Serum Pregnancy-Associated Plasma Protein A in Patients With Heart Failure

Journal of Cardiac Failure Vol. 17 No. 10 2011

Serum Pregnancy-Associated Plasma Protein A in Patients With Heart Failure AKIRA FUNAYAMA, MD, TETSURO SHISHIDO, MD, PhD, SHUNSUKE NETSU, MD, MITSUNORI ISHINO, MD, TOSHIKI SASAKI, MD, PhD, SHIGEHIKO KATOH, MD, PhD, HIROKI TAKAHASHI, MD, PhD, TAKANORI ARIMOTO, MD, PhD, TAKUYA MIYAMOTO, MD, PhD, JOJI NITOBE, MD, PhD, TETSU WATANABE, MD, PhD, AND ISAO KUBOTA, MD, PhD Yamagata, Japan

ABSTRACT Background: Pregnancy-associated plasma protein A (PAPP-A) proteolyzes insulin-like growth factor (IGF)ebinding proteins and thus increases IGF-1 bioactivity. PAPP-A has been reported to be involved in various pathophysiologic abnormalities; however, the clinical significance of PAPP-A has not been examined in cases of heart failure (HF). We hypothesized that PAPP-A levels might be correlated with the severity of HF. Methods and Results: PAPP-A and B-type natriuretic peptide (BNP) levels were measured in 262 subjects (182 HF patients and 80 control subjects). PAPP-A levels were higher in patients with HF than in control subjects and increased with advancing New York Heart Association functional class. There were 53 cardiac events during a mean follow-up period of 796 days. PAPP-A levels were higher in patients with cardiac events than in event-free patients. Patients were divided into 3 groups on the basis of their PAPP-A and BNP levels. Kaplan-Meier analysis demonstrated that the group with both high BNP with high PAPP-A had a significantly higher cardiac event rate than other groups. Conclusions: Serum PAPP-A levels were related to the severity of HF and associated with a high risk for adverse cardiac events in HF patients, suggesting that PAPP-A might be involved in the pathogenesis of HF. (J Cardiac Fail 2011;17:819e826) Key Words: Heart failure, risk stratification, biomarker, insulin-like growth factors.

Heart failure (HF) is a major health problem, with an increasingly high mortality rate, which parallels the increase in the elderly population and high prevalence of heart failure in the elderly.1e3 While earlier basic clinical studies have advanced the modern treatment of drugs targeting neurohormonal mechanisms such as angiotensin-converting enzyme inhibitors (ACEis) and b-blockers,4 HF is still one of the

leading causes of death in industrialized countries, so it is important to investigate the underlying mechanisms of this condition and develop more effective prognosis and treatment. As a consequence, new biomarkers that facilitate risk stratification in patients with HF are of great importance. It has been reported that IGF-1 levels are low and correlate with the severity of ventricular dysfunction.5,6 It also has been shown that serum IGF-1 levels at the time of infarction could be used to predict later development of HF.7 Furthermore, in the Framingham Heart Study, serum IGF-1 levels were inversely associated with the risk for congestive HF in elderly people without a previous myocardial infarction.8 Pregnancy-associated plasma protein A (PAPP-A) was originally isolated in the plasma of pregnant women9,10 and widely used to exclude fetal trisomy in the first trimester of gestation.11 PAPP-A has been identified as a metalloproteinase that cleaves inhibitory insulin-like growth factorebinding protein 4 (IGFBP-4) and is thought to be a major regulator of local IGF action.12e14 Kelley et al15 have shown that IGFBP-4 binds with IGF-1 and consequently prevents the interaction of IGFs with type 1 IGF receptors. Therefore, PAPP-A is thought to be a major

From the Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan. Manuscript received October 29, 2010; revised manuscript received April 20, 2011; revised manuscript accepted May 26, 2011. Reprint requests: Tetsuro Shishido, MD, PhD, Department of Cardiology, Pulmonology and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, Japan 990-9585. Tel: þ81-23-628-5302; Fax: þ81-23-628-5305. E-mail: [email protected] Funding: Grants-in-Aid for Scientific Research (nos. 21590923, 21790701, 22790684, 23591028, and 23790830) from the Ministry of Education Culture, Sport, Science, and Technology, a grant-in-aid from the Global Century Center of Excellence (COE) program of the Japan Society for the Promotion of Science, and Japan Heart Foundation Research Grant. See page 825 for disclosure information. 1071-9164/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2011.05.011

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820 Journal of Cardiac Failure Vol. 17 No. 10 October 2011 regulator of local IGF action. Furthermore, increasing evidence suggests that PAPP-A is associated with wound healing, bone remodeling, and vascular repair processes.16e21 Although, several clinical studies have suggested that PAPP-A relates to regulation of local IGF action and pathophysiologic modulation in patients with renal impairment, asthma, lung cancer, and acute coronary syndromes,19,22e26 the relationship between serum PAPP-A and HF has not been previously examined. Therefore, the purpose of the present study was to examine whether: (1) serum levels of PAPP-A are related to the severity of HF; and (2) serum PAPP-A is useful in predicting adverse clinical outcomes in patients with HF. Methods Study Population We prospectively enrolled 182 consecutive patients with HF [113 men and 69 women; mean (SD) age 70 (12) years] who had been admitted for the treatment of worsening HF. We also enrolled 80 age-matched subjects without signs of significant heart disease [50 men and 30 women; mean (SD) age 67 (9) years]. Control patients were selected from our catheterization laboratory after undergoing coronary angiography for suspected coronary artery disease. Control patients were excluded if they had significant coronary artery disease, systolic or diastolic dysfunction (defined as left ventricular ejection fraction [LVEF] !50% and left ventricular end-diastolic pressure !10 mm Hg), valvular heart disease, or myocardial hypertrophy on coronary angiography and echocardiography. Furthermore, control patients had normal results on routine laboratory testing. The diagnosis of HF was made by 2 cardiologists who used the generally accepted Framingham criteria, including a history of dyspnea and symptomatic exercise intolerance, signs of pulmonary congestion, peripheral edema, the presence of moist rales on auscultation, and radiologic or echocardiographic evidence of left ventricular enlargement or dysfunction. The diagnosis of dilated cardiomyopathy was based on the definition put forth by the World Health Organization and International Society and Federation of Cardiology Task Force. The diagnosis of ischemic heart disease was based on previous myocardial infarction. Informed consent was obtained from each of the patients before the study, and the protocol was approved by the human investigations committee of our institution. Blood samples were obtained from all of the patients at admission. The glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) equation with the Japanese coefficient.27 Transthoracic echocardiography was performed by experienced echocardiographers who were blinded to the biochemical data; the examination was performed using an ultrasound instrument (Hewlett-Packard Sonos 7500; Philips Medical Systems, Andover, Massachusetts) equipped with a sector transducer (carrier frequency 2.5 or 3.75 MHz). Demographics and clinical data, including age, gender, and New York Heart Association (NYHA) functional class at admission, were collected from hospital medical records and patient interviews. Physicians who were blinded to the results of the tests for biochemical markers and administered medical therapy evaluated the patients independently on the basis of measurements such as improvement in symptoms, physical examination findings, and radiologic findings of pulmonary congestion. The diagnosis of hypertension, diabetes, and hyperlipidemia were established on the

basis of the patient’s medical records or history of currently or previously received medical therapy. Patients who were excluded from this study were those with clinical or electrocardiographic evidence suggestive of acute coronary syndrome within 6 months preceding admission, those with active hepatic or pulmonary diseases or malignant diseases, and those who had undergone coronary artery bypass grafting, valvuloplasty, or valve replacement. Measurement of Serum PAPP-A Blood samples obtained at admission for measurement of serum levels of PAPP-A were drawn and centrifuged at 2,500g for 15 minutes at 4 C within 30 minutes of collection, and the serum obtained was stored at 70 C until analysis. PAPP-A is a heterotetrameric 2:2 complex with the proform of eosinophil major basic protein (proMBP) and is stable under standard living conditions. Serum PAPP-A in patients with cardiovascular disease (CVD) appears to be present as a homodimer, making it difficult to measure levels of PAPP-A by immunoassays that are designed to detect molecules formed by 2 antibodiesdone specific for PAPP-A and the other specific for proMBP.28,29 However, the ultrasensitive PAPP-A assay used in the present study was specifically developed to assess the value of PAPP-A as a marker for the clinical and biologic features associated with coronary heart disease19,23 as well as in relation to other pathophysiologic and inflammatory conditions.26,30 Serum PAPP-A concentration was measured by using a sandwich enzyme-linked immunosorbent assay (ELISA; DRG Instrument, Marburg, Germany) as previously reported. The minimum detection limit was 0.023 ng/mL. Serum PAPP-A measurements and assessment of HF were performed in duplicate by an investigator unaware of patients’ characteristics. Endpoints and Follow-Up No patients were lost to follow-up [mean (SD) 796 (698) days] after admission to Yamagata University Hospital. All of the patients were prospectively followed until the occurrence of cardiac events in every case. The endpoints were: (1) cardiac death, defined as death from worsening HF or sudden cardiac death; and (2) worsening HF requiring readmission. Sudden cardiac death was defined as death without definite premonitory symptoms or signs and was established by the attending physician. A review of medical records and follow-up telephone interviews to survey cardiac events were conducted by cardiologists who were blinded to the blood examination data. Cardiac events were adjudicated with the use of electrocardiography, chest x-rays, autopsy reports, death certificates, and witness statements. Statistical Analyses Results are presented as mean (SD) for continuous values and as percentages of the total number of patients for categoric variables. Skewed variables are presented as medians and interquartile ranges. Student unpaired t test and the chi-square test were used for comparisons of continuous and categoric variables, respectively, between 2 groups. If the data were not distributed normally, the Mann-Whitney U test was used. Comparisons of data among NYHA functional classes and quartiles based on PAPP-A levels were performed using the Kruskal-Wallis test. A Cox proportional hazards regression analysis was performed to evaluate the associations between cardiac events and measurements. Only variables with P values of !.05 on univariate Cox regression analysis were entered into multivariate Cox regression analysis. The cardiac eventefree curve was computed according to the Kaplan-Meier method and compared with

Serum PAPP-A in Heart Failure Patients the use of the log-rank test. The optimal cutoff values for PAPP-A and B-type natriuretic peptide (BNP) were determined as those with the largest sum of sensitivity plus specificity on each of the receiver operating characteristic (ROC) curves. Cutoff values of BNP (350 pg/mL) and PAPP-A (8.8 ng/mL) were determined by ROC curves as shown in Figure 3A. All P values reported are 2 sided, and a P value of !.05 was considered to be significant. Statistical analysis was performed with a standard statistical program package (JMP version 8; SAS Institute, Cary, North Carolina).

Results The baseline clinical characteristics of patients with HF and control subjects are listed in Table 1. The common logarithms of BNP (log10 BNP) and PAPP-A (log10 PAPP-A) were significantly higher and left ventricular end-diastolic dimension (LVEDD) significantly larger in patients with HF than in control subjects. The LVEF was significantly lower in patients with HF than in control subjects. As shown in Fig. 1A, serum PAPP-A levels were higher in patients with HF than in control subjects and increased with the severity of HF, reflected as increase in the NYHA functional class; they were the highest in patients with severe HF (NYHA functional class IV), worsening HF and BNP levels during the follow-up period (Fig. 1B). The clinical characteristics of patients with and without cardiac events are shown in Table 2. Compared with patients with cardiac events, those with cardiac events had higher NYHA functional class, higher levels of log10 PAPP-A and log10 BNP, and larger LVEDD. Patients with cardiac events were administered loop diuretics and spironolactone more frequently than event-free patients. In contrast, other variables, including age, gender, numbers of patients (those with hypertension, hyperlipidemia, and diabetes mellitus), estimated GFR, and LVEF, were not different between patients with and without cardiac events. To determine the risk factors for predicting cardiac events, we performed univariate (Table 3) and multivariate Cox proportional hazards regression analyses (Table 4). In the univariate analysis, log10 PAPP-A was significantly associated with cardiac events (per SD increase: hazard ratio 1.996; 95% confidence interval 1.372e2.905; P ! .01). Furthermore, age, NYHA functional class, estimated GFR, LVEDD, common logarithm of C-reactive protein (log10 CRP), log10 BNP, ACEis and/or angiotensin receptor blockers (ARBs), loop diuretics, and spironolactone were significantly related to cardiac events. Then, variables with P values of !.05 were entered into a multivariate Cox proportional hazards regression analysis. Log10 BNP, log10 PAPP-A, LVEDD, and loop diuretics were the independent predictors of cardiac events among these variables on multivariate analysis. Next, we classified all patients with HF into the following 4 groups according to their serum PAPP-A levels: 0.31e5.62 ng/mL (n 5 46; first quartile), 5.63e8.71 ng/mL (n 5 46; second quartile), 8.72e12.11 ng/mL (n 5 45; third quartile), and 12.12e38.80 ng/mL (n 5 45; fourth quartile). As shown in Fig. 2A, the Cox proportional hazards regression analysis



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revealed that the fourth quartile was associated with the highest risk for cardiac events among quartiles of PAPP-A levels (5.63-fold that of the first quartile: P ! .01). Furthermore, Kaplan-Meier analysis demonstrated that the fourth quartile had a significantly higher cardiac event rate than the lower 3 quartiles (P 5 .0002; Fig. 2B). We divided the patients into 3 groups based on the PAPP-A and BNP cutoff values determined by ROC curves, as shown in Fig. 3A: (1) low BNP þ low PAPP-A group (n 5 59); (2) high BNP þ low PAPP-A or low BNP þ high PAPP-A (n 5 70); and (3) high PAPP-A þ high BNP group (n 5 53). As shown in Fig. 3B, Kaplan-Meier analysis demonstrated that the combination of high BNP and high PAPP-A group had a significantly higher cardiac event rate than other groups. The clinical characteristics of patients with ischemic and nonischemic cardiomyopathy are shown in Table 5. There were no statistically significant differences in log10 PAPP-A levels between patients with ischemic and nonischemic cardiomyopathy. There was a weakly positive correlation between the log10 PAPP-A level and log10 BNP level (R 5 0.234; P ! .01). The log10 PAPP-A level was not correlated with estimated GFR (R 5 0.136; P 5 .65) or age (R 5 0.107; P 5 .15). In contrast, the log10 BNP level was well correlated with estimated GFR (R 5 0.387; P ! .01) and age (R 5 0.283; P ! .01). Discussion The findings of the present study highlighted several new and important points: (1) Serum PAPP-A levels were significantly elevated in patients with HF compared with healthy control subjects; (2) PAPP-A levels increased with the severity of HF; (3) PAPP-A levels were higher in patients with cardiac events than in those without cardiac events; (4) multivariate Cox proportional-hazard regression analysis demonstrated that PAPP-A was an independent factor that can be used to predict adverse clinical outcomes in patients with HF; and (5) the group with the highest level of PAPP-A was associated with the highest risk for cardiac events among the 4 groups. PAPP-A, which belongs to the metzincin superfamily of metalloproteinases,12,14,15 was originally isolated in 1974 as one of the placental proteins in pregnant women.1 Importantly, PAPP-A is expressed in a wide variety of reproductive and nonreproductive organs and cells.16e18,20,30,31 Bayes-Genis et al19 demonstrated the presence of PAPP-A in unstable plaques in the coronary arteries. High serum levels of PAPP-A have been observed in patients with acute coronary syndromes.19,32,33 A recent study has shown that the levels of circulating PAPP-A in patients with CVD differ from those in the serum of pregnant women.34 In the present study, gender and age were not associated with PAPP-A concentration (data not shown). The findings of the earlier studies and ours suggest that increased levels of PAPP-A in patients with HF might reflect the degree of heart damage against inflammation, reactive oxygen species, and mechanical stress.

822 Journal of Cardiac Failure Vol. 17 No. 10 October 2011 Table 1. Clinical Characteristics of 182 Patients With Heart Failure (HF) and 80 Control Subjects Variable Age (y) Men/women NYHA functional class (I/II/III/IV) Hypertension Diabetes melitus Hyperlipidemia Etiology of heart failure Ischemic heart disease Dilated cardiomyopathy Hypertensive heart disease Hypertrophic cardiomyopathy Valvular heart disease Other Blood examination Estimated GFR (mL min1 1.73 m2) CRP (mg/dL) Log10 CRP (mg/dL) PAPP-A (ng/mL) Log10PAPP-A (ng/mL) BNP (pg/mL) Log10 BNP (pg/mL) Echocardiography LVEDD (mm) LVEF (%) Cardiac deaths Rehospitalizations Medications at admission ACEis and/or ARBs b-Blockers Calcium channel blockers Loop diuretics Spironolactone Statins

Control (n 5 80) 67 6 9 50/30 48 (60%) 13 (16%) 28 (35%)

P Value

70 6 12 113/69 28/67/59/28 97 (53%) 47 (26%) 53 (29%)

NS NS d NS !.05 NS

50 55 16 35 6 20

d d d d d d 76.9 6 17.4 0.04, 0.02e0.09 1.30 6 0.43 5.2, 3.42e6.68 0.66 6 0.32 25,12.1e49.1 1.37 6 0.39 47.5 6 6.4 68.9 6 7.9 d d 21 6 46 0 0 25

HF (n 5 182)

(26%) (8%) (57%) (0%) (0%) (25%)

(28%) (30%) (9%) (19%) (3%) (11%)

d d d d d d

66.5 6 20.9 0.32, 0.10e1.18 0.41 6 0.62 8.8, 5.8e12.1 0.90 6 0.29 322, 89.2e873.0 2.42 6 0.68

!.05 !.05 !.01 !.01 !.01 !.01 !.01

54.6 6 12.3 47.6 6 17.9 24 (13%) 29 (16%)

!0.01 !0.01 d d

129 59 38 101 51 27

(71%) (32%) (21%) (55%) (28%) (15%)

!.01 !.01 !.01 !.01 !.01 NS

NYHA, New York Heart Association; GFR, glomerular filtration rate; CRP, C-reactive protein; PAPP-A, pregnancy-associated plasma protein A; BNP, B-type natriuretic peptide; LVEDD, left ventricular dimension at end diastole; LVEF, left ventricular ejection fraction; ACEis, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II recepter blockers; NS, not significant. Data are expressed as mean 6 SD, n (%), or median (interquartile range).

There was a weakly positive correlation between PAPP-A and BNP levels. BNP is a useful marker for diagnosis of impaired ventricular function, assessing risk, and predicting the outcome in patients with HF.35 However, even when clinical

A

findings are combined with BNP levels, there is substantial variation in the outcome.36 Therefore, it is unlikely that a single marker would present all of the information needed for clinical decision making, and the combination of several

B

Fig. 1. (A) Association between serum PAPP-A level and NYHA functional class. (B) Association between plasma BNP level and NYHA functional class. *P ! .001 vs control; yP ! .01 vs NYHA functional class I; zP ! .01 vs NYHA functional class II; xP ! .01 vs NYHA functional class III.

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Table 2. Comparisons of Clinical Characteristics of 182 Patients With Heart Failure Between Those With and Without Cardiac Events Variable

Event Free (n 5 129)

Cardiac Events (n 5 53)

P Value

69 6 12 85/44 25/50/40/14 69 (53%) 41 (32%) 38 (29%)

72 6 12 28/25 3/17/19/14 25 (47%) 12 (23%) 9 (17%)

NS NS !.01 NS NS NS

9 22 6 0 9 7

!.05 !.05 NS d NS NS

Age (y) Men/women NYHA functional class (I/II/III/IV) Hypertension Diabetes melitus Hyperlipidemia Etiology of heart failure Ischemic heart disease Dilated cardiomyopathy Hypertensive heart disease Hypertrophic cardiomyopathy Valvular heart disease Other Blood examination Estimated GFR (mL min1 1.73 m2) Log10 CRP (mg/dL) Log10 PAPP-A (ng/mL) Log10 BNP (pg/mL) Echocardiography LVEDD (mm) LVEF (%) Medications at admission ACEis and/or ARBs b-Blockers Calcium channel blockers Loop diuretics Spironolactone Statins

41 33 10 6 26 13

(32%) (25%) (8%) (5%) (20%) (10%)

68.3 6 0.48 6 0.84 6 2.27 6

(17%) (42%) (11%) (0%) (17%) (13%)

20.9 0.61 0.28 0.67

59.6 6 22.1 0.22 6 0.62 1.02 6 0.25 2.77 6 0.55

NS !.05 !.01 !.01

53.6 6 9.6 49.1 6 17.2

57.7 6 12.1 43.4 6 19.3

!.05 NS

81 44 29 54 28 18

(62%) (34%) (22%) (42%) (22%) (14%)

42 15 9 47 23 9

!.05 NS NS !.01 !.01 NS

(78%) (28%) (17%) (87%) (43%) (17%)

Abbreviations as in Table 1. Data are expressed as mean 6 SD or n (%).

biomarkers may provide helpful information for understanding different aspects of the interrelated pathophysiologic processes of HF.37 In the present study, PAPP-A was not correlated with estimated GFR or age, whereas BNP level

Table 3. Univariate Analysis of Predicting All Cardiac Events in Patients With Heart Failure Variable

Hazard Ratio

Age* Gender (women vs men) NYHA functional class Hypertension Diabetes mellitus Hyperlipidemia Ischemic heart disease Dilated cardiomyopathy Estimated GFR* Log10 CRP* Log10 PAPP-A* Log10 BNP* LVEDD* LVEF* ACEis and/or ARBs b-Blockers Calcium channel blockers Loop diuretics Spironolactone Statins Abbreviations as in Table 1. *Per 1 SD increase.

95% Confidence Interval P Value

1.453 1.252 1.703 1.299 1.415 1.694 1.857 0.615 0.666 1.372 1.996 2.587 1.464 0.747 0.458 1.089 1.338

1.039e1.995 0.628e2.499 1.280e2.265 0.762e2.217 0.745e2.690 0.828e3.465 0.907e3.803 0.357e1.059 0.499e0.898 1.034e1.821 1.372e2.905 1.773e3.774 1.097e1.969 0.543e1.018 0.240e0.874 0.600e1.978 0.654e2.739

!.05 NS !.01 NS NS NS NS NS !.01 NS !.01 !.01 !.01 NS !.05 NS NS

0.132 0.501 0.625

0.060e0.294 0.291e0.863 0.304e1.284

!.01 !.05 NS

was well correlated with estimated GFR and age. As shown Fig. 3B, the combination of PAPP-A and BNP could improve risk stratification for the prediction of cardiac events in HF patients. Our study suggests that PAPP-A may be a novel marker in addition to a prognostic model including BNP and severity of HF symptoms. In recent years, it has become apparent that inflammatory mechanisms are involved in the atherogenic process.38e41 There is now substantial evidence to suggest that the activation of proinflammatory factors also may play an important role in the HF process, because inflammation is related to prognosis and risk in patients with HF.42e44 A number of

Table 4. Multivariate Analysis of Predicting All Cardiac Events in Patients With Heart Failure Variable Age* NYHA functional class Estimated GFR* Log10 PAPP-A* Log10 BNP* LVEDD* ACEis and/or ARBs Loop diuretics Spironolactone

Hazard Ratio

95% Confidence Interval

P Value

1.167 1.030

0.823e1.679 0.692e1.532

NS NS

0.991 2.061 2.010 1.390 0.949 0.165 1.609

0.693e1.434 1.201e3.526 1.214e3.329 0.990e1.969 0.420e2.147 0.064e0.426 0.732e3.538

NS !.01 !.01 NS NS !.01 NS

Abbreviations as in Table 1. *Per 1 SD increase.

824 Journal of Cardiac Failure Vol. 17 No. 10 October 2011

A

B

Fig. 2. Patients were divided into 4 groups on the basis of PAPP-A levels: #5.62 ng/mL (n 5 46; first quartile), 5.63e8.71 ng/mL (n 5 46; second quartile), 8.72e12.11 ng/mL (n 5 45; third quartile), and $12.12 ng/mL (n 5 45; fourth quartile). (A) Hazard ratios relative to first quartile. yP ! .01 vs first quartile. (B) Kaplan-Meier analysis of cardiac eventefree rate among the 4 groups.

studies have demonstrated a positive correlation between serum PAPP-A and CRP levels in dialysis and renal transplant patients.22,23 However, in the present study, we did not find significant positive correlations between serum PAPP-A level and CRP in patients with HF (data not shown). We did not evaluate the levels of other inflammatory cytokines in this study population; therefore, further studies are needed to investigate the relationship between inflammation and PAPP-A in patients with HF. The metalloproteolytic activity of PAPP-A affects the interaction between IGFBP-4 and IGFs. PAPP-A functions as a protease and cleaves IGFBP-4 to release IGF-1, thereby increasing the local IGF-1 activity.12,15 Earlier studies have found that PAPP-A is secreted from human fibroblasts, human osteoblasts, marrow stromal cells, and vascular smooth muscle cells.12,13,16,17,30,31 In experimental models, overexpression of IGF-1 can protect from cardiomyocyte

A

1

death after infarction and attenuate ventricular dilation, wall stress, and cardiac hypertrophy.45 IGF-1 can additionally recruit cardiomyoblasts in the aging murine heart, preventing ventricular dysfunction.46 Therefore, IGF-1 may represent a key pathway contrasting myocyte senescence and cardiomyocyte damage after an ischemic insult and mechanical stress.47,48 It has been reported that IGF-1 levels were low and correlate with the severity of ventricular dysfunction.5,6 Experimental and clinical data suggest that signaling from damaged cardiomyocyte causes changes in IGF-10 s regulatory system, including compensatory increases in PAPP-A, probably aimed at expanding cardiac tissue IGF-1 concentrations. In the present study, we did not measure the levels of IGF-1 and IGFBP-4; therefore, future studies must incorporate molecular mechanisms that produce PAPP-A in patients with HF and modulate IGF systems.

B

8.8 ng/ml

Group 1

0

0.6

350 pg/ml

0.4 ROC curve for PAPP-A, AUC: 0.703 ROC curve for BNP, AUC: 0.658

0.2

Event rate (%)

Sensitivity

0.8

Kaplan-Meier survival curve

20 Group 2

40 60 80

Group 3 Log rank P < 0.001

100

0 0

0.2

0.4

0.6

1-Specificity

0.8

1

0

500

1000

1500

Follow-up period (days)

Fig. 3. (A) Receiver operating characteristic (ROC) curve analysis of BNP and PAPP-A. AUC, area under the ROC curve. (B) Patients were divided into patients into 3 groups based on the PAPP-A and BNP cutoff values determined by ROC curves: (1) low BNP þ low PAPP-A group (n 5 59); (2) high BNP þ low PAPP-A group or low BNP þ high PAPP-A group (n 5 70); and (3) high PAPP-A þ high BNP group (n 5 53). Kaplan-Meier analysis of cardiac eventefree rate among the 3 groups.

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Table 5. Comparisons of Clinical Characteristics of Patients With Ischemic and Nonischemic Cardiomyopathy Variable Age (y) Men/women NYHA functional class (I/II/III/IV) Hypertension Diabetes melitus Hyperlipidemia Blood examination Estimated GFR (mL min1 1.73 m2) Log10 CRP (mg/dL) Log10 PAPP-A (ng/mL) Log10 BNP (pg/mL) Echocardiography LVEDD (mm) LVEF (%) Medications at admission ACEis and/or ARBs b-Blockers Calcium channel blockers Loop diuretics Spironolactone Statins

Ischemic (n 5 50)

Nonischemic (n 5 132)

P Value

72 6 11 36/14 11/17/13/9 23 (46%) 20 (40%) 20 (40%)

70 6 13 77/55 17/50/46/19 71 (54%) 33 (25%) 27 (21%)

NS NS NS NS !.05 !.05

66.0 6 0.31 6 0.90 6 2.34 6

19.7 0.63 0.19 0.80

66.5 6 22.3 0.43 6 0.62 0.90 6 0.31 2.44 6 0.63

NS NS NS NS

53.8 6 9.5 50.0 6 18.7

54.9 6 10.7 46.6 6 17.7

NS NS

36 16 11 29 16 7

(72%) (32%) (22%) (58%) (32%) (14%)

93 45 27 72 35 20

(70%) (34%) (20%) (55%) (27%) (15%)

NS NS NS NS NS NS

Abbreviations as in Table 1. Data are expressed as mean 6 SD or n (%).

The present study has certain limitation. The diagnosis of ischemic heart disease was based on previous myocardial infarction, which although it is a specific diagnosis, lacks sensitivity for ischemic causes of cardiomyopathy. Because coronary angiography was not carried out in all of the patients with HF, we have no detailed data on coronary arteries to support the specificity for ischemic heart disease. Moreover, we did not evaluate the levels of IGF-1 or IGFBP-4 in the present study. Therefore, association of PAPP-A with bioactivity of IGF-1 or levels of IGFBP-4 in failing heart will be investigated in the future study. In conclusion, high serum PAPP-A levels were found in patients with HF, and this level was found to be independently associated with an increased risk of cardiac events. These data indicate that serum PAPP-A can serve as a useful prognostic factor for the evaluation of patients with heart failure.

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Disclosures None. 13.

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