Fibroblast growth factor 23 independently predicts adverse outcomes after an acute coronary syndrome.

AIMS: Abnormalities of mineral metabolism (MM) have been related to cardiovascular disorders. There are no reports on the prognostic role of MM after an acute coronary syndrome (ACS). We aim to assess the prognostic role of MM after an ACS. METHODS AND RESULTS: Plasma levels of components of MM [fibroblast growth factor 23 (FGF23), calcidiol, parathormone, klotho, and phosphate], high-sensitivity C-reactive protein, and N-terminal-pro-brain natriuretic peptide were measured in 1190 patients at discharge from an ACS. The primary outcome was a combination of acute ischaemic events, heart failure (HF) and death. Secondary outcomes were the separate components of the primary outcome. Age was 61.7 ± 12.2 years, and 77.1% were men. Median follow-up was 5.44 (3.03-7.46) years. Two hundred and ninety-four patients developed the primary outcome. At multivariable analysis FGF23 (hazard ratio, HR 1.18 [1.08-1.29], P < 0.001), calcidiol (HR 0.86 [0.74-1.00], P = 0.046), previous coronary or cerebrovascular disease, and hypertension were independent predictors of the primary outcome. The predictive power of FGF23 was homogeneous across different subgroups of population. FGF23 (HR 1.45 [1.28-1.65], P < 0.001) and parathormone (HR 1.06 1.01-1.12]; P = 0.032) resulted as independent predictors of HF. FGF23 (HR 1.21 [1.07-1.37], P = 0.002) and calcidiol (HR 0.72 [0.54-0.97), P = 0.028) were independent predictors of death. No biomarker predicted acute ischaemic events. FGF23 predicted independently the primary outcome in patients with estimated glomerular filtration rate > 60 mL/min/1.73 m2 . CONCLUSIONS: FGF23 and other components of MM are independent predictors of HF and death after an ACS. This effect is homogeneous across different subgroups of population, and it is not limited to patients with chronic kidney disease.

Early and late onset cardiotoxicity following anthracycline-based chemotherapy in breast cancer patients: Incidence and predictors.

INTRODUCTION: Cardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data on longitudinal studies about early and late onset cardiotoxicity in this group of patients is scarce. The objective of the present study was to assess predictors of early and late onset cardiotoxicity in patients with breast cancer treated with A. METHODS: 100 consecutive patients receiving anthracycline-based chemotherapy (CHT) to treat breast cancer were included in this prospective study. All patients underwent evaluation at baseline, at the end of CHT, 3 months after the end of CHT and 1 and 4 years after the beginning of CHT. Clinical data, systolic and diastolic echo parameters and cardiac biomarkers including high sensitivity Troponin T (TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP) and Heart-type fatty acid binding protein (H-FABP) were assessed. RESULTS: Mean doxorubicin dose was 243 mg/m2. Mean follow-up was 51.8 ± 8.2 months. At one-year incidence of anthracycline related-cardiotoxicity (AR-CT) was 4% and at the end of follow-up was 18% (15 patients asymptomatic left ventricular systolic dysfunction, 1 patients heart failure and 2 patients a sudden cardiac death). Forty-nine patients developed diastolic dysfunction (DD) during first year. In the univariate analysis DD during first year was the only parameter associated with AR-CT (Table 1). In the logistic regression model DD was independently related with the development of AR-CT, with an odds ratio value of 7.5 (95% CI 1.59-35.3). CONCLUSIONS: Incidence of late-onset cardiotoxicity is high but mostly subclinical. Diastolic dysfunction early after chemotherapy is a strong predictor of anthracycline cardiotoxicity.

N-Terminal Pro-Brain Natriuretic Peptide Plasma Levels Are Associated with Intermediate-Term Follow-Up Cancer in Coronary Patients.

N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels are increased in patients with cancer. In this paper, we test whether NT-proBNP may identify patients who are going to receive a future cancer diagnosis (CD) in the intermediate-term follow-up. We studied 962 patients with stable coronary artery disease and free of cancer and heart failure at baseline. This sample represents a re-analysis of a previous work expanding the sample size and the follow-up. NT-proBNP, galectin-3, monocyte chemoattractant protein-1, high-sensitivity C-reactive protein, high-sensitivity cardiac troponin I (hsTnI), and calcidiol (vitamin D) plasma levels were assessed. The primary outcome was new CD. After 5.40 (2.81-6.94) years of follow-up, 59 patients received a CD. NT-proBNP [HR 1.036 CI (1.015-1.056) per increase in 100 pg/mL; p = 0.001], previous atrial fibrillation (HR 3.140 CI (1.196-8.243); p = 0.020), and absence of previous heart failure (HR 0.067 CI (0.006-0.802); p = 0.033) were independent predictors of receiving a CD in the first three years of follow-up. None of the variables analyzed predicted a CD beyond this time. The number of patients developing heart failure during follow-up was 0 (0.0%) in patients receiving CD in the first three years of follow-up, 2 (6.9%) in those receiving a CD diagnosis beyond this time, and 40 (4.4%) in patients not developing cancer (p = 0.216). These numbers suggest that future heart failure was not a confounding factor. In patients with coronary artery disease, NT-proBNP was an independent predictor of CD in the first three years of follow-up but not later, suggesting that it could be detecting subclinical undiagnosed cancers.

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

Chronic 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 m(2). 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 m(2) (eGFR categories G2-G5), with 55.3 % of patients exhibiting values of 60-89 ml/min/1.73 m(2) (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 m(2). Then, mild decreases in eGFR must be taken in consideration by the clinician because they are associated with progressive abnormalities of mineral metabolism.

Diastolic Dysfunction Following Anthracycline-Based Chemotherapy in Breast Cancer Patients: Incidence and Predictors.

INTRODUCTION: Cardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data from longitudinal studies of diastolic dysfunction (DD) in this group of patients are scarce. The objective of the present study was to assess the incidence, evolution, and predictors of DD in patients with breast cancer treated with anthracyclines. METHODS: This analytical, observational cohort study comprised 100 consecutive patients receiving anthracycline-based chemotherapy (CHT) for breast cancer. All patients underwent clinical evaluation, echocardiogram, and measurement of cardiac biomarkers at baseline, end of anthracycline-based CHT, and at 3 months and 9 months after anthracycline-based CHT was completed. Fifteen patients receiving trastuzumab were followed with two additional visits at 6 and 12 months after the last dose of anthracycline-based CHT. A multivariate analysis was performed to find variables related to the development of DD. Fifteen of the 100 patients had baseline DD and were excluded from this analysis. RESULTS: At the end of follow-up (median: 12 months, interquartile range: 11.1-12.8), 49 patients (57.6%) developed DD. DD was persistent in 36 (73%) but reversible in the remaining 13 patients (27%). Four patients developed cardiotoxicity (three patients had left ventricular systolic dysfunction and one suffered a sudden cardiac death). None of the patients with normal diastolic function developed systolic dysfunction during follow-up. In the logistic regression model, body mass index (BMI) and age were independently related to the development of DD, with the following odds ratio values: BMI: 1.19 (95% confidence interval [CI]: 1.04-1.36), and age: 1.12 (95% CI: 1.03-1.19). Neither cardiac biomarkers nor remaining clinical variables were predictors of DD. CONCLUSION: Development of diastolic dysfunction after treatment with anthracycline or anthracycline- plus trastuzumab chemotherapy is common. BMI and age were independently associated with DD following anthracycline chemotherapy.

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 findings.

Usefulness of a combination of monocyte chemoattractant protein-1, galectin-3, and N-terminal probrain natriuretic peptide to predict cardiovascular events in patients with coronary artery disease.

Patients with coronary artery disease may develop not only ischemic events but also heart failure and death due to previous myocardial damage. The purpose of this study was to test the prognostic value of a panel of plasma biomarkers related to vascular (monocyte chemoattractant protein-1 [MCP-1] and soluble tumor necrosis factor-like weak inducer of apoptosis) and myocardial damage (galectin-3, N-terminal fragment of brain natriuretic peptide [NT-proBNP], and neutrophil gelatinase-associated lipocalin) in 706 patients with chronic coronary artery disease followed for 2.2 ± 0.99 years. Secondary outcomes were the incidence of acute ischemic events (ST elevation myocardial infarction, non-ST elevation acute coronary syndrome, stroke, or transient ischemic attack) and death or heart failure. The primary outcome was the combination of the secondary outcomes. Cox proportional hazards model was used for analysis. Fifty-three patients developed acute ischemic events. Increasing MCP-1 plasma levels (p = 0.002), age, and body mass index predicted this outcome independently. Thirty-three patients developed death and/or heart failure. Galectin-3 (p = 0.007), NT-proBNP plasma levels (p = 0.004), hypertension, glomerular filtration rate, and the use of nitrates and anticoagulants were associated with this outcome independently. The development of the primary outcome was predicted independently by MCP-1 (p <0.001), NT-proBNP (p = 0.005), and galectin-3 (p = 0.019); hypertension; atrial fibrillation; and treatment with nitrates. Every biomarker with a value above the median increased the risk of developing this outcome by 1.832 (95% confidence interval 1.356 to 2.474, p <0.001). High-sensitivity C-reactive protein and lipid levels were not associated with any outcome. In conclusion, increasing MCP-1, galectin-3, and NT-proBNP plasma levels are associated with a greater incidence of cardiovascular events.

Apoptosis and acute cellular rejection in human heart transplants.

INTRODUCTION AND OBJECTIVES: Apoptosis has been implicated in the pathophysiology of various forms of heart disease. Acute cellular rejection leads to morbidity after heart transplantation and invasive techniques are needed for its diagnosis. We investigated the presence of cardiomyocyte apoptosis in transplanted hearts, its progression, its relationship with rejection, and the possibility that serological markers of apoptosis can be used to detect rejection noninvasively. METHODS: Overall, 130 endomyocardial biopsies obtained sequentially from 14 consecutive patients during the first 6 months following heart transplantation underwent histochemical analysis. The degree of acute rejection was determined, myocyte apoptosis was assessed using the TUNEL method, and caspase-3 activity was measured. In the first 10 patients, soluble Fas, tumor necrosis factor-alpha (TNFα) and interleukin 6 levels were determined in serum collected at biopsy. RESULTS: Apoptotic cells were detected in 81.5% of biopsies. No significant correlation was found between the apoptotic index and either the degree of rejection or the time from transplantation; there was only a trend to higher values during prolonged episodes of rejection, which did not reach statistical significance. An inverse correlation was observed between the degree of rejection and the TNFα level (rs=-0.33; P=.003). There was no correlation with any other variable. CONCLUSIONS: Cardiomyocyte loss due to apoptosis was observed in transplanted hearts, but no correlation was observed with either acute rejection or the time from transplantation. Our findings suggest there could be an inverse correlation between rejection and the serum TNFα level. No serum parameter evaluated was regarded as suitable for the noninvasive diagnosis of acute rejection.