Circulating fibroblast growth factor-23 plasma levels predict adverse cardiovascular outcomes in patients with diabetes mellitus with coronary artery disease.

BACKGROUND: Abnormalities of fibroblast growth factor-23 (FGF-23) plasma levels predict adverse outcomes in patients with coronary artery disease. However, FGF-23 has a different behaviour in the presence of type 2 diabetes mellitus (T2D). We explored whether the presence of T2D affects the predictive power of FGF-23. METHODS: In 704 patients with stable coronary artery disease, FGF-23, calcidiol, parathormone (PTH) and phosphate plasma levels were prospectively assessed. The primary outcome was the development of acute ischemic events (acute coronary syndrome, stroke or transient ischemic attack), heart failure or death. RESULTS: One hundred seventy-three (24.6%) patients had T2D, without differences in age, sex or estimated glomerular filtration rate as compared with non-diabetic patients. Serum PTH was lower and phosphate higher in T2D than in non-diabetic patients, without differences in FGF-23 or calcidiol levels. During follow-up (2.15 ± 0.99 years), 26 (15.2%) T2D and 51 (9.6%) non-diabetic patients developed the outcome (p = 0.048). T2D patients who developed the outcome had higher FGF-23 [112.0 (59.9, 167.6) vs 68.9 (54.2, 93.0) RU/mL; p = 0.002], PTH [71.3 (47.3, 106.6) vs 51.9 (40.8, 66.2) pg/mL; p = 0.004) and phosphate (3.53 ± 0.71 vs 3.25 ± 0.50 mg/dL; p = 0.017) levels than T2D subjects who remained stable. These differences were not significant in non-diabetic patients. By multivariable Cox proportional hazard model, FGF-23 predicted independently the outcome in T2D patients [hazard ratio = 1.277; 95% CI (1.132, 1.442)] but not in those without T2D. CONCLUSIONS: FGF-23 plasma levels predict adverse cardiovascular outcomes in coronary artery disease patients who have T2D but not in those without T2D. This finding should be confirmed in larger studies. Copyright © 2016 John Wiley & Sons, Ltd.

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.

The Prognostic Value of High-Sensitive Troponin I in Stable Coronary Artery Disease Depends on Age and Other Clinical Variables.

OBJECTIVES: To study the prognostic value of high-sensitive troponin (hs-cTn) I in stable coronary artery disease. METHODS: In total, we studied 705 patients. Secondary outcomes were the incidence of: (1) acute ischemic events and (2) heart failure or death. The primary outcome was the composite of them. RESULTS: Patients with hs-cTnI >0 ng/ml (62.1%) were older, had a lower estimated glomerular filtration rate, more frequent a history of hypertension, atrial fibrillation, ejection fraction <40%, and therapy with angiotensin-converting enzyme inhibitors, diuretics and acenocumarol. The follow-up period was 2.2 ± 0.99 years. Fifty-three patients suffered an acute ischemic event, 33 died or suffered heart failure and 78 developed the primary outcome. By univariate Cox's regression analysis, hs-cTnI >0 was associated with a higher risk of developing the primary outcome [relative risk = 2.360 (1.359-4.099); p = 0.001] and heart failure or death [relative risk = 5.932 (1.806-19.482); p < 0.001], but not with acute ischemic events. Statistical significance was lost after controlling for age. By logistic regression analysis, age [relative risk = 1.026 (1.009-1.044); p = 0.003], ejection fraction <40% [relative risk = 4.099 (2.043-8.224); p < 0.001], use of anticoagulants [relative risk = 2.785 (1.049-7.395); p = 0.040] and therapy with angiotensin-converting enzyme inhibitors [relative risk = 1.471 (1.064-2.034); p = 0.020], and estimated glomerular filtration rate [relative risk = 0.988 (0.977-0.999); p = 0.027] were associated with hs-cTnI >0. CONCLUSIONS: In stable coronary disease, hs-cTnI is associated with the incidence of heart failure or death, but this relationship depends on other variables.

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.

Cardiac Rehabilitation Increases Plasma Klotho Levels.

Background: Mineral metabolism (MM), mainly fibroblast growth factor-23 (FGF-23) and klotho, has been linked to cardiovascular (CV) diseases. Cardiac rehabilitation (CR) has been demonstrated to reduce CV events, although its potential relationship with changes in MM is unknown. Methods: We performed a prospective, observational, case-control study, with acute coronary syndrome (ACS) patients who underwent CR and control patients (matched by age, gender, left ventricular ejection fraction, diabetes, and coronary artery bypass grafting), who did not. The inclusion dates were from August 2013 to November 2017 in CR group and from July 2006 to June 2014 in control group. Clinical, biochemical, and MM biomarkers were collected at discharge and six months later. Our objective was to evaluate differences in the modification pattern of MM in both groups. Results: We included 58 CR patients and 116 controls. The control group showed a higher prevalence of hypertension (50.9% vs. 34.5%), ST-elevated myocardial infarction (59.5% vs. 29.3%), and treatment with angiotensin-converting enzyme inhibitors (100% vs. 69%). P2Y12 inhibitors and beta-blockers were more frequently prescribed in the CR group (83.6% vs. 96.6% and 82.8% vs. 94.8%, respectively). After six months, klotho levels increased in CR patients whereas they were reduced in controls (+63 vs. -49 pg/mL; p < 0.001). FGF-23 was unchanged in the CR group and reduced in controls (+0.2 vs. -17.3 RU/dL; p < 0.003). After multivariate analysis, only the change in klotho levels was significantly different between groups (+124 pg/mL favoring CR group; IC 95% [+44 to +205]; p = 0.003). Conclusions: In our study, CR after ACS increases plasma klotho levels without significant changes in other components of MM. Further studies are needed to clarify whether this effect has a causal role in the clinical benefit of CR.

Absence of High Lipoprotein(a) Levels Is an Independent Predictor of Acute Myocardial Infarction without Coronary Lesions.

The pathophysiological mechanisms underlying Myocardial Infarction with Non-Obstructive Coronary Artery Disease (MINOCA) are still under debate. Lipoprotein (a) [Lp(a)] has proinflammatory and prothrombotic actions and has been involved in the pathogenesis of atherosclerosis. However, no previous studies have linked Lp(a) levels with the probability of developing MINOCA. Moreover, the relationship between MINOCA and the plasma levels of other proatherogenic and proinflammatory molecules such as Interleukin-18 (IL18) and proprotein convertase subtilisin/kexin type 9 (PCSK9) has not been studied. We conducted a prospective, multicenter study involving 1042 patients with acute myocardial infarction (AMI). Seventy-six patients had no significant coronary lesions. All patients underwent plasma analysis on admission. MINOCA patients were younger (57 (47-68) vs. 61 (52-72) years; p = 0.010), more frequently female (44.7% vs. 21.0%; p < 0.001), and had lower rates of diabetes and of Lp(a) > 60 mg/dL (9.2% vs. 19.8%; p = 0.037) than those with coronary lesions; moreover, High Density Lipoprotein cholesterol (HDL-c) levels were higher in MINOCA patients. The absence of Lp(a) > 60 mg/dL and of diabetes were independent predictors of MINOCA, as well as female sex, high HDL-c levels, and younger age. IL-18 and PCSK9 levels were not predictors of MINOCA. During a follow-up of 5.23 (2.89, 7.37) years, the independent predictors of the primary outcome (acute ischemic events or death) in the whole sample were Lp(a) > 60 mg/dL, older age, low estimated Glomerular Filtration rate (eGFR), hypertension, previous heart failure (HF), coronary artery bypass graft, use of insulin, and no therapy with acetylsalicylic acid. In conclusion, in AMI patients, the absence of high Lp(a) levels, as well high HDL-c levels, were independent predictors of the inexistence of coronary artery disease. High Lp (a) levels were also an independent predictor of ischemic events or death.

NT-proBNP Levels Influence the Prognostic Value of Mineral Metabolism Biomarkers in Coronary Artery Disease.

Background. Mineral metabolism (MM) system and N-terminal pro-brain natriuretic peptide (NT-ProBNP) have been shown to add prognostic value in patients with stable coronary artery disease (SCAD). However, the influence of NT-ProBNP on the prognostic role of MM in patients with SCAD has not been shown yet. The objective of this study is to assess the influence of NT-ProBNP on the prognostic role of MM markers in patients with SCAD. Methods: We analyzed the prognostic value of MM markers (parathormone (PTH), klotho, phosphate, calcidiol (25-hydroxyvitamin D3), and fibroblast growth factor-23) in 964 patients with SCAD and NT-ProBNP > 125 pg/mL vs. patient with NT-ProBNP ≤ 125 pg/mL included in five hospitals in Spain. The main outcome was the combination of death, heart failure, and ischemic events (any acute coronary syndrome, ischemic stroke, or transient ischemic attack). Results: A total of 622 patients had NT-proBNP > 125 pg/mL and 342 patients had NT-ProBNP ≤ 125 pg/mL. The median follow-up was 5.1 years. In the group of NT-proBNP > 125 pg/mL, the patients were older, and there were more females and smokers than in the group of patients with normal NT-proBNP. Additionally, the proportion of patients with hypertension, atrial fibrillation, ejection fraction < 40%, cerebrovascular attack, or prior coronary artery bypass graft was higher in the high NT-proBNP group. In the high NT-proBNP patients, the predictors of poor prognosis were PTH (HR = 1.06 (1.01−1.10), p < 0.001) and NT-proBNP (HR = 1.02 (1.01−1.03), p = 0.011), along with age (HR = 1.039 (1.02−1.06), p < 0.001), prior coronary artery bypass graft (HR = 1.624 (1.02−2.59), p = 0.041), treatment with statins (HR = 0.32 (0.19−0.53), p < 0.001), insulin (HR = 2.49 (1.59−4.09), p < 0.001), angiotensin receptor blockers (HR = 1.73 (1.16−2.56), p = 0.007), nitrates (HR = 1.65 (1.10−2.45), p = 0.014), and proton pump inhibitors (HR = 2.75 (1.74−4.36), p < 0.001). In the NT-proBNP ≤ 125 pg/mL subgroup, poor prognosis predictors were plasma levels of non-high-density lipoprotein (non-HDL) cholesterol (HR = 1.01 (1.00−1.02), p = 0.014) and calcidiol (HR = 0.96 (0.92−0.99), p = 0.045), as well as treatment with verapamil (HR = 11.28 (2.54−50.00), p = 0.001), and dihydropyridines (HR = 3.16 (1.63−6.13), p = 0.001). Conclusion: In patients with SCAD and NT-ProBNP > 125 pg/mL, PTH and NT-ProBNP, which are markers related to ventricular damage, are predictors of poor outcome. In the subgroup of patients with NT-ProBNP ≤ 125 pgm/L, calcidiol and non-HDL cholesterol, which are more related to vascular damage, are the independent predictors of poor outcome. Then, in patients with SCAD, baseline NT-ProBNP may influence the type of biomarker that is effective in risk prediction.

Impact of renal function on the prognostic value of mineral metabolism in patients with chronic ischaemic heart disease patients with chronic ischaemic heart disease. / Impacto de la función renal en el valor pronóstico del metabolismo mineral en pacientes con cardiopatía isquémica crónica.

BACKGROUND: Parathormone (PTH) is a component of the Mineral Metabolism (MM) system that has been shown recently to add prognostic value in pts. with stable coronary artery disease (SCAD) and average renal function. However, the influence of renal function on the prognostic role of PTH in pts. with SCAD has not been shown yet. PURPOSE: To assess the influence of estimated glomerular filtration rate (eGFR) on the prognostic role of PTH and other MM markers in pts. with SCAD. METHODS: We analyzed the prognostic value of MM markers (PTH, klotho, phosphate, calcidiol [25-hydroxyvitamin D], and fibroblast growth factor-23 [FGF23]) in 964 pts. with SCAD and eGFR<60ml/min/1.73 m2 (LGFR) vs pts. with eGFR≥60ml/min/1.73 m2 (HGFR) included in five hospitals of Madrid. The main outcome was the combination of death with ischemic events (any acute coronary syndrome, ischemic stroke or transient ischemic attack). eGFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). RESULTS: Age was 60.0 (52.0-72.0) years, 76.2% of patients were men, and eGFR was 80.4 (65.3-93.1) ml/min/1,73 m2. Median follow-up was 5.39 (2.81-6.92) years. There were 790 pts. with HGFR and 174 with LGFR. In HGFR pts., predictors of ischemic events or death were plasma levels of calcidiol [HR=0.023 (0.94-0.99) p=0.023], FGF23 [HR=1.00 (1.00-1.003) p=0.036], non-HDL cholesterol [HR=1.01 (1.00-1.01) p=0.026] and high sensitivity troponin I [HR=5.12 (1.67-15.59) p=0.004], along with age [HR=1.03 (1.01-1.05) p=0.01], treatment with statins [HR=0.36 (0.19-0.68) p=0.002], nitrates [HR=1.13 (1.07-2.79) p=0.027], dihydropyridines [HR=1.71 (1.05-2.77) p=0.032], verapamil [HR=5.71 (1.35-24.1) p=0.018], and proton-pump inhibitors [HR=2.23 (1.36-3.68) p= 0.002]. In the LGFR subgroup, predictors of death or ischemic events were PTH plasma levels, [HR=1.01 (1.00-1.01) p=0.005], eGFR [HR=0.96 (0.94-0.99) p=0.004], age [HR=1.06 (1.02-1.10) p=0.003], caucasian race [HR=0.04 (0.004-0.380) p=0.005], and treatment with insulin [HR=2.6 (1.20-5.63) p=0.015]. CONCLUSIONS: In pts. with SCAD, PTH is an independent predictor of poor outcomes only in those with eGFR<60ml/min/1.73 m2, while in pts. with eGFR≥60ml/min/1.73 m2 calcidiol and FGF23 become the only components of MM that may predict prognosis. Then, renal function influences the predictive power of MM markers in pts. with SCAD.

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 < 2 mg/L. Neither MCP-1 nor NT-proBNP was associated with primary outcome in patients with CRP < 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.

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 < 0.001) were independent predictors of the primary outcome but also for the secondary outcome of heart failure or death (HR 1.066 [CI 1.016-1.119]; P = 0.009 and HR 1.024 [CI 1.014-1.034]; P < 0.001, respectively). PTH was the only biomarker that predicted ischaemic events (HR 1.052 [1.010-1.096]; P = 0.016). Patients were divided in two subgroups according to FGF23 plasma levels. PTH retained its prognostic value only in patients with FGF23 levels above the median (>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.

Atorvastatin modifies the protein profile of circulating human monocytes after an acute coronary syndrome.

Aggressive treatment with high-dose atorvastatin reduces more effectively the incidence of cardiovascular events than moderate statin therapy. The mechanism of this benefit has not been fully elucidated. In order to know the potential effects of statin treatment on the protein expression of circulating monocytes in acute coronary syndrome (ACS) patients, a proteomic analysis of these cells was carried out by 2-DE and MS. Twenty-five patients with non-ST-elevation acute coronary syndrome (NSTEACS) were randomized, the fourth day after admission, to receive ATV 80 mg/dL (n = 14) or conventional treatment (CT) (n = 11), for two months. Blood was withdrawn at the end of the treatment, and monocytes were extracted for proteomic analysis and their protein expression patterns determined. Age, sex, total cholesterol, LDL, HDL, triglycerides, body mass index, presence of hypertension, diabetes, and smoking status were not significantly different between the two groups of patients. The expression of 20 proteins was modified by intensive ATV. Among the most relevant results stand out the normalization by intensive ATV treatment of the expression of proteins that modulate inflammation and thrombosis such as protein disulfide isomerase ER60 (PDI), Annexin I, and prohibitin, or that have other protective effects as HSP-70. Thus, this approach shed light at the molecular level of the beneficial mechanisms of anti-atherothrombotic drugs.

Effect of intensive atorvastatin therapy on prostaglandin E2 levels and metalloproteinase-9 activity in the plasma of patients with non-ST-elevation acute coronary syndrome.

Inflammation plays a pivotal role in the pathophysiology of non-ST elevation acute coronary syndromes (NSTEACS). Intensive statin therapy reduces the recurrence of cardiovascular events after acute coronary syndromes. The aim of this study was to examine nuclear factor-kappa B activity in peripheral blood mononuclear cells, prostaglandin E2 (PGE2) and leukotriene B4 levels, and matrix metalloproteinase-9 (MMP-9) activity in plasma from patients with NSTEACS (at 0 days, 4 days, 2 months, and 6 months), patients with stable coronary artery disease, and healthy controls. On day 4, patients with NSTEACS were randomized to receive atorvastatin 80 mg/day (n = 14) or standard treatment (n = 16) during 2 months to study its effect on these parameters. Nuclear factor-kappa B activity (by electrophoretic mobility shift assay), PGE2 levels (by enzyme-linked immunosorbent assay), and MMP-9 activity (by gelatin zymography) in the plasma of patients with NSTEACS were significantly increased compared with patients with coronary artery disease and healthy controls. At 6 months, MMP-9 activity was normalized, whereas nuclear factor-kappa B activity and PGE2 levels were still increased. Leukotriene B4 plasma levels (by enzyme-linked immunosorbent assay) were similar in patients with NSTEACS and those with coronary artery disease but were significantly higher than those of healthy subjects. There was a significant correlation between plasma PGE2 levels and MMP-9 activity in patients with NSTEACS (r = 0.754, p <0.01). Atorvastatin 80 mg/day reduced circulating PGE2 levels (median 222.4 [interquartile range 157.4 to 253.5] vs 550.8 [276.9 to 613.0] pg/ml, p = 0.006) and MMP-9 activity (0.0025 [0.0017 to 0.0035] vs 0.0280 [0.0057 to 0.0712] arbitrary units, p = 0.03). In conclusion, nuclear factor-kappa B activity in peripheral blood mononuclear cells, and plasma PGE2 levels and MMP-9 activity, increase during NSTEACS. Atorvastatin 80 mg/day normalizes PGE2 levels and MMP-9 activity, providing additional mechanisms by which intensive atorvastatin therapy may reduce the incidence of cardiovascular events.

Long-term safety and efficacy of ivabradine in patients with chronic stable angina.

OBJECTIVE: To assess the long-term safety and antianginal efficacy of two doses of ivabradine, a novel selective and specific inhibitor of the sinus node I(f) current. METHODS: In a randomized double-blind, parallel-group study 386 patients with chronic stable angina were randomized to either ivabradine 5 mg b.i.d. (n = 198, group 1) or ivabradine 7.5 mg b.i.d. (n = 188, group 2) for 12 months. Concomitant medication included antithrombotic agents, lipid-lowering agents, long-acting nitrates and dihydropyridine calcium antagonists. Safety was assessed on the basis of reported adverse events at 1, 3, 6, 9 and 12 months. Antianginal efficacy was based on the reduction in the weekly number of angina attacks and in the consumption of short-acting nitrates from month 0 (baseline) to month 12. RESULTS: Ivabradine was well tolerated. Phosphene-like mild transient visual symptoms were the most frequently reported adverse events but led to treatment withdrawal in only 4 patients. Resting heart rate was reduced by 9 bpm in group 1 and 12 bpm in group 2. Sinus bradycardia caused treatment withdrawal in only three cases. The QTc (Bazett) interval did not increase. At month 12 relative to month 0 there was a significant reduction in the number of angina attacks per week. CONCLUSION: Ivabradine at the recommended doses of 5 and 7.5 mg b.i.d. was well tolerated and demonstrated antianginal efficacy in patients with documented coronary artery disease treated with concomitant antianginal medications.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Effect of combined beta-blocker and angiotensin-converting enzyme inhibitor treatment on 1-year survival after acute myocardial infarction: findings of the PRIAMHO-II registry]. / Efecto de la asociación de bloqueadores beta e inhibidores de la enzima de conversión en la supervivencia al año tras un infarto agudo de miocardio. Resultados del registro PRIAMHO II.

INTRODUCTION AND OBJECTIVES: Clinical trials have shown that combining beta-blockers and angiotensin-converting enzyme (ACE) inhibitors has an additive effect in reducing mortality in patients with left ventricular dysfunction following acute myocardial infarction. Whether this additive effect also occurs in unselected post-myocardial infarction patients is unknown. METHODS: In total, 5397 patients who were discharged from hospital after suffering an acute myocardial infarction were followed for 1 year. The primary endpoint was all-cause mortality. The effects of the medications on 1-year survival were analyzed using a Cox regression model, which included propensity scores for beta-blocker and ACE inhibitor use to take account of any potential imbalance in drug prescription rates. RESULTS: At hospital discharge, 55.9% of patients were receiving beta-blockers and 45.1%, ACE inhibitors. The 1-year mortality rate was 5.5%. Overall, combination of the two medications significantly reduced the 1-year mortality rate (hazard ratio [HR]=0.51; 95% confidence interval [IC], 0.32-0.82); P<.005) to a greater extent than ACE inhibitors alone (HR=0.78; 95% CI, 0.54-1.12; P=.2) or beta-blockers alone (HR=0.67; 95% CI, 0.43-1.05; P=.08). The same trend was also observed in low-risk patients without acute heart failure who had an ejection fraction > or =40%. CONCLUSIONS: In unselected post-myocardial infarction patients, combined prescription of beta-blockers and ACE inhibitors had an additive effect on the 1-year survival rate.

[Similarities and differences among patients with symptomatic atherosclerosis affecting several territories. The AIRVAG cohort (Integral Attention to Global VAscular Risk)]. / Similitudes y diferencias entre los pacientes con aterosclerosis sintomática de distintos territorios. Cohorte AIRVAG (Atención Integral al Riesgo VAscular Global).

BACKGROUND AND OBJECTIVE: Even though atherosclerosis is a systemic disease, few prospective studies have evaluated in a thorough and systematic manner the whole vascular tree in patients with clinical damage of different territories. PATIENTS AND METHOD: Prospective protocolized study of 269 consecutive patients younger than 70, attended because of symptomatic arteriosclerosis of any territory -53% coronary (CHD), 32% cerebrovascular (CVD), 15% peripheral (PVD)-. Patients underwent evaluation of risk factors and their control, systematic non-invasive study of the vascular tree (Doppler-ultrasound) and comparison between groups according to the index territory. RESULTS: Even though all risk factors were represented in the 3 groups, male sex, smoking and diabetes were more frequent in PVD and dyslipemia was more common in CHD (p < 0.05) Abdominal aortic diameter and carotid intima-media thickness were similar for all groups, while the number of carotid plaques was higher in PVD. CHD patients more often presented left ventricular hypertrophy and reduced ejection fraction. PVD patients showed a marked reduction of the ankle-brachial index as well as increased C-reactive protein and homocysteine (p < 0.05). Severe unsuspected vascular lesions were found in 13% of cases (95% confidence interval, 9.5-17.6%). Risk factor control was better for CHD, followed by CVD and PVD, but was globally poor. CONCLUSIONS: The systematic evaluation of the vascular tree detects generalized atherosclerotic lesions, in some cases severe and clinically unsuspected. New markers to identify patients at very high risk are necessary. Peripheral vascular disease identifies a group of patients of particular risk. Risk factor control is deficient, particularly among PVD patients.

[Moderate coronary lesion with severe vasospasm and the development of collateral circulation in a patient with effort angina and ST-segment depression]. / Espasmo coronario severo en una lesión moderada y desarrollo de circulación colateral en un paciente con angina estable y descenso del segmento ST con el esfuerzo.

Coronary collateral circulation usually develops as a consequence of recurrent ischemia associated with severe stenosis. In exceptional cases, it can develop with moderate coronary lesions if there is severe recurrent vasospasm. In this situation, the presenting clinical features of vasospastic angina (i.e., effort angina with ST-segment depression) can be identical to those of a severe permanent lesion. We present a patient who exhibited effort angina and ST-segment depression on treadmill testing. Angiography showed severe right coronary artery stenosis and the development of coronary collateral circulation from the other main artery. After repeated intracoronary bolus injection of nitroglycerin, only a moderate stenosis was still apparent and the collateral circulation had disappeared.

[Underrecognized peripheral arterial disease in patients with acute coronary syndrome: prevalence of traditional and emergent cardiovascular risk factors]. / Enfermedad arterial periférica desconocida en pacientes con síndrome coronario agudo: prevalencia y patrón diferencial de los factores de riesgo cardiovascular tradicionales y emergentes.

INTRODUCTION AND OBJECTIVES: Peripheral arterial disease (PAD) frequently coexists with coronary artery disease. Our objective was to determine the prevalence of traditional and emergent cardiovascular risk factors in patients with acute coronary syndrome (ACS), with or without PAD. PATIENTS AND METHOD: A prospective study of 141 consecutive patients (< 70 years old) admitted to our hospital with ACS was performed. PAD was diagnosed when the ankle-brachial index (ABI) was < or = 0.9. Traditional cardiovascular risk factors were evaluated. C-reactive protein, homocysteine, amyloid A, lipoprotein (a), fibrinogen, apolipoprotein A1, and apolipoprotein B100 serum levels, and microalbuminuria were measured. Specific genotypes were also determined. RESULTS: Patients were divided into two groups according to whether PAD was present (37 patients, 26% of total, ACS-PAD group) or absent (104 patients, ACS group). In the ACS-PAD group, patients were older, and diabetes and hypertension were significantly more common. Moreover, levels of C-reactive protein (3.1 mg/L vs 2.18 mg/L; P<.05), homocysteine (11.45 mmol/L vs 9.4 mmol/L; P<.01), amyloid A (5.2 mg/mL vs 3.7 mg/mL; P<.05), and microalbuminuria (4.89 mg/L vs 3.1 mg/L; P<.05) were significantly higher in this group. Logistic regression analysis showed that poorly controlled diabetes (OR = 6.3; 95% CI, 1.1-36.7), time-dependent tobacco exposure (OR = 1.5 per decade; 95% CI, 1.2-2.0), and high pulse pressure (OR = 1.9 per 10 mmHg; 95% CI, 1.3-2.7) were independent predictors of the presence of PAD. CONCLUSIONS: Several traditional and emergent cardiovascular risk factors were more prevalent in patients with acute coronary syndrome and peripheral arterial disease. Moreover, some factors were independent predictors of peripheral arterial disease.

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

BACKGROUND: Patients 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. METHODS: We 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. RESULTS: Twenty 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. CONCLUSIONS: CHD 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.

[Impact of plasma pro-B-type natriuretic peptide amino-terminal and galectin-3 levels on the predictive capacity of the LIPID Clinical Risk Scale in stable coronary disease]. / Impacto de los niveles plasmáticos de pro-péptido natriurético tipo B aminoterminal, proteína quimiotáctica de monocitos-1 y galectina3 en la capacidad predictiva de eventos de la escala clínica LIPID en la enfermedad coronaria estable.

INTRODUCTION: At present, there is no tool validated by scientific societies for risk stratification of patients with stable coronary artery disease (SCAD). It has been shown that plasma levels of monocyte chemoattractant protein-1 (MCP-1), galectin-3 and pro-B-type natriuretic peptide amino-terminal (NT-proBNP) have prognostic value in this population. OBJECTIVE: To analyze the prognostic value of a clinical risk scale published in Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study and determining its predictive capacity when combined with plasma levels of MCP-1, galectin-3 and NT-proBNP in patients with 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 the occurrence 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 of the primary endpoint, with an area under the ROC curve (Receiver Operating Characteristic) of 0.642 (0.579 to 0.705); P<0.001. A composite score was developed by adding the scores of the LIPID and scale decile levels of MCP -1, galectin -3 and NT-proBNP. The predictive value improved with an area under the curve of 0.744 (0.684 to 0.805); P<0.001 (P=0.022 for comparison). A score greater than 21.5 had a sensitivity of 74% and a specificity of 61% for the development of the primary endpoint (P<0.001, log -rank test). CONCLUSION: Plasma levels of MCP-1, galectin -3 and NT-proBNP improve the ability of the LIPID clinical scale to predict the prognosis of patients with SCAD.