Serum levels of different tumour markers in patients with chronic heart failure

BACKGROUND: serum levels of carbohydratic antigen 125 (CA 125), a tumour marker related to ovarian cancer, are increased in patients with heart failure (CHF). To our knowledge there are no data concerning the levels of other tumour markers in CHF. METHODS: we measured serum levels of Alpha-Fetoprotein (AFP), Carcinoembrionic antigen (CEA), CA 19.9, CA 15.3 and CA 125, in 191 pts (86 males, mean age 67+/-10 years) with mild to severe CHF due to left ventricular systolic dysfunction. RESULTS: Only CA-125 was increased in CHF patients: mean values were significantly higher (P<0.05) in NYHA classes III (60+/-22 UI/ml) and IV (192+/-115 UI/ml) compared to NYHA class I-II patients (16+/-11). Mean values of the other tumor markers were within the normal range. AFP was above the upper normal limit in 2/191 patients (1%), CEA in 5/191 (2.6%), CA 19.9 in 0, CA 15.3 in 2/191 (1%) and CA 125 in 126/191 patients (66%). In 30 NYHA IV patients, tumour markers were repeated after 5-20 days of aggressive medical treatment, when a clinical improvement (reduction of at least 1 NYHA class) was reached: mean serum levels of CA 125 decreased from 107+/-85 to 19+/-8 U/ml (P<0.05); no changes in other tumour markers were observed. CONCLUSIONS: Of the tumour markers evaluated, only CA 125 seems to be related to the presence and severity of CHF and shows significant changes in response to medical therapy. The biologic and clinical relevance of this observation needs to be defined.     

胶原纤维增生对慢性心力衰竭的影响及氯沙坦钾的干预作用

目的:探讨血清Ⅰ型前胶原羧基端肽(P Ⅰ P)和Ⅲ型前胶原氨基端肽(PⅢP)与心衰和心室重构的关系,同时观察氯沙坦钾的干预作用。方法:将40例慢性心衰患者随机分为常规治疗组和氯沙坦钾组(每天口服氯沙坦钾50mg)。20例无心脑血管和肝脏疾病者设为对照组。所有患者于治疗前采用放射免疫分析法测定P Ⅰ P、PⅢP、血管紧张素Ⅱ(AngⅡ)、醛固酮,超声心动图测定室间隔厚度(IVST)、左室后壁厚度(LVPWT)、左室舒张末期内径(LVEDd)、左室射血分数(LVEF),治疗后20周两治疗组重复测定上述指标。结果:与对照组相比常规治疗组和氯沙坦钾组P Ⅰ P、PⅢP、AngⅡ、醛固酮、LVEDd、LVMI水平明显升高(P<0.01),LVEF明显降低(P<0.01)。P Ⅰ P、PⅢP与LVEDd、LVMI呈正相关,与LVEF呈负相关(P<0.01)。经20周治疗后上述血检指标和超声心动图指标与治疗前比较在常规治疗组中无显著差异(P>0.05),在氯沙坦钾组血检指标和LVEDd、LVMI则显著降低(P<0.05),LVEF明显升高(P<0.05),治疗后的两组有显著差异(P<0.01)。结论:心衰患者心肌间质胶原增生致使心脏发生重构,氯沙坦钾有抑制心室重构作用。     

Serum levels of Apelin-36 are decreased in older hospitalized patients with heart failure

PurposeApelin is an endogenous peptide, it is a potent inotropes, a peripheral vasodilator, involved in fluid homeostasis, balancing the harmful effects of Ang-II-AT1 system. The apelin-APJ axis is down regulated in chronic heart failure (CHF), but the role of apelin has not yet been studied in elderly patients with CHF. The aim of our study is to investigate serum levels of apelin-36 in a group of older subjects with CHF.Subjects/Materials and methodsThe study population consisted of 30 consecutive patients aged 80 ± 7.8 years with CHF. Serum apelin levels were quantified by enzyme immunoassay (ELISA). Results were considered significant if P was < 0.05.ResultsMean values of apelin-36 in CHF patients were 0.47 ± 0.21 ng/mL, and 0.95 ± 0.37 ng/mL in control subjects (P < 0.0001). Patients in IV NYHA class showed lower levels of apelin (0.38 ± 0.16 ng/mL). Direct correlations between apelin levels and ADLs (P = 0.0008, r = 0.61), and IADLs (P = 0.008, r = 0.50) were observed.Discussion and conclusionsThis study confirms that apelin levels are decreased in patients with CHF, also in the elderly and frail; since apelin represents a potential, promising novel therapeutic target for patients with CHF, geriatric patients should be considered for future clinical trials.     

Serum HER2 levels are increased in patients with chronic heart failure

BACKGROUND: The use of trastuzumab, an antibody against the human epidermal growth factor receptor 2 (HER2), in patients with HER2 positive metastatic breast cancer, is related to cardiotoxicity. AIMS: To investigate whether serum HER2 is increased in heart failure patients and related to disease severity. METHODS: Serum HER2, plasma tumor necrosis factor (TNF)-alpha and its soluble (s) receptors (sTNF-R1 and 2) were determined with ELISA in chronic heart failure patients and age and gender-matched healthy controls. RESULTS: Serum HER2 was higher (P=0.013) in 50 heart failure patients (18 female; median age 57 (range 33-77) years), mean 12.1+/-S.D. 2.3 ng/mL, than in 15 controls, 10.4+/-2.6 ng/mL. Serum HER2 levels correlated inversely with left ventricular ejection fraction (P=0.037) and were highest among NYHA class III patients, followed by NYHA class II patients and controls (P=0.029, Kruskal-Wallis test). STNF-R1 (P<.001) and sTNF-R2 (P=0.015) were higher in patients than controls, and correlated positively with HER2 (P=0.027 and P=0.036, respectively). CONCLUSIONS: Serum HER2 levels are increased in chronic heart failure patients. Further research is necessary to determine whether HER2 plays a role in the pathophysiology of heart failure.     

Tumour marker levels in patients with chronic heart failure

BACKGROUND: Carbohydrate Antigen 125 (CA 125), a marker for ovarian cancer has been reported to increase in relation to the severity of heart failure. OBJECTIVE: To evaluate the serum levels of CA 125 and other tumour markers, in patients with chronic heart failure. METHODS: Blood levels of CA 125 and other tumour markers were determined in 44 heart failure patients (16 males and 28 females; age 66.3+/-6.5 years) before and after optimal medical treatment. Levels were also evaluated in 30 healthy volunteers (11 males and 19 females; age 65.7+/-9.8 years). The results in the heart failure patients were grouped according to clinical status (New York Heart Association Class). The mean duration of follow-up was 3+/-1.5 months. RESULTS: The mean serum level of CA 125 was 81.9+/-91 in the patient group and 7.5+/-4.8 in control group (p<0.001). The mean CA 19-9 level in the patient group (16.8+/-16.6) was significantly higher than in the control group (4.5+/-2.6) (p<0.001). CA 125 levels increased as the New York Heart Association (NYHA) functional class increased (Class I/II: 17.7+/-22.4 U/ml; Class III: 99.6+/-92.1 U/ml; Class IV 136.4+/-102.8 U/ml; p<0.05). There were no significant differences in serum CA 125 and other tumour marker levels before and after optimisation of treatment. Significantly higher serum CA 125 levels were found in patients with pericardial effusion (p=0.002) when compared to patients without pericardial effusion. CONCLUSION: Among the tumour markers evaluated, only CA 125 seems to be specifically related to the presence and severity of heart failure and also the presence of pericardial fluid. Therefore, measurements of CA 125 serum levels might be proposed for the serial assessment of heart failure. Whether CA 125 has a specific biological role in heart failure requires further investigation.     

Disturbed carnitine regulation in chronic heart failure — Increased plasma levels of palmitoyl-carnitine are associated with poor prognosis

Background/objectives

Heart failure is characterized by disturbed energy metabolism and impaired mitochondrial function. L-carnitine plays a critical role in fatty acid transport into the mitochondria and may thus influence inflammation and myocardial function. The aim of this study was to investigate carnitine metabolism in relation to progression of heart failure (HF).

Methods and results

We examined plasma levels of free L-carnitine as well as several of its precursors and derivates in HF patients (n = 183) and matched healthy controls (n = 111) as well as their relationship with cardiac dysfunction as assessed by echocardiographic measurements, inflammation (CRP) and neurohormonal activation (NT-proBNP) in addition to the prognostic value of carnitine derivates in relation to mortality in these patients. High levels of the carnitine derivates acetyl-carnitine and in particular palmitoyl-carnitine were associated with the degree of HF as evaluated by clinical (NYHA functional class) and neurohormonal assessments. Moreover, plasma levels of palmitoyl-carnitine were associated with serious adverse events (i.e., all-cause mortality and heart transplantation) during follow-up, independently of more established risk markers such as CRP and NT-proBNP, when analyzed by cox-regression and continous net reclassification improvement, but not c-statistics.

Conclusions

Our findings support a role for disturbed carnitine metabolism in the pathogenesis of HF, and suggest that some of its derivates could give prognostic information in these patients.     

免疫球蛋白对心梗后心衰大鼠心功能及非梗死区胶原的影响

目的 研究免疫球蛋白对心肌梗死后心衰大鼠心功能的影响及非梗死区胶原的抑制作用.方法 将结扎左冠状动脉前降支并饲养6 w的24只存活雌性Wistar大鼠,分为假手术组、模型组及免疫球蛋白组,每组8只.连续腹腔注射给药4 w后测定大鼠血流动力学参数,Masson染色观察非梗死区心肌胶原的沉积.结果 免疫球蛋白能明显升高左心室内压最大上升和最大下降速率(+dp/dtmax及-dp/dtmax),能明显升高左心室收缩压(LVSP),降低左心室舒张末压(LVEDP)(P＜0.05或P<0.01),但对心率(HR)、收缩压(SBP)、舒张压(DBP)无明显影响(P>0.05).Masson染色可见非梗死区心肌胶原沉积明显减轻.结论 免疫球蛋白对梗死后心衰大鼠非梗死区心肌间质胶原重构有显著的抑制作用,其作用机制与减轻胶原沉积有关.     

The levels of hemoglobin are positively associated with arterial stiffness in community-dwelling Chinese adults

Background and aimsHemoglobin (Hb) concentrations are known to be related to cardiovascular diseases. This study investigated the association between Hb levels and arterial stiffness, as assessed by measurement of the brachial-ankle pulse wave velocity (baPWV).Methods and results3576 adults (2139 males and 1437 females) from the general Chinese population who had their physical check-ups in the health examination centers of Jiangmen Central Hospital were enrolled into the study. The anthropometrics and laboratory data as well as the baPWV and Hb levels were subsequently obtained. Age-adjusted partial correlation and multivariable stepwise linear regression analyses were used to evaluate the relationships between Hb and baPWV for men and women separately. In both sexes, Hb levels were positively associated with body mass index, total cholesterol, low-density lipoprotein cholesterol, triglycerides, glutamic-pyruvic transaminase, γ-glutamyltranspeptidase, uric acid and baPWV, but negatively correlated with the estimated glomerular filtration rate. Multivariable linear regression analysis showed that Hb was significantly and independently associated with arterial stiffness in men (β = 0.043, 95% CI 0.010–0.077, p < 0.05) and women (β = 0.035, 95% CI 0.001–0.069, P < 0.05), after adjustment for confounding factors.ConclusionThe data indicate that high Hb concentration significantly correlate with increased baPWV in general Chinese population.     

B-vitamin levels and genetics of hyperhomocysteinemia are not associated with arterial stiffness

Background and aimsHyperhomocysteinemia is associated with arterial stiffness, but underlying pathophysiological mechanisms explaining this association are to be revealed. This study was aimed to explore two potential pathways concerning the one-carbon metabolism. A potential causal effect of homocysteine was explored using a genetic risk score reflecting an individual's risk of having a long-term elevated plasma homocysteine level and also associations with B-vitamin levels were investigated.Methods and resultsBaseline cross-sectional data of the B-PROOF study were used. In the cardiovascular subgroup (n = 567, 56% male, age 72.6 ± 5.6 yrs) pulse wave velocity (PWV) was determined using applanation tonometry. Plasma concentrations of vitamin B12, folate, methylmalonic acid (MMA) and holo transcobalamin (holoTC) were assessed and the genetic risk score was based on 13 SNPs being associated with elevated plasma homocysteine. Associations were examined using multivariable linear regression analysis. B-vitamin levels were not associated with PWV. The genetic risk score was also not associated with PWV. However, the homocysteine–gene interaction was significant (p < 0.001) in the association of the genetic risk score and PWV. Participants with the lowest genetic risk of having long-term elevated homocysteine levels, but with higher measured homocysteine levels, had the highest PWV levels.ConclusionHomocysteine is unlikely to be causally related to arterial stiffness, because there was no association with genetic variants causing hyperhomocysteinemia, whereas non-genetically determined hyperhomocysteinemia was associated with arterial stiffness. Moreover, the association between homocysteine and arterial stiffness was not mediated by B-vitamins. Possibly, high plasma homocysteine levels reflect an unidentified factor, that causes increased arterial stiffness.     

Matrix metalloproteinase-1 and -2 levels are differently regulated in acute exacerbation of heart failure in patients with and without left ventricular systolic dysfunction

Matrix metalloproteinases (MMPs) play important roles in progression of chronic heart failure (HF) by regulating cardiac extracellular matrix metabolism. However, there is no report to investigate the difference of circulating MMP-1 and MMP-2 levels between systolic HF (SHF) and diastolic HF (DHF), particularly in light of acute exacerbation of HF. We assessed 110 HF patients who were admitted because of an acute exacerbation. They were divided into two groups: SHF [n = 68, left ventricular ejection fraction (LVEF) <45%] or DHF (n = 42, LVEF ≥45%). Ten patients without HF served as controls. Serum MMP-1 and MMP-2, and plasma brain natriuretic peptide (BNP) levels were examined on admission and at discharge. Serum MMP-1 level was higher on admission in both SHF and DHF than in controls. It was higher in SHF than in DHF and did not change at discharge in both groups. Serum MMP-2 level was equally higher on admission in SHF and DHF than in controls. It decreased in both groups at discharge. Treatment-induced changes in LVEF and BNP level correlated with those in MMP-2 level in SHF but not in DHF. Circulating MMP-1 and MMP-2 levels showed different dynamics between SHF and DHF in acute exacerbation and after treatment. These differences in circulating MMP-1 and MMP-2 levels may be related to the phenotype of HF.     

贫血增加慢性心力衰竭患者死亡率

目的调查贫血在慢性心力衰竭(CHF)住院患者中发生率,以及与CHF患者死亡率的关系。方法收集2007年1月1日至2009年12月31日在北京协和医院心内科住院,年龄≥21岁,临床诊断为心力衰竭,且左心室射血分数(LVEF)≤45%的缺血性(心肌梗死后至少40 d以上)或非缺血性心肌病患者进行回顾性研究,根据是否贫血[血红蛋白<120 g/L(男性)或110 g/L(女性)]分为两组,贫血组和对照组,并进行电话随访。结果共242例患者入选,对197例进行随访,14例(7.1%)失访,经过平均(20±9)个月(2～41个月)随访,共36例(20%)发生全因死亡,包括贫血组13例(34%)和对照组23例(16%)(χ2=6.415,P=0.011)。结论贫血在CHF住院患者中常见,贫血增加CHF死亡率,因此在积极抗心力衰竭治疗同时应高度重视贫血的纠正,以更好地改善CHF患者预后。     

Arterial-wave reflections are increased in heart failure patients with a left-ventricular assist device

BACKGROUND: Chronic heart failure (HF) is associated with increased central arterial pulse-wave reflections, which may contribute to increased myocardial oxygen demand. Although the treatment of HF via left-ventricular assist device (LVAD) placement has recently become widespread, the effects of LVAD therapy on central arterial pulse-wave reflections are unknown. METHODS: Central aortic pulse-wave analysis was performed on patients with end-stage HF awaiting cardiac transplantation and on healthy age-matched controls using the SphygmoCor (Akor Medical, Sydney, Australia) system. Arterial pulse-wave data were compared between patients receiving LVAD support versus those receiving intravenous inotropic drugs and healthy control patients. RESULTS: Five patients on LVAD support were compared with 10 patients on inotropic drugs and 10 healthy control patients. Aortic augmented pressure and the aortic augmentation index (AI(a)) were higher in LVAD patients compared with inotrope and control patients, despite similar brachial and aortic blood pressures between groups. The AI(a) was significantly higher in LVAD patients than in patients on inotropic drugs (28.2% +/- 10% v 7.9% +/- 9%, P < or = .01). Additionally, there was a significantly higher aortic systolic tension time index, an index of left-ventricular myocardial oxygen demand, in the LVAD group compared with the inotrope group (2655 +/- 298 mm Hg/sec/min v 1748 +/- 303 mm Hg/sec/min, P < .01). CONCLUSIONS: Central arterial pressure-wave reflection is increased in end-stage HF patients on LVAD support compared with those on inotropic drugs, leading to an increase in aortic augmented pressure, AI(a), and systolic tension time index. The AI(a) is also higher in LVAD patients than in healthy controls. This increased central arterial-wave reflection places an additional hemodynamic load on the LVAD device and may have relevance to the medical management of patients after LVAD placement and to the longevity of the LVAD device itself.     

Predictive importance of left ventricular myocardial stiffness for the prognosis of patients with congestive heart failure

Objectives

This study was designed to determine the prognostic importance of left ventricular (LV) myocardial stiffness, a hemodynamic index which is closely related to B-type natriuretic peptide (BNP) concentration in patients with congestive heart failure (CHF).

Background

While elevated BNP, an abnormality of cardiac neurohormones, is known to be an independent marker of death or re-admission, it remains to be clarified whether there is also a strong predictor directly related to cardiac dysfunction.

Methods

LV performance variables and stress–strain analyses including diastolic myocardial stiffness constant (K_m) were obtained from 37 patients with initial CHF by the combined simultaneous measurement of echocardiographic and hemodynamic data. Survivors were monitored for a mean of 23 months, with the main endpoint being combined death or first re-admission for CHF.

Results

Ten patients (27%) were primary endpoint cases. Both K_m and plasma BNP levels were higher in the event than in the event-free group. By Cox proportional hazards analysis, K_m ≥ 4.0 was identified as the only variable with significant and independently incremental predictive power to affect the primary endpoint (adjusted hazard ratio = 7.354, 95% confidence interval 1.379–39.232, p = 0.02).

Conclusions

In patients with CHF, increased myocardial stiffness may have greater prognostic significance compared to other conventional predictors. Increased myocardial stiffness may be considered to be an important prognostic factor independent of the loading conditions.     

Serum osteoprotegerin and osteopontin levels are associated with arterial stiffness and the presence and severity of coronary artery disease

Background

Osteopontin (OPN) and osteoprotegerin (OPG) have recently emerged as key factors in both vascular remodeling and development of atherosclerosis. Arterial stiffness has an independent predictive value for cardiovascular events. We evaluate the relationship between OPG, OPN serum levels and vascular function in coronary artery disease (CAD) patients.

Methods

The study population was consisted of 409 subjects (280 with CAD and 129 without CAD). Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. OPG and OPN levels were measured, as markers of vascular remodeling and calcification, by ELISA. Gensini score was used to evaluate the extent of CAD.

Results

CAD patients, compared to those without CAD, had higher OPG (3.91 ± 1.87 pmol/l vs. 2.88 ± 1.32 pmol/l, p < 0.001) and logOPN levels (1.81 ± 0.18 ng/ml vs. 1.71 ± 0.24 ng/ml, p < 0.001) and impaired PWV (8.94 ± 2.21 m/s vs. 8.28 ± 1.91 m/s, p = 0.006). Furthermore, PWV was associated with serum OPG levels (r = 0.19, p < 0.001) and with serum logOPN levels (r = 0.10, p = 0.049). Multivariate linear regression analysis revealed that increased OPG (p = 0.013) and logOPN (p = 0.006) levels are associated with 3‐vessel CAD and Gensini score (p = 0.04 for OPG and p = 0.09 for OPN), independently of other known cardiovascular risk factors.

Conclusion

The present study revealed that serum OPG and OPN levels are positively associated with arterial stiffness, and with the extent of CAD. These preliminary results suggest that OPG and OPN levels are significantly correlated with vascular function contributing to the pathogenesis of atherosclerosis in CAD. Further studies are needed to explore the mechanisms of action of OPG and OPN in CAD.     

慢性心力衰竭患者中贫血的患病情况

目的研究慢性心力衰竭(心衰)中贫血的患病情况及贫血与心功能的关系。方法183例慢性心衰患者通过临床、实验室评价和心脏超声心动图检查,参照NYHA分级,心功能Ⅰ~Ⅱ级(轻中度心衰组)86例,Ⅲ~Ⅳ级(重度心衰组)97例。比较2组的左室射血分数、左室舒张末期内径、血液学参数、患贫血率和病死率。结果183例慢性心衰患者中贫血(血红蛋白<120g/L)者43例(24.0%),重度心衰组中贫血患者(30.0%)明显多于轻中度心衰组(16.0%),P<0.05。平均随访17个月,轻中度心衰组死亡4例(5.0%),重度心衰组死亡18例(19.0%),2组相比差异有统计学意义(P<0.01)。贫血患者与非贫血患者相比病死率更高,分别为23.0%和9.0%,P<0.01。结论慢性心衰患者常伴有贫血,贫血的程度与心衰的严重程度有关,贫血使心衰患者死亡的危险性增高。     

Myocardial stiffness is an important determinant of the plasma brain natriuretic peptide concentration in patients with both diastolic and systolic heart failure.

AIMS: Plasma brain natriuretic peptide (BNP) concentration increases in proportion to heart failure (HF) severity. Although plasma BNP decreases to a certain level by optimal treatment, there is significant heterogeneity in the baseline value among individuals. The underlying mechanism of the steady-state plasma BNP levels remains still controversial. We investigated the hypothesis that myocardial stiffness (K(m)) is a major determinant of the plasma BNP level. METHODS AND RESULTS: In 19 patients with diastolic HF [DHF; left ventricular ejection fraction (LVEF) > or =4 5%], 18 with systolic HF (SHF; LVEF < 45%), and 12 controls, left ventricular (LV) performance variables and the results of the stress-strain analyses were obtained by the combined simultaneous measurement of echocardiographic and haemodynamic data, and compared with the plasma BNP level. In DHF, a significant correlation was observed between plasma BNP and fractional shortening (P = 0.010), pulmonary capillary wedge pressure (P = 0.030), end-diastolic pressure (P = 0.006), time constant of the LV isovolumic-pressure decline (P = 0.049), end-diastolic stress (P = 0.012), and K(m) (P = 0.004), respectively. In SHF, a significant correlation was observed between plasma BNP and end-diastolic stress (P = 0.036), chamber stiffness (P = 0.048), and K(m) (P = 0.003), respectively. CONCLUSION: In stable conditions, K(m) may be the most important determinant of the plasma BNP production in patients with both DHF and SHF.