos JA, Sabatine MS, Murphy SA, Demopoulos LA, DiBattiste PM, McCabe CH, Gibson CM, Cannon CP, Braunwald E. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol. 2003; 41: 1264–1272.

    McDonagh TA, Cunningham AD, Morrison CE, McMurray JJ, Ford I, Morton JJ, Dargie HJ. Left ventricular dysfunction, natriuretic peptides, and mortality in urban population. Heart. 2001; 86: 21–26.

    Wallen T, Landahl S, Hedner T, Nakao K, Saito Y. Brain natriuretic peptide predicts mortality in the elderly. Heart. 1997; 77: 264–267.

    Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004; 350: 655–663.

    Rubattu S, Stanzione R, Angelantonio E, Zanda B, Evangelista A, Tarasi D, Gigante B, Pirisi A, Brunetti E, Volpe M. Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans. Stroke. 2004; 35: 814–818.

    Estrada V, Tellez MJ, Moya J, Fernandez-Durango R, Egido J, Cruz AF. High plasma levels of endothelin-1 and atrial natriuretic peptide in patients with acute ischemic stroke. Am J Hypertens. 1994; 7: 1085–1089.

    Eguchi K, Kario K, Shimada K, Mori T, Nii T, Ibaragi K. Circadian variation of blood pressure and neurohumoral factors during the acute phase of stroke. Clin Exp Hypertens. 2002; 24: 109–114.

    Nogami M, Shiga J, Takatsu A, Endo N, Ishiyama I. Immunohistochemistry of atrial natriuretic peptide in brain infarction. Histochem J. 2001; 33: 87–90.

    Giuffrida R, Bellomo M, Polizzi G, Malatino LS. Ischemia-induced changes in the immunoreactivity for endothelin and other vasoactive peptides in the brain of the mongolian gerbil. J Cardiovasc Pharmacol. 1992; 20: S41–S44.

    Sviri GE, Shik V, Raz B, Soustiel JF. Role of brain natriuretic peptide in cerebral vasospasm. Acta Neurochir. 2003; 145: 851–860.

    Tapanainen JM, Still AM, Airaksinen KE, Huikuri HV. Prognostic significance of risk stratifiers of mortality, including T wave alternans, after acute myocardial infarction: results of a prospective follow-up study. J Cardiovasc Electrophysiol. 2001; 12: 645–652.

    Magga J, Puhakka M, Hietakorpi S, Punnonen K, Uusimaa P, Risteli J, Vuolteenaho O, Ruskoaho H, Peuhkurinen K. Atrial natriuretic peptide, B-type natriuretic peptide, and serum collagen markers after acute myocardial infarction. J Appl Physiol. 2004; 96: 1306–1311.

    Concato J, Peduzzi P, Holford TR, Feinstein AR. Importance of events per independent variable in proportional hazards analysis. J Clin Epidemiol. 1995; 48: 1495–1501.

    Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, Ogawa H, Okumura K, Mukoyama M, Nakao K. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation. 1994; 90: 195–203.

    Takahashi K, Totsune K, Sone M, Ohneda M, Murakami O, Itoi K, Mouri T. Human brain natriuretic peptide like immunoreactivity in human brain. Peptides. 1992; 13: 121–123.

    Richards MA, Nicholls GM, Espiner EA, Lainchbury JG, Troughton RW, Elliott J, Frampton C, Turner J, Crozier IG, Yandle TG. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation. 2003; 107: 2786–2792.

    Herring N, Zaman JAB, Paterson DJ. Natriuretic peptides like NO facilitate cardiac vagal transmission and bradycardia via a cGMP pathway. Am J Physiol Heart Circ Physiol. 2001; 281: H2318–H2327.

    Thomas CJ, and Woods RL. Guanylyl cyclase receptors mediate cardiopulmonary vagal reflex actions of ANP. Hypertension. 2003; 41: 279–285.

    Mkikallio AM, Mkikallio TH, Korpelainen JT, Sotaniemi KA, Huikuri HV, Myllyl VV. Heart rate dynamics predict poststroke mortality. Neurology. 2004; 62: 1822–1826.

    Casco VH, Veinot JP, Kuroski de Bold ML, Masters RG, Stevenson MM, de Bold AJ. Natriuretic peptide system gene expression in human coronary arteries. J Histochem Cytochem. 2002; 50: 799–809.

    Osajima A, Okazaki M, Kato H, Anai H, Tsuda Y, Segawa K, Tanaka H, Tamura M, Takasugi M, Nakashima Y. Clinical significance of natriuretic peptides and cyclic GMP in hemodialysis patients with coronary artery disease. Am J Nephrol. 2001; 21: 112–119.

    Cruchala M, Ciecwierz D, Wasag B, Targonski R, Dubaniewicz W, Nowak A, Sobiczewski W, Ochman K, Romanowski P, Limon J, Rynkiewicz A. Association of the SCA I atrial natriuretic peptide gene polymorphism with nonfatal myocardial infarction and extent of coronary artery disease. Am Heart J. 2003; 145: 125–131.

    Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000; 355: 1126–1130.


医学百科App—医学基础知识学习工具


页:
返回顶部】【打印本文】【放入收藏夹】【收藏到新浪】【发布评论



察看关于《Natriuretic Peptides and Mortality After Stroke》的讨论


关闭

网站地图 | RSS订阅 | 图文 | 版权说明 | 友情链接
Copyright © 2008 39kf.com All rights reserved. 医源世界 版权所有
医源世界所刊载之内容一般仅用于教育目的。您从医源世界获取的信息不得直接用于诊断、治疗疾病或应对您的健康问题。如果您怀疑自己有健康问题,请直接咨询您的保健医生。医源世界、作者、编辑都将不负任何责任和义务。
本站内容来源于网络,转载仅为传播信息促进医药行业发展,如果我们的行为侵犯了您的权益,请及时与我们联系我们将在收到通知后妥善处理该部分内容
联系Email: