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Background: Elevated plasma interleukin-6 (IL-6) concentrations are frequently observed in patients with acute heart failure (AHF). However, the predictive value of serial IL-6 measurements beyond brain natriuretic peptide (BNP) remains poorly characterized.Methods and Results: This was a retrospective analysis of the PROTECT cohort (2033 patients with AHF). Plasma IL-6 and BNP levels were determined on days 1, 2, 7 and 14 after admission for AHF in 1591 (78.3%), 1462 (71.9%), 1445 (71.1%) and 1451 (71.4%) patients, respectively. The primary endpoint was 180-day all-cause mortality. The median day-1 IL-6 concentration was 11.1 pg/mL (IQR: 6.6, 20.9) and decreased to 10.1 pg/mL (IQR: 5.6-18.5) at day-7. Higher cross-sectional IL-6 concentrations at all time-points predicted the primary endpoint, independent of a risk model for this cohort and changes in BNP. Each doubling of IL-6 between day-1 and day-7 predicted the primary endpoint independent of baseline IL-6 concentrations, the risk model, baseline BNP and changes in BNP [HR (95% CI): 1.18 (1.07-1.30), p=0.0013]. Collectively, 214 (17%) patients experienced at least a doubling of their IL-6 concentrations between day-1 and day-7.Conclusions: We demonstrate that the temporal evolution patterns of IL-6 in patients with AHF have additive prognostic value independent of changes in BNP. [ABSTRACT FROM AUTHOR]

Objective: To assess the association between serially measured N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum levels and disease severity in children with pulmonary arterial hypertension (PAH), and to assess its predictive value for death or (heart-)lung transplantation.Study Design: This was a longitudinal cohort study of the Dutch National Network for Pediatric Pulmonary Hypertension conducted between 2003 and 2017. Data on NT-proBNP and disease severity markers (World Health Organization Functional Class [WHO-FC], 6-minute walking distance [6MWD], and tricuspid annular plane systolic excursion [TAPSE]) were collected every 3 to 6 months from 82 children with PAH. The outcome measure was death or (heart-)lung transplantation. Also, NT-proBNP levels over time were compared between survivors and nonsurvivors.Results: The median patient age was 8.8 years (IQR, 4.6-13.5 years), and 61% were female. The median duration of follow-up was 4.8 years (IQR, 1.9-10.0 years). At all times during the course of disease, higher NT-proBNP levels were associated with higher WHO-FC (β = 0.526; 95% CI, 0.451-0.600), lower 6MWD z-score (β = -0.587; 95% CI, -0.828 to -0.346), lower TAPSE z-score (β = -0.783; 95% CI, -1.016 to -0.549), and elevated risk of death or (heart-)lung transplantation (hazard ratio 16.61; 95% CI, 7.81-35.33). Compared with survivors, nonsurvivors had NT-proBNP levels that were higher at first measurement and increased exponentially over time (P = .005). Changes in NT-proBNP serum level over time were predictive of outcome.Conclusions: Throughout the disease course of pediatric PAH, serial measurements of NT-proBNP are associated with disease severity and transplant-free survival. Monitoring NT-proBNP levels over time provides important prognostic information that can support clinical decision making in combination with other established prognostic markers. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2005.12.012 Byline: Jochem Hogenhuis (a), Adriaan A. Voors (a), Tiny Jaarsma (a), Hans L. Hillege (b), Arno W. Hoes (c), Dirk J. van Veldhuisen (a) Abstract: In patients with acute heart failure (HF) presenting at the emergency department, a B-type natriuretic peptide (BNP) level Author Affiliation: (a) Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands (b) Trial Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (c) Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands Article History: Received 26 August 2005; Accepted 24 December 2005 Article Note: (footnote) The NHF-COACH study is financially supported by the Netherlands Heart Foundation (Grant 2000Z003). Prof van Veldhuisen is an established investigator of the Netherlands Heart Foundation (Grant D97.017).

Objectives This study evaluated a biochemical validation of patient-reported symptom onset time in patients with ST-segment elevation myocardial infarction (STEMI). Background Symptom onset time is an important metric but has never been formally validated. Methods The Mayo Clinic Percutaneous Coronary Intervention (PCI) Registry was interrogated to obtain baseline, procedural, and outcome data on 607 STEMI patients undergoing primary PCI. Biochemical onset time was determined by backward extrapolation of serial increasing cardiac troponin T (cTnT) measurements. Results The median patient-reported onset time was 12 min later than the calculated time of first cTnT increase and was therefore estimated to be 4.2 h later than the biochemical onset time (interquartile range: 1.9 to 11.1 h; p < 0.001), assuming a 4-h interval between coronary occlusion and first cTnT increase. Conventional ischemic time showed no association with infarct size (correlation with peak cTnT: r = 0.023; p = 0.61) or 1-year mortality (hazard ratio: 0.97 per doubling; 95% confidence interval: 0.68 to 1.40; p = 0.88). However, after recalculation of ischemic time with biochemical onset time, significant associations with infarct size (r = 0.14; p = 0.001) and 1-year mortality (hazard ratio: 1.70 per doubling; 95% confidence interval: 1.20 to 2.40; p = 0.003) were found. When underestimation of ischemic time by patient-reported onset time increased, so did the risk of mortality. Conclusions Although our point estimate should be interpreted with caution, our study indicates that the actual onset of STEMI is likely to be earlier than the patient-reported onset time. Recalculation of ischemic time with biochemical onset time greatly enhanced its prognostic value. Underestimation of ischemic time by patient-reported onset time occurred more often in high-risk patients. [ABSTRACT FROM AUTHOR]

Background Although the thromboembolic risk after pulmonary valve replacement (PVR) with mechanical valves is presumed to be high, recent studies suggest promising short-term and mid-term results. However, large studies reporting long-term mortality and valve-related complications are missing. Methods We describe valve-related complications in 66 patients with a mechanical pulmonary valvar prosthesis implanted between 1987 and 2013. Results Mean follow-up duration was 5.9 ± 4.8 years (median 4.9). Mean age at time of implantation was 35 ± 13 years. The most frequent underlying cardiac diagnosis was tetralogy of Fallot (77%). Valvar thrombosis or pannus was reported in 7 patients (10%) of which 4 in the setting of inadequate anticoagulation or pregnancy. Redo PVR was performed in 6 patients. Freedom from redo PVR in survivors after 5 and 10 years was 96% and 89%, respectively. Survival after 5 and 10 years was 91% and 81%, respectively. Main cause of death was end-stage heart failure. Conclusions Success of PVR using mechanical valvar prostheses over 26 years was limited because of valvar thrombosis (often in the setting of pregnancy or incompliance with anticoagulation therapy) or pannus. Performance of mechanical prostheses in the pulmonary position may improve when valvar thrombosis is prevented by patient selection, avoiding mechanical valves in patients at increased risk of valvar thrombosis, and by strict compliance to anticoagulation therapy. [ABSTRACT FROM AUTHOR]

Background: The Atrial Fibrillation Follow-up Investigation of Rhythm Management trial showed that digoxin was associated with increased mortality in patients with atrial fibrillation.Objectives: To assess the association of digoxin with cardiovascular (CV) morbidity and mortality in patients with permanent atrial fibrillation enrolled in the Dutch Rate Control Efficacy in Permanent AF: A Comparison Between Lenient Versus Strict Rate Control II trial as well as to assess the role of digoxin to achieve heart rate targets.Methods: The primary outcome was a composite of CV morbidity and mortality. Secondary outcomes included CV hospitalization and all-cause mortality or heart failure (HF) hospitalization. Of the 614 patients, 608 (99%) completed the dose-adjustment phase. Outcome events were analyzed from the end of the dose-adjustment phase until the end of follow-up. The median follow-up period was 2.9 years (interquartile range 2.7-3.0 years).Results: In total, 284 patients (46.7%) used digoxin after the dose-adjustment phase (median dosage 0.250 mg; interquartile range 0.0625-0.750 mg). These patients were more often women, previously admitted for HF, had an increased left ventricular end-systolic diameter, and more often randomized to strict rate control. By using Cox proportional hazards regression analysis, the use of digoxin was not associated with an increased risk for the primary and secondary outcomes. For the primary outcome, the 3-year estimated cumulative incidence was 12.9% vs 13.4% in the digoxin group vs the no-digoxin group (unadjusted hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.62-1.52). Incidence was 19.4% vs. 19.5% for CV hospitalization (unadjusted HR 1.00; 95% CI 0.69-1.45) and 6.6% vs. 9.9% for all-cause mortality or HF hospitalization (unadjusted HR 0.62; 95% CI 0.34-1.13) in the digoxin group vs the no-digoxin group.Conclusion: The use of digoxin was not associated with increased morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: This single-center study analyzed the occurrence of severe thrombocytopenia and its clinical effect after concomitant and isolated aortic valve replacement (AVR) with the stentless Freedom Solo (FS) prosthetic valve (Sorin Group, Saluggia, Italy). Methods: Between October 2009 and February 2012, 151 consecutive patients underwent AVR with a FS, either isolated (lone-FS group) or concomitant with another procedure (all-FS group). These groups were compared with 152 consecutive patients implanted with a stented Edwards Lifesciences Perimount (EP) bioprosthesis (Edwards Lifesciences, Irvine, CA). Primary end point was the incidence of severe thrombocytopenia (platelet count < 50 × 109/L). Secondary end points were clinical outcomes, administered transfusions (red blood cells, thrombocytes, frozen plasma), and adverse events. Rinsing the FS before implantation with saline solution was also evaluated. Results: Platelet counts were significantly lower in the all-FS and lone-FS groups than in the EP group during the first 5 days (p < 0.001). Average nadir was 102 ± 50 in lone-FS group and 130 ± 35 in lone-EP group (p < 0.001). Independent predictors for severe thrombocytopenia were FS, body surface area, and preoperative platelet count. No significant difference was found in transfusions or adverse events. Intensive care unit stay was slightly increased in the lone-FS group (p = 0.04). Rinsing the FS did not prevent thrombocytopenia. Conclusions: AVR with FS was associated with severe thrombocytopenia during the first postoperative days. Besides a slightly longer hospitalization in the intensive care unit in the FS group, the clinical outcome did not differ significantly, indicating thrombocytopenia was a transient and self-recovering phenomenon, not affecting clinical outcome. Rinsing the FS did not prevent thrombocytopenia. [Copyright &y& Elsevier]

Abstract: Renal insufficiency is common in patients with heart failure (HF), with both acute kidney injury and worsening renal function being associated with poor prognosis. The interplay between cardiac and renal failure has been termed the cardiorenal syndrome and is currently the subject of intense investigation. Urinary biochemistry has several advantages over blood or serum analyses, including lower costs, better patient comfort, and higher sensitivity to renal injury. However, urinalysis is currently not part of routine daily practice in cardiology. Recent advances in proteomics have allowed identification of numerous novel urinary biomarkers, many of which show promise in HF populations. In this review, we aim to provide an overview of both traditional and novel urinary biomarkers, examining evidence for diagnostic and prognostic value in HF as well as potential clinical utility. [Copyright &y& Elsevier]

Background: Although previously conducted meta-analyses suggest that nurse-led disease management programs in heart failure (HF) can improve patient outcomes, uncertainty regarding the cost-effectiveness of such programs remains. Methods: To compare the relative merits of 2 variants of a nurse-led disease management program (basic or intensive support by a nurse specialized in the management of patients with HF) against care as usual (routine follow-up by a cardiologist), a trial-based economic evaluation was conducted alongside the COACH study. Results: In terms of costs per life-year, basic support was found to dominate care as usual, whereas the incremental cost-effectiveness ratio between intensive support and basic support was found to be equal to €532,762 per life-year; in terms of costs per quality-adjusted life-year (QALY), basic support was found to dominate both care as usual and intensive support. An assessment of the uncertainty surrounding these findings showed that, at a threshold value of €20,000 per life-year/€20,000 per QALY, basic support was found to have a probability of 69/62% of being optimal against 17/30% and 14/8% for care as usual and intensive support, respectively. The results of our subgroup analysis suggest that a stratified approach based on offering basic support to patients with mild to moderate HF and intensive support to patients with severe HF would be optimal if the willingness-to-pay threshold exceeds €45,345 per life-year/€59,289 per QALY. Conclusions: Although the differences in costs and effects among the 3 study groups were not statistically significant, from a decision-making perspective, basic support still had a relatively large probability of generating the highest health outcomes at the lowest costs. Our results also substantiated that a stratified approach based on offering basic support to patients with mild to moderate HF and intensive support to patients with severe HF could further improve health outcomes at slightly higher costs. [Copyright &y& Elsevier]

Background: The renin-angiotensin-aldosterone system (RAAS) plays a key role in the progression of heart failure (HF) and concomitant kidney dysfunction. Despite the use of RAAS blockade, sustained activation of RAAS has been suggested to link with adverse outcome. We aimed to investigate the prognostic value of active plasma renin concentration (APRC) and prorenin in patients with HF treated with RAAS-blocking agents and its relationship with kidney function parameters. Methods: One hundred clinically stable patients with HF, treated with RAAS-blocking agents, were studied. Renal function parameters including effective renal plasma flow and glomerular filtration rate were measured invasively. The combined end point consisted of all-cause mortality, heart transplantation, and admission to hospital for HF. Results: Mean age was 58 ± 12 years, and 76% were men. Mean left ventricular ejection fraction was 28 ± 9, and median APRC levels were 24.3 ng/mL per hour. Active plasma renin concentration was most strongly associated with mean arterial pressure (r = 0.60, P < .001). In multivariate linear regression analysis, age, mean arterial pressure, angiotensin II concentration, and use of aldosterone antagonists were significantly related with APRC (adjusted R 2 = 0.53). Patients in the highest quartile of APRC had a worse prognosis. In multivariate analysis, APRC remained associated with worse prognosis: HR 2.87 (95% CI 1.14-7.20), P = .025. Prorenin did not show prognostic value. The prognostic value of APRC was strongest in patients with decreased kidney function. Conclusions: Our data indicate that APRC is a strong prognostic factor in patients with HF in the presence of RAAS inhibition, especially in patients with kidney dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: The frequently occurring condition of renal failure in heart failure (HF) has been termed the cardiorenal syndrome. However, the importance of renal insufficiency in HF has only been embraced in the last decade, and therefore, the pathophysiology of cardiorenal failure is still poorly understood. The main driving force of renal failure in HF is probably hemodynamic derangement, with both reduced renal perfusion and increased venous pressure as the most important driving forces. Different cardiorenal connectors may modulate this relationship. Furthermore, renal failure is not only limited to reduced filtration but also includes glomerular hypertension and tubulointerstitial hypoxia, leading to loss of glomerular integrity and tubular damage. Recognition of these key pathophysiologic pathways in the concept of the cardiorenal syndrome is needed to value the interrelationship and incremental contribution of different risk markers and possible new treatments to improve renal function and outcome in this complex and bidirectional interplay between the heart and the kidney. [Copyright &y& Elsevier]

Background: The PREVEND IT investigated whether treatment targeted at lowering urinary albumin excretion (UAE) would reduce adverse cardiovascular events. We obtained extended follow-up data to approximately 10 years to investigate the long-term effects of fosinopril 20 mg and pravastatin 40 mg on cardiovascular outcomes in subjects with UAE >15 mg per 24 hours. Methods: The original PREVEND IT consisted of 864 participants and 839 survivors after 4 years. For every survivor, the primary end point determined by the combined incidence of cardiovascular mortality and hospitalization for cardiovascular morbidity was registered in several national databases and electronic hospital systems. Results: Mean total follow-up of the extended PREVEND IT was 9.5 years (range 9.4-10.7 years). Four years of treatment with fosinopril was not associated with a reduction in the primary end point compared with placebo (hazard ratio 0.87, 95% CI 0.61-1.24 [P = .42]) during long-term follow-up. After 9.5 years, subjects with a baseline UAE in the upper quintile (>50 mg/24 hours) had a total event rate of 29.5% and were at a higher risk for developing cardiovascular disease compared with less UAE (hazard ratio 2.03, 95% CI 1.38-2.97 [P ≤ .01]). In addition, 4 years of fosinopril treatment resulted in a risk reduction of 45% (95% CI 6%-75% [P = .04]) in this group compared with placebo. Subjects originally assigned to pravastatin had no overall risk reduction in the primary end point (P = .99). Conclusions: Elevated UAE is associated with increased cardiovascular mortality and morbidity after 9.5 years of follow-up, with a doubling of the risk if the UAE is >50 mg per 24 hours. In this group, the benefits of 4-year treatment with fosinopril were sustained during posttrial follow-up for cardiovascular mortality and morbidity. We propose that UAE be used to estimate risk in the general population and that large clinical trials be designed to confirm the hypothesis that angiotensin-converting enzyme–inhibitor treatment may be beneficial in patients with mildly elevated UAE despite the absence of other comorbidities. [Copyright &y& Elsevier]

Background: Secondary prophylaxis using aspirin is standard of care after coronary artery bypass graft surgery. Limited data are available for long-term results. We evaluated the effect of aspirin, aspirin with dipyridamole, and vitamin K antagonists (VKA) on 14-year clinical outcome of patients included in the Prevention of Coronary Artery Bypass Graft Occlusion by Aspirin, Dipyridamole, and Acenocoumarol/Phenprocoumon Study (CABADAS). Methods: All 726 Dutch patients for whom antithrombotic therapy with aspirin (n = 248), aspirin with dipyridamole (n = 234), or VKA (n = 244) was randomly allocated were included. The primary endpoint was occurrence of major adverse cardiac events (MACE). Outcomes were retrospectively evaluated during 14-year follow-up. Results: Cumulative incidences for MACE over 14 years were 49%, 50%, and 59% for patients treated with aspirin, aspirin with dipyridamole, and VKA, respectively. Although the overall occurrence of MACE did not significantly differ among the three treatment groups (p = 0.12), patients treated with VKA were at higher risk of MACE than patients treated with aspirin with dipyridamole (hazard ratio 1.3, 95% confidence interval: 1.0 to 1.8, p = 0.041) and patients treated with aspirin alone (hazard ratio 1.1, 95% confidence interval: 0.86 to 1.5, p = 0.37). This difference was attributed to an increased risk of repeat revascularization in patients treated with VKA, without any differences in cardiac death and myocardial infarction among the three treatment groups. However, the observed high rate of repeat revascularization in patients treated with VKA could reflect an a priori increased probability for repeat revascularization due to the specific conditions surrounding VKA therapy (ie, more intense patient–doctor contacts). Conclusions: This study with 14-year clinical outcome provides further evidence for the use of aspirin as secondary prophylaxis after coronary artery bypass graft surgery. [ABSTRACT FROM AUTHOR]

Abstract: Background: Comparisons of heart failure (HF) patients with an unselected healthy sample in terms of quality of life (QoL) and depressive symptoms might prove misleading. We compared QoL and depressive symptoms of a HF population with an age- and gender-matched sample of community dwelling elderly. Methods and Results: Data were collected from 781 HF patients (36% female; age 72 ± 9; New York Heart Association II-IV) and 781 age- and gender-matched community-dwelling elderly. Participants completed the Medical Outcome Study 36-item General Health Survey, the Cantril''s Ladder of life, and the Center for Epidemiological Studies-Depression scale (CES-D). Analysis of variance techniques with Welch F test and chi-square tests were used to describe differences in QoL and depressive symptoms between different groups. For both men and women with HF, QoL was reduced and depressive symptoms were elevated when compared with their elderly counterparts (CES-D ≥16: 39% vs. 21%, P < .001). HF patients had more chronic conditions—specifically diabetes and asthma/chronic obstructive pulmonary disease. Impaired QoL and depressive symptoms were most prevalent among HF patients with comorbidities. Prevalence was also higher in HF patients in the absence of these conditions. Conclusions: HF has a large impact on QoL and depressive symptoms, especially in women with HF. Differences persist, even in the absence of common comorbidities. Results demonstrate the need for studies of representative HF patients with direct comparisons to age- and gender-matched controls. [Copyright &y& Elsevier]

Background: Data on long-term response to bosentan in adults and especially children with pulmonary arterial hypertension (PAH) associated with systemic-to-pulmonary shunt are scarce. Methods: We studied bosentan efficacy in 30 patients (20 adults, 10 children) with the disease at short- (4 months), and long-term follow-up (through 2.7 years). World Health Organization functional class (WHO class), transcutaneous oxygen saturation, and 6-minute walk distance were assessed at baseline, 4 months, 1 year, 1.5 years, and at latest follow-up (median 2.7 years). Results: At baseline, children tended to have more severe disease compared with adults with regard to WHO class and congenital heart defects. At 4 months'' follow-up, WHO class and 6-minute walk distance significantly improved in both adults and children. During long-term follow-up, this improvement persisted through 1 year but declined thereafter in the total group. In the children, a progressive decline in exercise capacity was observed from 1-year follow-up, whereas in the adults, improvement lasted longer. No change from baseline was seen in transcutaneous oxygen saturation. Three (10%) patients died, 2 (7%) discontinued bosentan, and 5 (17%) required additional PAH therapy (of whom 1 eventually died). One- and 2-year persistence of beneficial bosentan effect was 68% and 43% (total group), 78% and 57% (adults), and 50% and 20% (children), respectively. Conclusions: Our experience with bosentan suggests short-term improvement in both adults and children with PAH associated with systemic-to-pulmonary shunt. At long-term follow-up, a progressive decline in beneficial bosentan effect was observed. The decline appeared most pronounced in the pediatric patients, who, in this study, tended to have more severe disease at baseline. [Copyright &y& Elsevier]

Abstract: Background: Renal impairment is associated with increased mortality in heart failure (HF). Recently, reports suggest that worsening renal function (WRF) is another predictor of clinical outcome in HF. The present study was designed to establish the proportion of patients with HF that exhibits (WRF) and the associated risk for mortality and hospitalization by conducting a systematic review and meta-analysis. Methods and Results: A systematic search of MEDLINE revealed 8 studies on the relationship between WRF and mortality in 18,634 patients with HF. The mortality risk associated with WRF was estimated using random-effects meta-analysis. WRF was defined as an increase in serum creatinine ≥0.2 mg/dL or a corresponding decrease in estimated glomerular filtration rate ≥5 mL·min·1.73 m2. Subgroup analysis included differentiation between in- and out-hospital patients, degree of WRF and time until end point occurrence. WRF developed in 4,734 (25%) patients and was associated with a higher risk for mortality (odds ratio [OR] = 1.62; 95% confidence interval [CI] 1.45–1.82, P < .001) and hospitalization (OR = 1.30, 95% CI 1.04–1.62, P = .022). The severity of WRF was also associated with greater mortality. Patients with impaired renal function at baseline were more prone to progressive renal function loss. Conclusions: WRF predicts substantially higher rates of mortality and hospitalization in patients with HF. [Copyright &y& Elsevier]

Abstract: Introduction: Renal function is one of the strongest prognostic markers in patients with chronic heart failure, but it has been suggested that this might be due to (local, i.e. renal) vascular atherosclerosis. The aim of the present study is to evaluate the prognostic value of renal function in both ischemic and non-ischemic mild chronic heart failure. Methods: From 161 patients with early chronic heart failure and NYHA class II, who had been enrolled in a multicenter trial, ischemic chronic heart failure was present in 120 patients and non-ischemic chronic heart failure in 41 patients. Estimated glomerular filtration rate was calculated by the Cockcroft–Gault equation (GFRc). Results: Follow-up duration was 13 years (mean 11.7 years). Mean age was 60.5±8.0 years, 86% was male and mean left ventricular ejection fraction was 0.29±0.08. Baseline characteristics were not statistically different between the groups. Multivariate Cox regression analysis revealed that in non-ischemic chronic heart failure, renal function was an important predictor of all-cause mortality (Relative Risk; 1.65 (1.05–2.58); p =0.029). In contrast, in ischemic chronic heart failure, renal function was not related to all-cause mortality (Relative Risk; 1.07 (0.92–1.23); p =0.40). Conclusion: In mild chronic heart failure, renal function is a prognostic risk marker for long-term mortality in non-ischemic chronic heart failure, but not in patients with coronary artery disease. These data suggest that renal vascular abnormalities are not primarily responsible for the prognostic value of renal function in patients with mild chronic heart failure. [Copyright &y& Elsevier]

Both reduced filtration power and increased excretion of albumin in the urine are powerful markers for renal and cardiovascular progressive function loss. These risk markers indicate the risk above and beyond the conventional existing risk markers/factors. The risk is substantial, because both reduced filtration and microalbuminuria are highly prevalent in the general population, matching in prevalence with the most well-known risk factor, hypertension. Therapeutic interventions to preserve renal and cardiovascular function, such as with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, are highly effective, particularly in those patients that have reduced filtration power. In addition, short-term reduction of albuminuria that follows the renin-angiotensin-aldosterone-system intervention appears to be predictive of long-term cardiovascular and renal protection. In conclusion, estimated glomerular filtration rate as well as albumin excretion in the urine are powerful predictors for cardiovascular and renal outcome and should be used as such. Intervention and prevention could be aimed at not only at reducing conventional risk markers, but also at reducing albuminuria. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Current guidelines of chronic heart failure (CHF) do not recommend the use of oral anticoagulants (OAC) or antiplatelet therapy (APT). We performed a post-hoc analysis to evaluate the effect of the use of anti-thrombotic therapy with APT and OAC. Patients and methods: We examined 427 patients with advanced CHF, and assessed the effects of the use of APT or OAC at baseline on mortality. We employed a Cox-proportional hazard model to value the effects of APT or OAC use. Results: After a mean follow-up of 3.4 years (range 2.0–5.4), 214 patients died (51%). Forty-one (41) percent (95%CI: 29–53%) of the patients on APT died, and 52% (47–57%) of the patients not on APT (P=0.07). Forty-eight (48) percent (42–54%) of the patients on OAC died, and 55% (46–63%) of the patients not on OAC (P=0.20). This effect of OAC was seen both in patients in sinus rhythm and in atrial fibrillation. After adjusting for important prognostic variables, such as age, LVEF, renal function, and NYHA class, both the use of APT (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.40–0.97; P=0.04) and the use of OAC (HR 0.60, 95%–CI 0.43–0.83; P&#60;0.01) were related to an improved prognosis. Conclusion: This post-hoc analysis suggests that in CHF patients the use of APT or OAC is associated with a higher survival. [Copyright &y& Elsevier]

The association between atherosclerotic risk factors and renal function in the general population. Background. Generalized atherosclerosis is increasingly recognized as an important cause of end-stage renal disease (ESRD). We questioned to what extent atherosclerotic risk factors determine renal function in the general population. Methods. We used baseline data of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study. A total of 8592 subjects, aged 28 to 75 years old, visited the outpatient clinic for blood pressure and anthropometric measurements, fasting blood sampling, and delivery of two 24-hour urine collections for creatinine clearance and albuminuria calculations. Design-based multivariate linear regression was used to estimate renal function. Results. In a multivariate model, male gender and body mass index (BMI) were associated with a higher renal function, while increasing diastolic blood pressure, serum triglycerides, use of antihypertensive or lipid-lowering medication were associated with a lower renal function. Age, systolic blood pressure, and plasma glucose showed an inverse U-shaped relationship with renal function. Cholesterol/high-density lipoprotein (HDL) ratio, smoking, and antidiabetic medication did not contribute to explain renal function. The atherosclerotic risk factors were related to renal function independently of albuminuria or C-reactive protein (CRP). Albuminuria and CRP itself were also related to renal function. Following gender and age, BMI, urinary albumin excretion (UAE), and plasma glucose had the strongest relation with renal function. Conclusion. We conclude that differences in renal function in the general population are (partly) explained by various atherosclerotic risk factors. Some risk factors are associated with elevated filtration, some with an impaired filtration, and others with both a higher and a lower renal function. [ABSTRACT FROM AUTHOR]

We evaluated the prognostic value of renal function in an initially “untreated” population with mild heart failure and compared the prognosis of this population with a matched controlled population. During a follow-up of 13 years (mean 11.7), 90 patients (56%) died. Mortality was higher compared with a matched controlled population. Multivariate Cox regression analysis demonstrated that beside the well-established risk markers of left ventricular ejection fraction and heart rate, renal function (estimated glomerular filtration rate, hazard ratio 1.16/10 ml/min/1.73 m2, p = 0.003) was the only additional independent predictor of cardiovascular mortality in patients with early heart failure. [Copyright &y& Elsevier]

C-reactive protein (CRP) and microalbuminuria (MA) have been identified as risk markers for cardiovascular disease (CVD). We questioned whether CRP and MA are similar markers of vascular disease in different regions of the vascular tree like the heart, kidneys and extremities or if they differ in their relationships with these vascular beds. Baseline levels of CRP and urinary albumin were measured in 6669 non-diabetic participants in the Prevention of Renal and Vascular ENdstage Disease (PREVEND) study, a Dutch cohort derived from the general population. We defined three domains of vascular disease; coronary heart disease (myocardial infarction or infarct pattern on the ECG), renal insufficiency (creatinine clearance <60 ml min−1) and peripheral artery disease (ankle brachial index <0.9 or lower limb revascularisation). The prevalence of an elevated CRP (27.7 vs. 17.9%) and MA (17.5 vs. 10.4%) were increased in subjects with vascular disease as compared with subjects without CVD. The prevalence of an elevated CRP was equal in subjects with either coronary heart disease, renal insufficiency or peripheral artery disease (28.4 vs. 29.5 vs. 26.0%, NS), whereas MA was most prevalent in subjects with coronary heart disease (22.5 vs. 12.8 vs. 14.9%, P<0.05). Using multivariate analyses, CRP was independently associated with all three domains of vascular disease, whereas MA was independently associated with coronary heart disease only. In addition, we found synergistic contributions of an elevated CRP and older age to the risk of vascular disease in all three domains. Thus, CRP and MA are risk markers for vascular disease, each showing a different risk profiling for different vascular beds. [Copyright &y& Elsevier]

C-reactive protein is associated with renal function abnormalities in a non-diabetic population. Background. C-reactive protein (CRP) has recently been introduced in cardiovascular medicine as a predictor of myocardial infarction, stroke and peripheral artery disease in different populations. We hypothesized that elevated CRP levels are associated with renal function abnormalities. Methods. To test this hypothesis, we studied the relationship between CRP levels and renal function loss measured as diminished creatinine clearance in a large non-diabetic population (7317 subjects). In addition, the associations and confounding effects of established renal risk factors that could explain the association between CRP and diminished renal filtration were studied. Also, the association of CRP with early alterations in renal function, such as those evidenced by a relatively high glomerular filtration (“hyperfiltration”), was examined. CRP levels were divided in quartiles. Subjects with CRP levels within the first quartile were defined as the reference group. Diminished renal filtration and hyperfiltration were defined as a creatinine clearance below or exceeding two times the prediction interval of the age- and sex-related reference group. Results. Elevated CRP levels were positively associated with cardiovascular and renal risk factors: age, body mass index, blood pressure, serum cholesterol level, smoking, plasma glucose level and elevated urinary albumin excretion. Elevated CRP was positively associated with diminished filtration (OR 1.8; 95% CI 1.2 to 2.6). In multivariate analyses, CRP was independently associated with a diminished filtration (OR 1.9; 95% CI 1.3 to 2.9). Interestingly, CRP also was associated with hyperfiltration (highest quartile, OR 1.7; 95% CI 1.2 to 2.5). However, body mass index accounted for most of the relationship between CRP and hyperfiltration. Conclusions. As in cardiovascular disease, CRP appears to be a risk marker for... [ABSTRACT FROM AUTHOR]

Studies the relationship electrocardiographic markers of myocardial ischemia and albumin in the urine of patients without diabetes mellitus. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on cardiology.

Objective: To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes.Study Design: Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations.Results: Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers.Conclusions: Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH. [ABSTRACT FROM AUTHOR]

Aims We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate (GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF are associated with increased mortality. Aliskiren can provide additional renin-angiotensin-aldosterone system inhibition and increases RBF in healthy individuals. Methods and results Patients with left ventricular ejection fraction ≤45% and estimated GFR 30 to 75 mL/min per 1.73 m 2 on optimal medical therapy were randomized 2:1 to receive aliskiren 300 mg once daily or placebo. Renal blood flow and GFR were measured using radioactive-labeled 125 I-iothalamate and 131 I-hippuran at baseline and 26 weeks. After 41 patients were included, the trial was halted based on an interim safety analysis showing futility. Mean age was 68 ± 9 years, 82% male, GFR (49 ± 16 mL/min per 1.73 m 2 ), RBF (294 ± 77 mL/min per 1.73 m 2 ), and NT-proBNP 999 (435-2040) pg/mL. There was a nonsignificant change in RBF after 26 weeks in the aliskiren group compared with placebo (−7.1 ± 30 vs +14 ± 54 mL/min per 1.73 m 2 ; P = .16). However, GFR decreased significantly in the aliskiren group compared with placebo (−2.8 ± 6.0 vs +4.4 ± 9.6 mL/min per 1.73 m 2 ; P = .01) as did filtration fraction (−2.2 ± 3.3 vs +1.1 ± 3.1%; P = .01). There were no significant differences in plasma aldosterone, NT-proBNP, urinary tubular markers, or adverse events. Plasma renin activity was markedly reduced in the aliskiren group versus placebo throughout the treatment phase ( P = .007). Conclusions Adding aliskiren on top of optimal HFREF medical therapy did not improve RBF and was associated with a reduction of GFR and filtration fraction. [ABSTRACT FROM AUTHOR]

Background In established cardiovascular disease and heart failure (HF), low hemoglobin levels are associated with unfavorable outcome. Whether hemoglobin levels are associated with the development of new-onset HF in the population is unclear. This study sought to investigate the relationship between hemoglobin levels and development of new-onset HF in the community. Methods In 6,744 patients from PREVEND, a prospective, community-based, cohort study, we analyzed the relationship between hemoglobin levels and the risk of new-onset HF. Results Mean age (±SD) was 53 ± 12 years, 49.8% was male, and mean hemoglobin level was 13.7 ± 1.2 g/dL. During a median follow-up of 8.3 years (interquartile range 7.8-8.9), 217 subjects (3.2%) were newly diagnosed with HF. The association between hemoglobin levels and the risk for new-onset HF was U shaped ( P < .001), remaining significant after full adjustment in a multivariable model with established cardiovascular risk factors ( P = .015). Furthermore, a increased annual HF incidence was already observed in subjects with high-normal hemoglobin levels (men >16 g/dL or women >15 g/dL; P = .041), whereas on the other side of the distribution, only severe anemia (men <11 g/dL or women <10 g/dL; P = .018) was associated with a higher annual incidence. Conclusions The impact of hemoglobin level on the risk of new-onset HF in the community is best described as U shaped. Interestingly, higher hemoglobin levels, already within the high-reference range, are associated with an increased incidence. This in contrast to anemia, where a higher annual HF incidence was only observed for severe anemia. [ABSTRACT FROM AUTHOR]

Background Erythropoiesis-stimulating agents (ESAs) have been investigated in small studies in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Erythropoiesis-stimulating agents did not show a clear effect on left ventricular function or clinical outcome, but some studies suggested an increased risk of thromboembolic events. Methods A systematic literature search in MEDLINE was performed, until December 2012. We included randomized clinical trials investigating the effect of ESAs in STEMI patients undergoing primary PCI, with ≥30 days of follow-up. The primary end point was a composite of all-cause mortality, myocardial infarction, and stent thrombosis after PCI. Secondary end point was all-cause mortality. Results Individual patient data were obtained from 10 of 11 trials, including 97.3% (1,242/1,277) of all patients randomized to control (n = 600) or to ESAs (n = 642). Baseline characteristics were well balanced between the treatment allocations. Mean follow-up time was 248 (±131) days. The primary end point occurred in 3.5% (20/577) in the control group and in 2.1% (13/610) in the ESA group (hazard ratio for ESAs, 0.63; 95% CI [0.31-1.27]; P = .20). Mortality occurred in 13 (2.3%) in the control group and 5 (0.8%) in the ESA group (hazard ratio for ESAs, 0.38; 95% CI [0.13-1.06]; P = .06). Conclusions Erythropoiesis-stimulating agent administration does not result in an increased risk of adverse cardiac events in STEMI patients undergoing primary PCI. Results of ongoing studies may provide further insight to the potential beneficial clinical effects of ESAs in STEMI patients. [ABSTRACT FROM AUTHOR]

Introduction: Advanced glycation end products (AGEs) are increased in patients with heart failure (HF). We studied the predictive value of plasma AGEs N ε-(carboxymethyl)lysine (CML), pentosidine, and the soluble form of its receptor (sRAGE) in a large HF population. Methods: In 580 patients hospitalized with HF, plasma AGEs were measured before discharge when patients were clinically stable. Patients were followed for a period of 18 months. Primary end point was a composite of death and HF admissions. CML was determined by liquid chromatography mass spectrometry, pentosidine by high-performance liquid chromatography and sRAGE by sequential sandwich immunoassay. Results: Mean age was 71 ± 11 years, 62% were men, and mean left ventricular ejection fraction was 0.32 ± 0.14. At baseline, mean CML level was 2.16 ± 0.73 μmol/L, median pentosidine was 0.043 (0.030-0.074) μmol/L, and median sRAGE level was 2.92 (1.90-4.59) ng/mL. CML and pentosidine levels were independently related to the composite end-point (HR, 1.20 per SD; 95% CI,1.05-1.37; P = .01 and HR, 1.15 per SD; 95% CI, 1.00-1.31; P = .045, respectively) and HF hospitalization (HR, 1.27 per SD; 95% CI, 1.10-1.48; P = .001 and HR, 1.27 per SD; 95% CI, 1.10-1.47; P = .001, respectively). Furthermore, CML levels were independently related to increased mortality (P = .006). Whereas sRAGE levels were univariately predictive for outcome, in multivariate models sRAGE did not reach statistical significance. Discussion: In HF patients, both CML and pentosidine predict HF hospitalization and the combined primary end-point (mortality or HF-hospitalization), whereas sRAGE did not predict events. In addition, CML was significantly and independently associated with a higher risk for mortality. [Copyright &y& Elsevier]

Background: Previous research has shown that women with congenital heart disease (CHD) are more susceptible to cardiovascular, obstetric, and offspring events. The causative pathophysiologic mechanisms are incompletely understood. Inadequate uteroplacental circulation is an important denominator in adverse obstetric events and offspring outcome. The relation between cardiac function and uteroplacental perfusion has not been investigated in women with CHD. Moreover, the effects of physiologic changes on pregnancy-related events are unknown. In addition, long-term effects of pregnancy on cardiac function and exercise capacity are scarce. Methods: Zwangerschap bij Aangeboren Hartafwijking (ZAHARA) II, a prospective multicenter cohort study, investigates changes in and relations between cardiovascular parameters and uteroplacental Doppler flow patterns during pregnancy in women with CHD compared to matched healthy controls. The relation between cardiovascular parameters and uteroplacental Doppler flow patterns and the occurrence of cardiac, obstetric, and offspring events will be investigated. At 20 and 32 weeks of gestation, clinical, neurohumoral, and echocardiographic evaluation and fetal growth together with Doppler flow measurements in fetal and maternal circulation are performed. Maternal evaluation is repeated 1 year postpartum. Implications: By identifying the factors responsible for pregnancy-related events in women with CHD, risk stratification can be refined, which may lead to better pre-pregnancy counseling and eventually improve treatment of these women. [Copyright &y& Elsevier]

Framingham score and microalbuminuria: Combined future targets for primary prevention? Background Risk assessment is the cornerstone of primary prevention of cardiovascular disease. Our objective was to evaluate the prognostic value of the Framingham score in microalbuminuric subjects without a history of cardiovascular disease and whether this risk score can predict the benefit of treatment with fosinopril or pravastatin. Methods Subjects were randomized to fosinopril 20 mg or matching placebo, and to pravastatin 40 mg or matching placebo (mean age 51 ± 12 years, 65% men, N =830). Prediction of 10-year risk for coronary heart disease by the Framingham score was performed using the risk factor categories with LDL cholesterol. Results Albuminuria was correlated with Framingham score at baseline ( P < 0.001). In the population with a Framingham risk score <20%, both albuminuria and Framingham risk score were independent predictors of the primary end point. A two-fold increase of albuminuria or the Framingham risk score was associated with a hazard ratio of 1.60 (95% CI 1.10–2.31), P =0.013 and 3.00 (95% CI 1.40–6.44), P =0.005, respectively. In contrast to fosinopril, pravastatin showed a significant beneficial effect on Framingham risk score after 4 years of follow-up ( P < 0.001). Furthermore, the observed absolute risk reduction in cardiovascular events was greater than calculated by the Framingham risk score. Conclusion The Framingham score is useful in microalbuminuric subjects as a prognostic tool. In addition, when considering the risk score as a target of intervention, the beneficial effects of therapies might be underestimated. Combining the Framingham score with the level of urinary albumin excretion is suggested as a primary prevention strategy with higher efficiency. [ABSTRACT FROM AUTHOR]

: ObjectivesWe sought to investigate whether microalbuminuria, a proposed marker of generalized vascular damage, enhances the prognostic value of ST-T segment changes for all-cause and cardiovascular mortality in the general population.: BackgroundST-T segment changes on the rest electrocardiogram (ECG) predict mortality in the general population. However, the excess risk seems to be low, particularly in nonhospitalized populations with a low cardiovascular risk profile.: MethodsIn a population of 7,330 male and female subjects, a total of 89 deaths (1.2%) occurred during a median three-year follow-up. In 69 of these, the cause of death was obtained from the Central Bureau of Statistics: 25 subjects died of cardiovascular causes (36%). Using computerized Minnesota coding, ST-T segment changes were coded as 4.1-4 and 5.1-4. Microalbuminuria was defined as a urinary albumin excretion of 30 to 300 mg per 24 h.: ResultsThe combination of ST-T segment changes and microalbuminuria showed a higher hazard ratio (HR) for all-cause mortality (HR 8.6 [95% confidence interval [CI] 4.8 to 15.2, p < 0.0001), as compared with ST-T segment changes in the absence of microalbuminuria (HR 1.3 [95% CI 0.7 to 2.5]), which was independent of other cardiovascular risk factors (HR 3.3 [95% CI 1.5 to 7.1], p = 0.002). The combination showed a higher HR when only cardiovascular deaths were taken into account, as compared with all-cause mortality (HR 24.5 [95% CI 7.9 to 76.0], p < 0.0001), which also counted for ST-T segment changes alone (HR 4.4 [95% CI 1.4 to 14.5], p = 0.02). After controlling for other risk factors, the HRs were 10.4 (95% CI 2.5 to 43.6, p = 0.001) for the combination and 2.7 (95% CI 0.6 to 12.3) for ST-T segment changes alone.: ConclusionsThis study suggests that, in subjects with ST-T segment changes on their rest ECG, microalbuminuria could identify those at increased risk of all-cause and cardiovascular mortality. [Copyright &y& Elsevier]