Insulin-like Growth Factor Binding Protein-7 Concentrations Research Articles

Abstract 11936: Cardiorenal Prognostic Significance of IGFBP-7 Concentrations in Chronic Heart Failure: Findings From EMPEROR-Pooled

Introduction: Insulin-like growth factor binding protein-7 (IGFBP-7) is a biomarker of tissue senescence with a role in heart failure (HF) pathophysiology. We examined the association of IGFBP-7 with risk of HF hospitalization or cardiovascular (CV) death and progression of renal disease in the EMPEROR-Reduced and EMPEROR-Preserved Trials. Methods: IGFBP-7 was measured in serum samples in the placebo and empaglifozin arms at baseline (N= 561, 564), 12 weeks (N=558, 557) and 52 weeks (N=355, 358). IGFBP-7 was measured using Roche Cobas Elecsys assay within the Biomarker Research Agreement of Boehringer Ingelheim, the sponsor of the EMPEROR trials and Roche Diagnostics International Ltd. Association between IGFBP-7 and risk of HF hospitalization or CV death, estimated glomerular filtration rate (eGFR) slope, and renal composite outcome of sustained eGFR reduction ≥40% or end-stage renal disease were evaluated using multivariable modeling. Results: Study participants with IGFBP-7 levels in the third tertile had a higher risk clinical profile compared to those with lower values. Empagliflozin was not meaningfully associated with change in IGFBP7 at 12 or 52 weeks. In Cox proportional hazards models adjusted for clinical variables, N-terminal pro-B type natriuretic peptide and high-sensitivity cardiac troponin T, baseline IGFBP-7 values above the second tertile predicted a higher risk of HF hospitalization or CV death (HR: 2.00 95% CI 1.28-3.10, p=0.002), higher rate of eGFR decline (β estimate: -2.45, 95% CI: -3.40 - -1.50, p for trend =0.005) and higher risk of renal composite endpoint (HR: 4.66, 95% CI: 1.61-13.53, p=0.005). Empagliflozin reduced risk for CV death/HF hospitalization irrespective of baseline IGFBP-7 (p-trend across IGFBP-7 tertiles=0.26). Concentrations of IGFBP-7 were moderately correlated with other prognostic HF biomarkers of tissue remodeling including fatty acid binding protein-3, growth differentiation factor-15, and angiopoietin-2. Conclusions: IGBP-7 was correlated with worse clinical presentation and associated with adverse cardiovascular outcomes even in models adjusted for conventional biomarkers. Empagliflozin did not significantly affect IGFBP-7 levels over time.

Urinary NGAL, IGFBP-7, and TIMP-2: novel biomarkers to predict contrast medium-induced acute kidney injury in children

Background Serum creatinine (SCr) is unreliable in detecting acute changes in kidney function. Early recognition of contrast-induced acute kidney injury (CI-AKI) can provide better opportunities for preventive interventions. Therefore, the purpose of this study is to examine the value of the combined detection of urinary neutrophil gelatinase-associated lipocalin (NGAL), insulin-like growth factor binding protein-7 (IGFBP-7), and tissue inhibitor of metalloproteinase-2 (TIMP-2) in the early diagnosis of children with CI-AKI. Methods A prospective, single-center clinical trial was performed and included 172 children aged 0–18 years. The dynamic changes of urinary NGAL, IGFBP-7, and TIMP-2 levels in children with intravascular injection of contrast medium were investigated to determine whether they can diagnose CI-AKI early. Results CI-AKI occurred in 20 of 137 enrolled patients, and the incidence was 14.59%. In the CI-AKI group, urinary levels of NGAL, IGFBP-7, TIMP-2, and [IGFBP-7]*[TIMP-2] were significantly increased 2 h after angiography and remained at high levels at 6 h. Using a cutoff value of 36.274 ng/mL, the specificity was 70.0%, and the sensitivity was 68.4% for the prediction of CI-AKI, which was excellent for urinary NGAL. When both urinary IGFBP-7 and TIMP-2 were used together, urinary [IGFBP-7]*[TIMP-2] at 0.417(ng/mL)2/1000 was regarded as the cutoff value. The specificity was 80.0%, and the sensitivity was 81.2%. Conclusions NGAL, IGFBP-7, and TIMP-2 concentrations in the urine of children after receiving injections of contrast medium increased faster than SCr and had good clinical value for the early diagnosis of CI-AKI in children. The combination of IGFBP-7 and TIMP-2 was better than either analyte alone.

Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence.

Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. We have measured plasma IGFBP7 concentrations in 2250 subjects with new-onset or worsening heart failure (BIOSTAT-CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT-proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all-cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25-2.46; HR 1.71, 95% CI 1.39-2.11; and HR 1.44, 95% CI 1.23-1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P<0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT-CHF validation cohort. IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways.

Insulin-Like Growth Factor-Binding Protein 7 (IGFBP-7)-New Diagnostic and Prognostic Marker in Symptomatic Peripheral Arterial Disease?-Pilot Study.

The aim of our study was to evaluate the importance of insulin-like growth-factor-binding protein 7 (IGFBP-7) as a potential marker of symptomatic peripheral artery disease (PAD) occurrence. The study group consisted of 145 patients with diagnosed PAD, who qualified for the invasive treatment. The control group consisted of 67 individuals representing the local population and an ischemic heart disease (IHD) group of 88 patients after myocardial infarction or percutaneous coronary intervention. Patients with PAD had significantly higher IGFBP-7 concentrations than control group (1.80 ± 1.62 vs. 1.41 ± 0.45 ng/mL, p = 0.04). No significant differences between PAD patients and IHD patients were found (1.80 ± 1.62 vs. 1.76 ± 1.04 ng/mL, p = 0.783). Patients with multilevel PAD presented significantly higher IGFBP-7 concentrations than patients with aortoiliac PAD—median 1.18 (IQR 0.48–2.23) vs. 1.42 ng/mL (0.71–2.63), p = 0.035. In the group of patients who died or had a major adverse cardiovascular event (MACE) during six months of follow-up, a statistically significant higher IGFBP-7 concentration was found (median 2.66 (IQR 1.80–4.93) vs. 1.36 ng/mL (IQR 0.65–2.34), p = 0.004). It seems that IGFBP-7 is elevated in patients with atherosclerotic lesions—regardless of their locations. Further research should be conducted to verify IGFBP-7 usefulness as a predictor of MACE or death.

IGFBP7 Concentration May Reflect Subclinical Myocardial Damage and Kidney Function in Patients with Stable Ischemic Heart Disease.

The objective of this study was to determine the associations between insulin-like growth-factor-binding protein 7(IGFBP7) concentrations and concentrations of troponin T(TnT), N-terminal pro-B-type natriuretic peptide(NT-proBNP) and the parameters of kidney function in patients with stable ischemic heart disease(IHD). The IHD group consisted of 88 patients, and the population group comprised 66 subjects without a history of IHD. IGFBP7, TnT and NTproBNP concentrations were measured. The IGFBP7 value was considerably higher in the IHD group (1.76 ± 1 ng/mL vs. 1.43 ± 0.44 ng/mL, respectively, p = 0.019). Additionally, IHD subjects had a significantly higher concentration of TnT and NTproBNP. In both groups there was a significant correlation between IGFBP7 and serum parameters of kidney function (creatinine concentration: population gr. r = 0.45, p < 0.001, IHD gr. r = 0.86, p < 0.0001; urea concentration: population gr. r = 0.51, p < 0.0001, IHD gr. r = 0.71, p < 0.00001). No correlation between IGFBP7 and microalbuminuria or the albumin to creatinine ratio in urine was found. Moreover, there was a significant correlation between IGFBP7 concentration and markers of heart injury/overload-TnT and NT-BNP(r = 0.76, p < 0.001 and r = 0.72, p < 0.001, respectively). Multivariate regression analysis in joint both revealed that the IGFBP7 concentration is independently associated with urea, creatinine and TnT concentrations (R2 for the model 0.76). IHD patients presented significantly higher IGFBP7 concentrations than the population group. Elevated IGFBP7 levels are associated predominantly with markers of kidney function and myocardial damage or overload.

Insulin-Like Growth Factor Binding Protein 7 Predicts Renal and Cardiovascular Outcomes in the Canagliflozin Cardiovascular Assessment Study.

To analyze the association between concentrations of plasma insulin-like growth factor binding protein 7 (IGFBP7) with renal and cardiac outcomes among participants with type 2 diabetes and high cardiovascular risk. Associations between IGFBP7 levels and clinical outcomes were assessed among participants in the Canagliflozin Cardiovascular Assessment Study (CANVAS) with type 2 diabetes and high cardiovascular risk. Among CANVAS participants, 3,577 and 2,898 had IGFBP7 measured at baseline and 1 year, respectively. Per log-unit higher concentration, baseline IGFBP7 was significantly associated with the composite renal end point of sustained 40% reduction in estimated glomerular filtration rate, need for renal replacement therapy, or renal death (hazard ratio [HR] 3.51; P < 0.001) and the composite renal end point plus cardiovascular death (HR 4.90; P < 0.001). Other outcomes, including development or progression of albuminuria, were also predicted by baseline IGFBP7. Most outcomes were improved by canagliflozin regardless of baseline IGFBP7; however, those with baseline concentrations ≥96.5 ng/mL appeared to benefit more from canagliflozin relative to the first progression of albuminuria compared with those with lower baseline IGFBP7 (HR 0.64 vs. 0.95; P interaction = 0.003). Canagliflozin did not lower IGFBP7 concentrations by 1 year; however, at 1 year, higher IGFBP7 concentrations more strongly predicted the composite renal end point (HR 15.7; P < 0.001). Patients with rising IGFBP7 between baseline and 1 year had the highest number of composite renal events. Plasma IGFBP7 concentrations predicted renal and cardiac events among participants with type 2 diabetes and high cardiovascular risk. More data are needed regarding circulating IGFBP7 and progression of diabetic kidney disease and its complications.

Application value of urinary IGFBP7 and TIMP-2 in acute kidney injury with decompensated hepatitis B virus-related liver cirrhosis

Objective: To investigate the application value of new urinary biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue matrix metalloproteinase inhibitor-2 (TIMP-2) in acute kidney injury with decompensated hepatitis B virus-related liver cirrhosis. Methods: 45 newly hospitalized cases with decompensated hepatitis B virus-related liver cirrhosis were selected. Among them, 19 cases were combined with AKI on admission (cirrhosis-AKI group), 26 cases without AKI (cirrhosis-non-AKI group), and 12 healthy cases (normal control group). First-morning urine samples were collected and IGFBP7 and TIMP-2 were detected by enzyme-linked immunosorbent assay (ELISA). Urinary IGFBP7 and serum creatinine (SCr) were dynamically monitored after hospitalization in cirrhosis-non-AKI group. Normally distributed measurement data were compared by t-test, and non-normally distributed measurement data were compared by rank sum test. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic accuracy of the indicators. Results: Urinary IGFBP7, IGFBP7 with TIMP-2 (IGFBP7×TIMP-2) in cirrhosis-AKI group (n = 19) were equally higher than that of the cirrhosis-non-AKI group (P < 0.05). Urinary IGFBP7, TIMP-2 and IGFBP7×TIMP-2 in cirrhosis-AKI group or cirrhosis-non-AKI group were significantly higher than those of the normal control group (P < 0.01). The AUC of urinary IGFBP7 and urinary IGFBP7×TIMP-2 for diagnosis of AKI were 0.703 (95% CI 0.547-0.860) and 0.700 (95% CI 0.541-0.859), respectively. In the liver cirrhosis-non-AKI group (n = 26), 5 cases of AKI were newly diagnosed according to the changes in SCr during hospitalization (progressive group). Urinary IGFBP7 was significantly increased 2 days before the diagnosis of AKI. The concentration of urinary IGFBP7 at admission in the progressive group (n = 5) was higher than that of the non-progressive group (n = 21) (P < 0.05). Conclusion: Urinary IGFBP7 and TIMP-2 concentrations were significantly increased in patients with decompensated hepatitis B virus-related liver cirrhosis. When AKI occurred, urinary IGFBP7 and IGFBP7×TIMP-2 was further increased. Urinary IGFBP7 is valuable for early AKI diagnosis, and may play a role in predicting AKI occurrence.

Echocardiographic assessment of insulin-like growth factor binding protein-7 and early identification of acute heart failure.

AimsConcentrations of insulin‐like growth factor binding protein‐7 (IGFBP7) have been linked to abnormal cardiac structure and function in patients with chronic heart failure (HF), but cardiovascular correlates of the biomarker in patients with more acute presentations are lacking.We aimed to determine the relationship between IGFBP7 concentrations and cardiac structure and to evaluate the impact of IGFBP7 on the diagnosis of acute HF among patients with acute dyspnoea.Methods and resultsIn this pre‐specified subgroup analysis of the International Collaborative of N‐terminal pro‐B‐type Natriuretic Peptide Re‐evaluation of Acute Diagnostic Cut‐Offs in the Emergency Department (ICON‐RELOADED) study, we included 271 patients with and without acute HF. All patients presented to an emergency department with acute dyspnoea, had blood samples for IGFBP7 measurement, and detailed echocardiographic evaluation.Higher IGFBP7 concentrations were associated with numerous cardiac abnormalities, including increased left atrial volume index (LAVi; r = 0.49, P < 0.001), lower left ventricular ejection fraction (r = −0.27, P < 0.001), lower right ventricular fractional area change (r = −0.31, P < 0.001), and higher tissue Doppler E/e′ ratio (r = 0.44, P < 0.001). In multivariable linear regression analyses, increased LAVi (P = 0.01), lower estimated glomerular filtration rate (P = 0.008), higher body mass index (P = 0.001), diabetes (P = 0.009), and higher concentrations of amino‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP, P = 0.02) were independently associated with higher IGFBP7 concentrations regardless of other variables. Furthermore, IGFBP7 (odds ratio = 12.08, 95% confidence interval 2.42–60.15, P = 0.02) was found to be independently associated with the diagnosis of acute HF in the multivariable logistic regression analysis.ConclusionsAmong acute dyspnoeic patients with and without acute HF, increased IGFBP7 concentrations are associated with a range of cardiac structure and function abnormalities. Independent association with increased LAVi suggests elevated left ventricular filling pressure is an important trigger for IGFBP7 expression and release. IGFBP7 may enhance the diagnosis of acute HF.

Diagnostic and Prognostic Utilities of Insulin-Like Growth Factor Binding Protein-7 in Patients With Dyspnea

ObjectivesThis study examined whether insulin-like growth factor binding protein-7 (IGFBP7) would aid in the diagnosis and prognosis of acute heart failure (HF) beyond N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration. BackgroundIGFBP7 is associated with impaired ventricular relaxation and worse prognosis. MethodsThe ICON-RELOADED (International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial that enrolled subjects presenting with dyspnea. Six-month prognosis for death or repeat hospitalization was obtained. ResultsAmong 1,449 patients, 274 (18.9%) were diagnosed with acute HF. Those with IGFBP7 concentrations in the highest quartile were older, male, had hypertension and HF, had lower estimated glomerular filtration rate (eGFR) and lowest ejection fraction (41 ± 20%; all p < 0.001). Independent predictors of IGFBP7 were age, male sex, history of diabetes, history of HF, and eGFR. Median concentrations of NT-proBNP (2,844 ng/ml vs. 99 ng/ml) and IGFBP7 (146.1 ng/ml vs. 86.1 ng/ml) were higher in those with acute HF (both; p < 0.001). Addition of IGFBP7 to NT-proBNP concentrations improved discrimination, therefore increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p < 0.001 for differences). Addition of IGFBP7 to a complete model of independent predictors of acute HF improved model calibration. IGFBP7 significantly reclassified acute HF diagnosis beyond NT-proBNP (net reclassification index: +0.25). Higher log2-IGFBP7 concentrations in patients with acute HF predicted death or rehospitalization at 6 months (hazard ratio: 1.84 per log2-SD; 95% confidence interval: 1.30 to 2.61; p = 0.001). In Kaplan-Meier analyses, supramedian concentrations of IGFBP7 were associated with shorter event-free survival (log-rank: p < 0.001). ConclusionsAmong patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk.

Discovery of novel biomarkers for atherosclerotic aortic aneurysm through proteomics-based assessment of disease progression

Since aortic aneurysms (AAs) are mostly asymptomatic, but they have a high mortality rate upon rupture, their detection and progression evaluation are clinically important issues. To discover diagnostic biomarkers for AA, we performed proteome analysis of aortic media from patients with thoracic atherosclerotic AA (TAAA), comparing protein levels between the aneurysm and normal tissue areas. After hierarchical clustering analysis of the proteome analysis data, tissue samples were classified into three groups, regardless of morphological features. This classification was shown to reflect disease progression stage identified by pathological examination. This proteomics-based staging system enabled us to identify more significantly altered proteins than the morphological classification system. In subsequent data analysis, Niemann-Pick disease type C2 protein (NPC2) and insulin-like growth factor-binding protein 7 (IGFBP7) were selected as novel biomarker candidates for AA and were compared with the previously reported biomarker, thrombospondin 1 (THBS1). Blood concentrations of NPC2 and IGFBP7 were significantly increased, while THBS1 levels were decreased in TAAA and abdominal atherosclerotic AA patients. Receiver operating characteristic analysis of AA patients and healthy controls showed that NPC2 and IGFBP7 have higher specificity and sensitivity than THBS1. Thus, NPC2 and IGFBP7 are promising biomarkers for the detection and progression evaluation of AA.

P5005Diagnostic and prognostic utilities of insulin-like growth factor-binding protein-7 in patients presenting to the emergency department with dyspnea: results from the ICON-RELOADED study

Abstract Background Increased activity of insulin-like growth factor–binding protein-7 (IGFBP7) is associated with cellular senescence, tissue aging, and obesity. Prior studies in chronic heart failure (HF) have linked IGFBP7 to impaired myocardial relaxation. The role of IGFBP7 measurement in acute HF remains unclear. Purpose To examine whether concentrations of IGFBP7 in patients presenting with dyspnea to the emergency department (ED) will aid in the diagnosis and prognosis of acute HF beyond N-terminal pro- B type natriuretic peptide (NT-proBNP). Methods The ICON-RELOADED (International Collaborative of NT-proBNP- Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial conducted at 19 sites in North America that enrolled subjects ≥22 years of age presenting to ED with complaints of dyspnea. Subjects were blindly adjudicated for the diagnosis of acute HF. A blood sample was taken at enrollment. Six-month prognosis for death/repeat hospitalization was obtained. IGFBP7 was measured using a pre-clinical research use only assay. Results Among 1449 patients (n=274 with acute HF), those with IGFBP7 concentrations in the highest quartile (&gt;123.7 ng/mL) were older, more likely to be male and to have a history of hypertension and HF (all p&lt;0.001). They also had lower estimated glomerular filtration rate (eGFR) and the lowest left ventricular ejection fraction (41% ± 21%) prior to study enrollment (all p&lt;0.001). Independent predictors of IGFBP7 included age, male sex, history of diabetes, history of HF, and eGFR (all p&lt;0.001). Median concentrations of NT-proBNP (2844 vs. 99 ng/mL) and IGFBP7 (146.1 vs. 86.1 ng/mL) were significantly higher in those with acute HF (both p&lt;0.001); addition of IGFBP7 to NT-proBNP concentrations improved discrimination, increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p&lt;0.001) (Figure 1). Addition of IGFBP7 to a complete model of independent predictors of acute HF (including NT-proBNP) improved model calibration; IGFBP7 also significantly re-classified acute HF diagnosis beyond NT-proBNP alone (net reclassification improvement +0.25; p&lt;0.001). Higher log2-IGFBP7 concentrations predicted death/rehospitalization at 6 months (hazard ratio 1.74 per log2-standard deviation, 95% confidence interval 1.26–2.40, p=0.001). In Kaplan-Meier analyses, supramedian concentrations of IGFBP7 were associated with shorter event-free survival (log-rank p&lt;0.001). ROC curve for diagnosis of acute HF Conclusions Among patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk. Acknowledgement/Funding Funding for this study was provided by Roche Diagnostics (Risch-Rotkreuz, Switzerland).

Insulin-like growth factor-binding protein 7 (IGFBP 7) as a new biomarker in coronary heart disease

PurposeThe role of insulin-like growth factor-binding protein-7 (IGFBP-7) in atherosclerosis is still not well-known. The objective of this study was to find out the following: 1) whether IGFBP-7 may act as a biomarker of coronary artery disease (CAD) occurrence and extent; 2) whether IGFBP-7 is potentially related to the classical and new markers of cardiovascular risk (carotid intima-media thickness - cIMT); 3) whether IGFBP-7 may be a marker of mortality in the group of patients with myocardial infarction (MI). Materials/MethodsThe study group consisted of 212 patients with MI and 75 patients with stable CAD, the control group included 100 healthy volunteers. IGFBP-7 serum concentration was measured. ResultsIGFBP-7 value was considerably higher in the study group (MI and CAD patients - 35.1 ng/ml (P = 0.000001) and 32.7ng/ml (P = 0.0001), respectively), than in the controls – 25.2ng/ml. No statistically significant differences between IGFBP-7 concentrations in the MI and CAD group were found. No relationship between IGFBP-7 and the coronary lesions advancement in the study group was observed. No changes in IGFBP-7 concentration in the MI patients during hospitalization were observed. In the group of MI patients who died during follow-up, a considerably higher cIMT values were found whereas no statistically significant difference was observed in relation to IGFBP-7 (34.6 vs. 35.2 ng/ml). ConclusionsIGFBP-7 is a good biomarker of CAD occurrence but not of its advancement. We demonstrated the existence of the relation between higher IGFBP-7 concentration and the selected classical risk factors of cardiovascular events as well as cIMT values. IGFBP-7 cannot serve as a marker of acute ischemia. Also, IGFBP-7 was not confirmed as a predictor of mortality in the MI patients.

IGFBP7 (Insulin-Like Growth Factor-Binding Protein-7) and Neprilysin Inhibition in Patients With Heart Failure.

Increased activity of IGFBP7 (insulin-like growth factor-binding protein-7) is associated with cellular senescence, tissue aging, and obesity. IGFBP7 may be related to heart failure with preserved ejection fraction, a disease of elderly obese people. In a subset of patients with heart failure with preserved ejection fraction (N=228) randomized to receive sacubitril/valsartan versus valsartan, IGFBP7 concentrations were measured at baseline, 12 weeks, and 36 weeks. Patient characteristics and echocardiographic measures including left atrial (LA) size and volume, ratio of early mitral inflow velocity/annular diastolic velocity, and ratio of early diastole/peak late diastolic velocity were assessed as a function of IGFBP7 concentration. Effect of sacubitril/valsartan on IGFBP7 concentrations was analyzed. With increasing baseline IGFBP7 quartiles, LA size and LA volume index (LAVi) were higher (both P<0.001); modest association between IGFBP7 and higher early mitral inflow velocity/annular diastolic velocity ( P=0.03) and early diastole/peak late diastolic velocity ratio ( P=0.04) was also seen. IGFBP7 concentrations were higher in those with LAVi ≥34 mL/m2 compared with lower LAVi at all time points (all P<0.01). IGFBP7 independently predicted LAVi at baseline even in the presence of NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentrations; highest LAVi was seen in those with elevation in both biomarkers. Treatment with sacubitril/valsartan resulted in lower IGFBP7 concentrations over 36 weeks compared with valsartan (adjusted treatment effect, -7%; P<0.001). Among patients with heart failure with preserved ejection fraction, concentrations of the cellular senescence biomarker IGFBP7 were associated with abnormalities in diastolic filling and LA dilation. Treatment with sacubitril/valsartan resulted in lower IGFBP7 concentrations compared with valsartan. URL: https://www.clinicaltrials.gov . Unique identifier: NCT00887588.

Comparison of Prognostic Usefulness of Serum Insulin-Like Growth Factor-Binding Protein 7 in Patients With Heart Failure and Preserved Versus Reduced Left Ventricular Ejection Fraction

We aimed to characterize of the role of insulin-like growth factor-binding protein 7 (IGFBP-7) in heart failure (HF) pathophysiology. IGFBP-7 has been associated with cardiac hypertrophy and diastolic dysfunction in HF. In 86 patients with HF with a preserved ejection fraction (HFpEF) (ejection fraction [EF] ≥45%) and 79 with HF with a reduced ejection fraction (HFrEF), we assessed concentrations of serum IGFBP-7, correlations between serum IGFBP-7 and clinical data, diastolic function, and associations with outcome. IGFBP-7 was lower in HFpEF than HFrEF (102 vs 152 µg/L, p <0.001) and correlated with New York Heart Association class (HFpEF: r = 0.25, p = 0.020; HFrEF: r=0.26, p = 0.022), N-terminal pro-brain natriuretic peptide (NT-proBNP) (HFpEF: r = 0.53, p <0.001; HFrEF: r = 0.50, p <0.001), and estimated glomerular filtration rate (eGFR) (HFpEF: r = -0.47, p <0.001; HFrEF: r = -0.45, p <0.001). In HFpEF, IGFBP-7 correlated with E/e' (r = 0.31, p = 0.012) and E/A ratio (r = 0.31, p = 0.011). In HFrEF, but not HFpEF, IGFBP-7 correlated with age (r = 0.29, p = 0.009) and atrial fibrillation (r = 0.34, p = 0.002). IGFBP-7 predicted the outcome in HFpEF (hazard ratio 4.19 [1.01 to 17.35], p = 0.048]) but not in HFrEF (0.72 [0.24 to 2.14], p = 0.554). In conclusion in HFrEF, IGFBP-7 was elevated and associated with HF severity but not prognostic, suggesting a marker of risk. In HFpEF, IGFBP-7 was less elevated but associated with markers of diastolic dysfunction, HF severity, and prognosis. IGFBP-7 may contribute to the progression of HFpEF possibly through inflammation and oxidative stress.

Longitudinal characterization of renal proximal tubular markers in normotensive and preeclamptic pregnancies.

Glomerular damage is common in preeclampsia (PE), but the extent and etiology of tubular injury are not well understood. The aim of this study was to evaluate tubular injury in patients with PE and to assess whether it predates clinical disease. We performed a prospective cohort study of 315 pregnant women who provided urine samples at the end of the second trimester and at delivery. This analysis included women who developed PE (n = 15), gestational hypertension (GH; n = 14), and normotensive controls (NC; n = 44). Urinary markers of tubular injury, α1-microglobulin (A1M), retinol-binding protein (RBP), kidney-injury molecule-1 (KIM1), complement C5b-9, tissue inhibitor metalloproteinase-2 (TIMP-2), and insulin-like growth factor binding protein-7 (IGFBP-7) were measured by enzyme-linked immunosorbent assay (ELISA) and reported in relation to urine creatinine concentration. Second-trimester concentrations of all markers were similar among groups. At delivery, A1M concentrations were higher in the PE group than in the GH and NC groups as an A1M/creatinine ratio >13 (66.7, 8.3, and 35%, respectively, P = 0.01). Concentrations of C5b-9 were higher in the PE group than in the GH and NC groups (medians 9.85, 0.05, and 0.28 ng/mg, respectively, P = 0.003). KIM1, RBP, TIMP-2, and IGFBP-7 concentrations did not differ among groups at delivery. In conclusion, proximal tubular dysfunction, as assessed by A1M and C5b-9, developed during the interval between the end of the second trimester and delivery in patients with PE. However, this was not matched by abnormalities in markers previously associated with tubular cell injury (KIM-1, IGFBP-7, and TIMP-2).

Urine Biomarkers of Tubular Renal Cell Damage for the Prediction of Acute Kidney Injury After Cardiac Surgery—A Pilot Study

To evaluate the perioperative course of urine levels of the renal damage biomarkers tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) and to evaluate the predictive value of elevated TIMP-2 × IGFBP7 concentrations to predict acute kidney injury (AKI) early after cardiac on-pump surgery. Prospective, observational cohort study. University hospital. The study comprised 110 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) between January and March 2014. None. Urinary TIMP-2 × IGFBP7 levels were quantified using a commercially available kit at the following measurement points: before surgery, 1 hour after starting CPB, 4 hours after weaning from CPB, and 24 hours after weaning from CPB (time points 1-4). Postoperative AKI was defined according to Kidney Disease Improving Global Outcomes criteria. AKI after cardiac surgery was diagnosed in 9 patients (8%). The perioperative course of TIMP-2 × IGFBP7 was significantly different in patients with and without postoperative AKI (p < 0.001). TIMP-2 × IGFBP7 levels were significantly higher in patients with AKI 1 hour after CPB start and 24 hours after weaning from CPB (p < 0.05). TIMP-2 × IGFBP7 levels >0.40 (ng/mL)2/1,000 measured at 1 hour after starting CPB were found to be the optimal cut-off, with a sensitivity of 0.778 and a specificity of 0.641. The negative predictive value was 0.972. Urine levels of TIMP-2 × IGFBP7 are predictive for AKI at an early time point (1 hour after starting CPB). Renal damage biomarkers such as TIMP-2 and IGFBP7 might be recommended as a supplement to traditionally used criteria of AKI prediction.

Insulin-Like Growth Factor–Binding Protein-7 as a Biomarker of Diastolic Dysfunction and Functional Capacity in Heart Failure With Preserved Ejection Fraction: Results From the RELAX Trial

ObjectivesThis study sought to investigate relationships between insulin-like growth factor–binding protein-7 (IGFBP7) and parameters of diastolic function or functional capacity in patients with heart failure and preserved ejection fraction (HFpEF) who were randomized to receive sildenafil or placebo. BackgroundIGFBP7 was previously found to be associated with diastolic function in heart failure with reduced ejection fraction, but it is unclear whether these associations are present in HFpEF. MethodsAt baseline and 24 weeks, IGFBP7, imaging studies, and peak oxygen consumption (Vo2max) were obtained and compared in 160 patients with HFpEF who were randomized to receive sildenafil or placebo. ResultsPatients with supramedian baseline IGFBP7 concentrations were older, had signs of systemic congestion and worse renal function, and had higher concentrations of prognostic heart failure biomarkers including amino-terminal pro-B-type natriuretic peptide (p < 0.05). Higher baseline IGFBP7 was modestly correlated with worse diastolic function: higher E velocity (Spearman correlation [ρ] = 0.40), E/E′ (ρ = 0.40), left atrial volume index (ρ = 0.39), and estimated right ventricular systolic pressure (ρ = 0.41; all p < 0.001) and weakly correlated with transmitral E/A (ρ = 0.26; p = 0.006). Notably, change in IGFBP7 was significantly correlated with change in E, E/A, E/E′, and right ventricular systolic pressure. Elevated baseline IGFBP7 was associated with lower baseline Vo2max (13.2 vs. 11.1 ml/min/kg; p < 0.001), and change in IGFBP7 was weakly inversely correlated with change in Vo2max (ρ = −0.19; p = 0.01). Subjects receiving sildenafil had a decrease in IGFBP7 over 24 weeks, in contrast to placebo-treated patients (median change in IGFBP7 −1.5 vs. +13.6 ng/ml; p < 0.001). ConclusionsIn patients with HFpEF, IGFBP7 may be a novel biomarker of diastolic function and exercise capacity.

Prognostic Value of Insulin-Like Growth Factor-Binding Protein 7 in Patients with Heart Failure and Preserved Ejection Fraction

BackgroundThe prognostic merit of insulin-like growth factor-binding protein 7 (IGFBP7) is unknown in heart failure and preserved ejection fraction (HFpEF). Methods and ResultsBaseline IGFBP7 (BL-IGFBP7; n = 302) and 6-month change (Δ; n = 293) were evaluated in the Irbesartan in Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. Primary outcome was all-cause mortality or cardiovascular hospitalization with median follow-up of 3.6 years; secondary outcomes included HF events. Median BL-IGFBP7 concentration was 218 ng/mL. BL-IGFBP7 was significantly correlated with age (R2 = 0.13; P < .0001), amino-terminal pro-B-type NP (R2 = 0.22; P < .0001), and estimated glomerular filtration rate (eGFR; R2 = 0.14; P < .0001), but not with signs/symptoms of HFpEF. BL-IGFBP7 was significantly associated with the primary outcome (hazard ratio [HR] = 1.007 per ng/mL; P < .001), all-cause mortality (HR = 1.008 per ng/mL; P < .001), and HF events (HR = 1.007 per ng/mL; P < .001). IGFBP7 remained significant for each outcome after adjustment for ln amino-terminal pro-B-type NP and eGFR but not all variables in the I-PRESERVE prediction model. After 6 months, IGFBP7 did not change significantly in either treatment group. ΔIGFBP7 was significantly associated with decrease in eGFR in patients randomized to irbesartan (R2 = 0.09; P = .002). ΔIGFBP7 was not independently associated with outcome. ConclusionsHigher concentrations of IGFBP7 were associated with increased risk of cardiovascular events, but after multivariable adjustment this association was no longer present. Further studies of IGFBP7 are needed to elucidate its mechanism. Clinical Trial Registrationwww.clinicaltrials.gov, NCT00095238

Abstract 14023: Insulin-like Growth Factor-binding Protein 7 as a Biomarker of Diastolic Dysfunction and Functional Capacity: Results From the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction (RELAX) Trial

Introduction: Insulin-like growth factor-binding protein 7 (IGFBP7) was previously found to be associated with diastolic function in heart failure (HF) with reduced ejection fraction (EF), but it is unclear whether such associations exist in HF with preserved EF (HFpEF), where diastolic function is of pivotal importance. Hypotheses: Baseline (BL) and change (Δ) in IGFBP7 will be significantly associated and correlated with BL and Δ in diastolic indices as well as peak oxygen consumption (VO2 max ) in patients with HFpEF. IGFBP7 will decrease with sildenafil therapy. Methods: At BL and 6 months (6M), IGFBP7, imaging studies, and VO2 max were obtained and compared in 160 HFpEF patients randomized to sildenafil or placebo. Results: Patients with supramedian BL IGFBP7 concentrations (&gt;219 ng/mL) were more likely to be older, to have more congestion and worse renal function, and to have elevated concentrations of several emerging or established HF biomarkers including amino-terminal pro-B-type natriuretic peptide, cystatin C, and highly sensitive troponin (all P&lt;0.05). Higher BL IGFBP7 was correlated with indices of worse diastolic function, including higher E velocity (ρ=0.395, P&lt;0.001), E/e’ (ρ=0.398, P&lt;0.001), left atrial volume index (ρ=0.386, P&lt;0.001), right ventricular systolic pressure (RVSP; ρ=0.413, P&lt;0.001), and transmitral E/A (ρ=0.258, P=0.006). IGFBP7 was also inversely correlated with aortic distensability (ρ= -0.301, P=0.02). There was no association or correlation with measures of systolic function. Notably, in analyses adjusted for respective baseline variables, ΔIGFBP7 was significantly correlated with Δ in E (ρ=0.114), E/A (ρ=0.225), E/e’ (ρ=0.174), and RVSP (ρ=0.282; all P&lt;0.03). Elevated BL IGFBP7 was associated with lower BL VO2 max (13.2 versus 11.1 mL/min/kg; P&lt;0.001) and ΔIGFBP7 was inversely correlated with ΔVO2 max (ρ=-0.19, P=0.01). Subjects receiving sildenafil had a decrease in IGFBP7 over 6M in contrast to placebo-treated patients (median ΔIGFBP7 -1.5 versus +13.6 ng/mL; P&lt;0.001). Conclusions: In patients with HFpEF, concentrations of IGFBP7 have unique relationships with measures of diastolic dysfunction and VO2 max . Rise in IGFBP7 may reflect worsening diastology and deteriorating VO2 max .

Reference intervals of urinary acute kidney injury (AKI) markers [IGFBP7]∙[TIMP2] in apparently healthy subjects and chronic comorbid subjects without AKI

Insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) have demonstrated significantly improved diagnostic performance in assessing risk for acute kidney injury (AKI) compared with existing biomarkers. We present the findings of a multi-site trial to determine the reference intervals for these biomarkers in apparently healthy adults and those with stable chronic morbid conditions without AKI. A urine specimen was collected from apparently healthy subjects (N=378) and subjects with at least one stable chronic morbidity (N=372). Specimens were kept frozen until analysis with the NephroCheck® Test (Astute Medical). The test is comprised of fluorescence immunoassays for IGFBP7 and TIMP-2 and is used with the Astute140® Meter which quantifies the concentration of each biomarker. The meter multiplies the concentrations of IGFBP7 and TIMP-2 and displays the result as a numerical value ([IGFBP7]∙[TIMP-2]) expressed in (ng/ml)(2)/1000 which is called the AKIRisk™ Score. The reference intervals (inner 95%) for [IGFBP7]∙[TIMP-2] in all subjects (N=750), apparently healthy subjects, and subjects with stable chronic morbidities were 0.04-2.22, 0.04-2.25, and 0.05-2.20 (ng/ml)(2)/1000 respectively. There was no statistical difference between reference intervals for apparently healthy and chronic stable morbid cohorts (p=0.42). Our investigation showed that urine [IGFBP7]∙[TIMP-2] values were not elevated in patients with stable chronic morbidities who did not have AKI.