N-terminal pro-brain natriuretic peptide is associated with a future diagnosis of cancer in patients with coronary artery disease

Objective Several papers have reported elevated plasma levels of natriuretic peptides in patients with a previous diagnosis of cancer. We have explored whether N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels predict a future diagnosis of cancer in patients with coronary artery disease (CAD). Methods We studied 699 patients with CAD free of cancer. At baseline, NT-proBNP, galectin-3, monocyte chemoattractant protein-1, soluble tumor necrosis factor-like weak inducer of apoptosis, high-sensitivity C-reactive protein, and high-sensitivity cardiac troponin I plasma levels were assessed. The primary outcome was new cancer diagnosis. The secondary outcome was cancer diagnosis, heart failure requiring hospitalization, or death. Results After 2.15±0.98 years of follow-up, 24 patients developed cancer. They were older (68.5 [61.5, 75.8] vs 60.0 [52.0, 72.0] years; p=0.011), had higher NT-proBNP (302.0 [134.8, 919.8] vs 165.5 [87.4, 407.5] pg/ml; p=0.040) and high-sensitivity C-reactive protein (3.27 [1.33, 5.94] vs 1.92 [0.83, 4.00] mg/L; p=0.030), and lower triglyceride (92.5 [70.5, 132.8] vs 112.0 [82.0, 157.0] mg/dl; p=0.044) plasma levels than those without cancer. NT-proBNP (Hazard Ratio [HR]=1.030; 95% Confidence Interval [CI]=1.008-1.053; p=0.007) and triglyceride levels (HR=0.987; 95%CI=0.975-0.998; p=0.024) were independent predictors of a new cancer diagnosis (multivariate Cox regression analysis). When patients in whom the suspicion of cancer appeared in the first one-hundred days after blood extraction were excluded, NT-proBNP was the only predictor of cancer (HR=1.061; 95% CI=1.034-1.088; p<0.001). NT-proBNP was an independent predictor of cancer, heart failure, or death (HR=1.038; 95%CI=1.023-1.052; p<0.001) along with age, and use of insulin and acenocumarol. Conclusions NT-proBNP is an independent predictor of malignancies in patients with CAD. New studies in large populations are needed to confirm these findingsThis work was supported by grants from Fondo de Investigaciones Sanitarias (PI05/0451, PI05/1497,PI05/2475, PI05/1043, PS09/01405, PI10/ 00072, and PI10/0234, PI14/1567, Programa de Estabilización to LBC); Spanish Society of Cardiology and Spanish Heart Foundation; Spanish Society of Arteriosclerosis; RECAVA (RD06/0014/0035, www. recava.com); Fundación Lilly; and Instituto de Salud Carlos III FEDER (FJD biobank: RD09/0076/00101)

Important abnormalities of bone mineral metabolism are present in patients with coronary artery disease with a mild decrease of the estimated glomerular filtration rate

The final publication is avilable at: Journal of Bone and Mineral Metabolism 30.9 (2015): 1-34Chronic kidney disease (CKD)–mineral and bone disorder (MBD) is characterized by increased circulating levels of parathormone (PTH) and fibroblast growth factor 23 (FGF23), bone disease, and vascular calcification, and is associated with adverse outcomes. We studied the prevalence of mineral metabolism disorders, and the potential relationship between decreased estimated glomerular filtration rate (eGFR) and CKD-MBD in coronary artery disease patients in a cross-sectional study of 704 outpatients 7.5 ± 3.0 months after an acute coronary syndrome. The mean eGFR (CKD Epidemiology Collaboration formula) was 75.8 ± 19.1 ml/min/1.73 m2. Our patients showed lower calcidiol plasma levels than a healthy cohort from the same geographical area. In the case of men, this finding was present despite similar creatinine levels in both groups and older age of the healthy subjects. Most patients (75.6 %) had an eGFR below 90 ml/min/1.73 m2 (eGFR categories G2–G5), with 55.3 % of patients exhibiting values of 60–89 ml/min/1.73 m2 (G2). PTH (r = −0.3329, p < 0.0001) and FGF23 (r = −0.3641, p < 0.0001) levels inversely correlated with eGFR, whereas calcidiol levels and serum phosphate levels did not. Overall, PTH levels were above normal in 34.9 % of patients. This proportion increased from 19.4 % in G1 category patients, to 33.7 % in G2 category patients and 56.6 % in G3–G5 category patients (p < 0.001). In multivariate analysis, eGFR and calcidiol levels were the main independent determinants of serum PTH. The mean FGF23 levels were 69.9 (54.6–96.2) relative units (RU)/ml, and 33.2 % of patients had FGF23 levels above 85.5 RU/ml (18.4 % in G1 category patients, 30.0 % in G2 category patients, and 59.2 % in G3–G5 category patients; p < 0.001). In multivariate analysis, eGFR was the main predictor of FGF23 levels. Increased phosphate levels were present in 0.7 % of the whole sample: 0 % in G1 category patients, 0.3 % in G2 category patients, and 2.8 % in G3–G5 category patients (p = 0.011). Almost 90 % of patients had calcidiol insufficiency without significant differences among the different degrees of eGFR. In conclusion, in patients with coronary artery disease there is a large prevalence of increased FGF23 and PTH levels. These findings have an independent relationship with decreased eGFR, and are evident at an eGFR of 60–89 ml/min/1.73 m2. Then, mild decreases in eGFR must be taken in consideration by the clinician because they are associated with progressive abnormalities of mineral metabolismFondo de Investigaciones Sanitarias (PI10/00072, PI14/00386, PIE13/00051, PI05/0451, PI05/1497, PI05/52475, PI05/1043, PS09/01405, PI14/1567) y FRIAT, Spanish Society of Cardiology, Spanish Heart Foundation, Spanish Society of Arteriosclerosis, REDINREN (RD012/0021), Biobank grants from Instituto de Salud Carlos III FEDER, RD09/0076/00101 (FJD Biobank) and Abbvie Laboratories. PN I+D+I 2008-2011 and ISCIII co-financed by FEDER, CIBERDEM and e-PREDIC

Differential profile in inflammatory and mineral metabolism biomarkers in patients with ischemic heart disease without classical coronary risk factors

AbstractBackgroundPatients with coronary heart disease (CHD) without classical cardiovascular risk factors (CRFs) are uncommon, and their profile has not been thoroughly studied. In CHD patients, we have assessed the differences in several biomarkers between those with and without CRF.MethodsWe studied 704 patients with CHD, analyzing plasma levels of biomarkers related to inflammation, thrombosis, renal damage, and heart failure: high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein-1 (MCP-1), galectin-3, N-terminal fragment of brain natriuretic peptide (NT-pro-BNP), calcidiol (vitamin D metabolite), fibroblast growth factor-23 (FGF-23), parathormone, and phosphate.ResultsTwenty patients (2.8%) exhibited no CRFs. Clinical variables were well balanced in both groups, with the logical exceptions of no use of antidiabetic drugs, lower triglyceride and glucose, and higher high-density lipoprotein cholesterol in no-CRF patients.No-CRF patients showed lower hs-CRP (2.574±3.120 vs. 4.554±9.786mg/L; p=0.018), MCP-1 (114.75±36.29 vs. 143.56±65.37pg/ml; p=0.003), and FGF-23 (79.28±40.22 vs. 105.17±156.61RU/ml; p=0.024), and higher calcidiol (23.66±9.12 vs. 19.49±8.18ng/ml; p=0.025) levels. At follow-up, 10.0% vs. 11.0% patients experienced acute ischemic event, heart failure, or death in the non-CRF and CRF groups, respectively (p=0.815, log-rank test). The limited number of non-CRF patients may have influenced this finding. A Cox regression analysis in the whole population showed that high calcidiol, and low MCP-1 and FGF-23 plasma levels are associated with a better prognosis.ConclusionsCHD patients without CRFs show a favorable biomarker profile in terms of inflammation and mineral metabolism. Further studies are needed to investigate whether this difference translates into a better prognosis

Mcp-1 predicts recurrent cardiovascular events in patients with persistent inflammation

Clinical data indicate that patients with C-reactive protein (CRP) levels higher than 2 mg per liter suffer from persistent inflammation, which is associated with high risk of cardiovascular disease (CVD). We determined whether a panel of biomarkers associated with CVD could predict recurrent events in patients with low or persistent inflammation and coronary artery disease (CAD). We followed 917 patients with CAD (median 4.59 ± 2.39 years), assessing CRP, galectin-3, monocyte chemoattractant protein-1 (MCP-1), N-terminal fragment of brain natriuretic peptide (NT-proBNP) and troponin-I plasma levels. The primary outcome was the combination of cardiovascular events (acute coronary syndrome, stroke or transient ischemic event, heart failure or death). Patients with persistent inflammation (n = 343) showed higher NT-proBNP and MCP-1 plasma levels compared to patients with CRP &lt; 2 mg/L. Neither MCP-1 nor NT-proBNP was associated with primary outcome in patients with CRP &lt; 2 mg/L. However, NT-proBNP and MCP-1 plasma levels were associated with increased risk of the primary outcome in patients with persistent inflammation. When patients were divided by type of event, MCP-1 was associated with an increased risk of acute ischemic events. A significant interaction between MCP-1 and persistent inflammation was found (synergy index: 6.17 (4.39–7.95)). In conclusion, MCP-1 plasma concentration is associated with recurrent cardiovascular events in patients with persistent inflammation.This research was funded by grants from Fondo de Investigaciones Sanitarias (PI14/1567, PI05/0451, PI16/01419, PI17/01615, PI17/01495, PI19/00128); RETOS-Colaboración (RTC2019-006826-1); Spanish Society of Arteriosclerosis; and Instituto de Salud Carlos III FEDER (FJD biobank: RD09/0076/00101

Parathormone levels add prognostic ability to N-terminal pro-brain natriuretic peptide in stable coronary patients

Aims: There are controversial data on the ability of the components of mineral metabolism (vitamin D, phosphate, parathormone [PTH], fibroblast growth factor-23 [FGF23], and klotho) to predict cardiovascular events. In addition, it is unknown whether they add any prognostic value to other well-known biomarkers. Methods and results: In 969 stable coronary patients, we determined plasma levels of all the aforementioned components of mineral metabolism with a complete set of clinical and biochemical variables, including N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hs-TnI), and high-sensitivity C-reactive protein. Secondary outcomes were ischaemic events (any acute coronary syndrome, stroke, or transient ischaemic attack) and heart failure or death. The primary outcome was a composite of the secondary outcomes. Median follow-up was 5.39 years. Age was 60 (52–72) years. Median glomerular filtration rate was 80.4 (65.3–93.1) mL/min/1.73 m2. One-hundred and eighty-five patients developed the primary outcome. FGF23, PTH, hs-TnI, and NT-proBNP were directly related with the primary outcome on univariate Cox analysis, while Klotho and calcidiol were inversely related. On multivariate analysis, only PTH (HR 1.058 [CI 1.021–1.097]; P = 0.002) and NT-proBNP (HR 1.020 [CI 1.012–1.028]; P 85.5 RU/mL) (P < 0.001) but not in patients with low FGF23 levels (P = 0.551). There was a significant interaction between FGF23 and PTH (P = 0.002). However, there was no significant interaction between PTH and both klotho and calcidiol levels. Conclusions: Parathormone is an independent predictor of cardiovascular events in coronary patients, adding complimentary prognostic information to NT-proBNP plasma levels. This predictive value is restricted to patients with high FGF23 plasma levels. This should be considered in the design of future studies in this field.This work was supported by grants from Instituto de Salud Carlos III (ISCIII) and Fondos FEDER (Fondo Europeo de Desarrollo Regional) European Union (PI05/0451, PI14/1567, PI17/01615, and PI17/01495); Spanish Society of Cardiology; Spanish Society of Arteriosclerosis; RECAVA (Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares) (RD06/0014/0035); and Instituto de Salud Carlos III FEDER (FJD biobank: RD09/0076/00101). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Design and rationale of a multicentre, randomised, double-blind, placebo-controlled clinical trial to evaluate the effect of vitamin D on ventricular remodelling in patients with anterior myocardial infarction: the VITamin D in Acute Myocardial Infarction (VITDAMI) trial

Introduction:Decreased plasma vitamin D (VD) levels are linked to cardiovascular damage. However, clinical trials have not demonstrated a benefit of VD supplements on left ventricular (LV) remodelling. Anterior ST-elevation acute myocardial infarction (STEMI) is the best human model to study the effect of treatments on LV remodelling. We present a proof-of-concept study that aims to investigate whether VD improves LV remodelling in patients with anterior STEMI. Methods and analysis:The VITamin D in Acute Myocardial Infarction (VITDAMI) trial is a multicentre, randomised, double-blind, placebo-controlled trial. 144 patients with anterior STEMI will be assigned to receive calcifediol 0.266 mg capsules (Hidroferol SGC)/15 days or placebo on a 2:1 basis during 12 months. Primary objective:to evaluate the effect of calcifediol on LV remodelling defined as an increase in LV end-diastolic volume >= 10\% (MRI). Secondary objectives:change in LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, diastolic function, sphericity index and size of fibrotic area; endothelial function; plasma levels of aminoterminal fragment of B-type natriuretic peptide, galectin-3 and monocyte chemoattractant protein-1; levels of calcidiol (VD metabolite) and other components of mineral metabolism (fibroblast growth factor-23 (FGF-23), the soluble form of its receptor klotho, parathormone and phosphate). Differences in the effect of VD will be investigated according to the plasma levels of FGF-23 and klotho. Treatment safety and tolerability will be assessed. This is the first study to evaluate the effect of VD on cardiac remodelling in patients with STEMI. Ethics and dissemination: This trial has been approved by the corresponding Institutional Review Board (IRB) and National Competent Authority (Agencia Espanola de Medicamentos y Productos Sanitarios (AEMPS)). It will be conducted in accordance with good clinical practice (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use-Good Clinical Practice (ICH-GCP)) requirements, ethical principles of the Declaration of Helsinki and national laws. The results will be submitted to indexed medical journals and national and international meetings.The VITDAMI trial is an investigator initiated study, sponsored by the Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz (IIS-FJD). Funding has been obtained from Fondo de Investigaciones Sanitarias (PI14/01567; http://www.isciii.es/) and Spanish Society of Cardiology (http://secardiologia.es/). In addition, the study medication has been provided freely by the pharmaceutical Company FAES FARMA S.A. (Leioa, Vizcaya, Spain; http://faesfarma.com/). This company was the only funder who collaborated in study design (IG-H).S

Impacto de los niveles plasmáticos de pro-péptido natriurético tipo B aminoterminal, proteína quimiotáctica de monocitos-1 y galectina 3 en la capacidad predictiva de eventos de la escala clínica LIPID en la enfermedad coronaria estable

This is the peer reviewed version of the following article: Clínica e Investigación en Arterioesclerosis 27.2 (2015) which has been published in final form at http://dx.doi.org/10.1016/j.arteri.2014.06.003Introducción: No existe ninguna herramienta validada para la estratificación de riesgo de lospacientes con enfermedad coronaria estable (ECE). Se ha visto que los niveles plasmáticos dela proteína quimioatractante de monocitos-1 (MCP-1), galectina-3 y pro-péptido natriuréticotipo B aminoterminal (NT-proBNP) tienen valor pronóstico en esta población. Objetivo: Analizar la utilidad pronóstica de la escala clínica de riesgo del estudio Long-TermIntervention with Pravastatin in Ischemic Disease (LIPID) y la mejora de su capacidad predictivaal combinarla con los niveles plasmáticos de MCP-1, galectina-3 y NT-proBNP en pacientes conECE.Métodos y resultados:Se analizaron 706 pacientes con ECE y antecedentes de síndrome coro-nario agudo (SCA). Se realizó un seguimietno de 2,2 ± 0,99 a˜nos. El objetivo primario era laaparición de un evento isquémico (cualquier SCA, infarto cerebral o accidente isquémico tran-sitorio), insuficiencia cardiaca o muerte.La escala clínica de riesgo predijo significativamente el desarrollo del objetivo primario, conun área bajo la curva receiver operating characteristic (ROC) de 0,642 (0,579-0,705); p 21,5 mostró una sensibilidad del 74% y una especificidad del 61% para el desarrollodel objetivo primario (p < 0,001; test de log-rank).Conclusión: Los niveles plasmáticos de MCP-1, galectina-3 y NT-proBNP mejoran la capacidadde la escala clínica LIPID para predecir el pronóstico de los pacientes con ECEIntroduction: At present, there is no tool validated by scientific societies for risk stratificationof patients with stable coronary artery disease (SCAD). It has been shown that plasma levelsof monocyte chemoattractant protein-1 (MCP-1), galectin-3 and pro-B-type natriuretic peptideamino-terminal (NT-proBNP) have prognostic value in this population.Objetive: To analyze the prognostic value of a clinical risk scale published in Long-term Inter-vention with Pravastatin in Ischemic Disease (LIPID) study and determining its predictivecapacity when combined with plasma levels of MCP-1, galectin-3 and NT-proBNP in patientswith SCAD.Methods and results: A total of 706 patients with SCAD and a history of acute coronary syndrome(ACS) were analyzed over a follow up period of 2.2 ± 0.99 years. The primary endpoint was theoccurrence of an ischemic event (any SCA, stroke or transient ischemic attack), heart failure,or death.A clinical risk scale derived from the LIPID study significantly predicted the development ofthe primary endpoint, with an area under the ROC curve (Receiver Operating Characteristic) of0.642 (0.579 to 0.705); P < 0.001. A composite score was developed by adding the scores of theLIPID and scale decile levels of MCP -1, galectin -3 and NT-proBNP. The predictive value improvedwith an area under the curve of 0.744 (0.684 to 0.805); P < 0.001 (P = 0.022 for comparison). Ascore greater than 21.5 had a sensitivity of 74% and a specificity of 61% for the development ofthe primary endpoint (P < 0.001, log -rank test).Conclusion: Plasma levels of MCP-1, galectin -3 and NT-proBNP improve the ability of the LIPIDclinical scale to predict the prognosis of patients with SCADFinanciación Sociedad Española de Arteriosclerosis, FIS (PI: 05/451,05/1497, 05/2475, 05/1043, 09/01405, 10/0234, Programa Estabilización a LBC), Sociedad Española de Cardiología,Fundación Española del Corazón, Ministerio de Ciencia e Innovación (SAF 2010/21852), Comunidad de Madrid (sGEN/0247/2006), Becas de Biobancos del Instituto Car-los III FEDER, RD09/0076/00101 (Biobanco FJD

Enfermedad arterial periférica desconocida en pacientes con síndrome coronario agudo: prevalencia y patrón diferencial de los factores de riesgo cardiovascular tradicionales y emergentes

Introducción y objetivos. La enfermedad arterial/vascular periférica frecuentemente se asocia con enfermedad coronaria. El objetivo es evaluar la prevalencia de factores de riesgo cardiovascular tradicionales y emergentes entre pacientes con síndrome coronario agudo (SCA) con o sin enfermedad vascular periférica. Pacientes y método. Realizamos un estudio prospectivo en 141 pacientes (< 70 años) que ingresaron consecutivamente por síndrome coronario agudo. El diagnóstico de enfermedad arterial periférica (EVP) se basó en un índice tobillo-brazo = 0,9. Se evaluaron los factores de riesgo cardiovascular tradicionales y se midieron las concentraciones séricas de proteína C reactiva, homocisteína, amiloide A, lipoproteína (a), fibrinógeno, apolipoproteína A1 y B100, y microalbuminuria. Además, se determinaron varios genotipos. Resultados. Los pacientes fueron estratificados en 2 grupos de acuerdo con la presencia (n = 37, el 26% del total, grupo SCA-EVP) o ausencia (n = 104, grupo SCA) de enfermedad arterial periférica. Los pacientes del grupo SCA-EVP eran más viejos y tenían una significativa mayor prevalencia de diabetes e hipertensión. Las concentraciones de proteína C reactiva, homocisteína, amiloide A y microalbuminuria fueron significativamente mayores en el grupo SCA-EVP (3,1 frente a 2,18 mg/l [p < 0,05]; 11,45 frente a 9,4 mmol/l [p < 0,01]; 5,2 frente a 3,7 mg/ml [p < 0,05], y 4,89 frente a 3,1 mg/l [p < 0,05], respectivamente). El análisis de regresión logística mostró que la diabetes mal controlada, la exposición al tabaco tiempo-dependiente y la presión de pulso fueron predictores independientes de la presencia de EVP. Conclusiones. Varios factores de riesgo cardiovascular tradicionales y emergentes son más prevalentes en pacientes con SCA y enfermedad arterial periférica, y algunos de ellos son predictores independientes de ésta

Enfermedad arterial periférica desconocida en pacientes con síndrome coronario agudo: prevalencia y patrón diferencial de los factores de riesgo cardiovascular tradicionales y emergentes

Introducción y objetivos. La enfermedad arterial/vascular periférica frecuentemente se asocia con enfermedad coronaria. El objetivo es evaluar la prevalencia de factores de riesgo cardiovascular tradicionales y emergentes entre pacientes con síndrome coronario agudo (SCA) con o sin enfermedad vascular periférica. Pacientes y método. Realizamos un estudio prospectivo en 141 pacientes (< 70 años) que ingresaron consecutivamente por síndrome coronario agudo. El diagnóstico de enfermedad arterial periférica (EVP) se basó en un índice tobillo-brazo = 0,9. Se evaluaron los factores de riesgo cardiovascular tradicionales y se midieron las concentraciones séricas de proteína C reactiva, homocisteína, amiloide A, lipoproteína (a), fibrinógeno, apolipoproteína A1 y B100, y microalbuminuria. Además, se determinaron varios genotipos. Resultados. Los pacientes fueron estratificados en 2 grupos de acuerdo con la presencia (n = 37, el 26% del total, grupo SCA-EVP) o ausencia (n = 104, grupo SCA) de enfermedad arterial periférica. Los pacientes del grupo SCA-EVP eran más viejos y tenían una significativa mayor prevalencia de diabetes e hipertensión. Las concentraciones de proteína C reactiva, homocisteína, amiloide A y microalbuminuria fueron significativamente mayores en el grupo SCA-EVP (3,1 frente a 2,18 mg/l [p < 0,05]; 11,45 frente a 9,4 mmol/l [p < 0,01]; 5,2 frente a 3,7 mg/ml [p < 0,05], y 4,89 frente a 3,1 mg/l [p < 0,05], respectivamente). El análisis de regresión logística mostró que la diabetes mal controlada, la exposición al tabaco tiempo-dependiente y la presión de pulso fueron predictores independientes de la presencia de EVP. Conclusiones. Varios factores de riesgo cardiovascular tradicionales y emergentes son más prevalentes en pacientes con SCA y enfermedad arterial periférica, y algunos de ellos son predictores independientes de ésta

Use of Proton-Pump Inhibitors Predicts Heart Failure and Death in Patients with Coronary Artery Disease.

Proton-pump inhibitors (PPIs) seem to increase the incidence of cardiovascular events in patients with coronary artery disease (CAD), mainly in those using clopidogrel. We analysed the impact of PPIs on the prognosis of patients with stable CAD.We followed 706 patients with CAD. Primary outcome was the combination of secondary outcomes. Secondary outcomes were 1) acute ischaemic events (any acute coronary syndrome, stroke, or transient ischaemic attack) and 2) heart failure (HF) or death.Patients on PPIs were older [62.0 (53.0-73.0) vs. 58.0 (50.0-70.0) years; p = 0.003] and had a more frequent history of stroke (4.9% vs. 1.1%; p = 0.004) than those from the non-PPI group, and presented no differences in any other clinical variable, including cardiovascular risk factors, ejection fraction, and therapy with aspirin and clopidogrel. Follow-up was 2.2±0.99 years. Seventy-eight patients met the primary outcome, 53 developed acute ischaemic events, and 33 HF or death. PPI use was an independent predictor of the primary outcome [hazard ratio (HR) = 2.281 (1.244-4.183); p = 0.008], along with hypertension, body-mass index, glomerular filtration rate, atrial fibrillation, and nitrate use. PPI use was also an independent predictor of HF/death [HR = 5.713 (1.628-20.043); p = 0.007], but not of acute ischaemic events. A propensity score showed similar results.In patients with CAD, PPI use is independently associated with an increased incidence of HF and death but not with a high rate of acute ischaemic events. Further studies are needed to confirm these findings