Von Willebrand Factor Improves Risk Prediction in Addition to N-Terminal Pro-B-type Natriuretic Peptide in Patients Referred to Coronary Angiography and Signs and Symptoms of Heart Failure and Preserved Ejection Fraction.

BACKGROUND Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF. METHODS AND RESULTS Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.26-1.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEF-related comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.05-1.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWF×NT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001). CONCLUSIONS vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients.

Evolving biomarkers improve prediction of long-term mortality in patients with stable coronary artery disease: the BIO-VILCAD score.

OBJECTIVE Algorithms to predict the future long-term risk of patients with stable coronary artery disease (CAD) are rare. The VIenna and Ludwigshafen CAD (VILCAD) risk score was one of the first scores specifically tailored for this clinically important patient population. The aim of this study was to refine risk prediction in stable CAD creating a new prediction model encompassing various pathophysiological pathways. Therefore, we assessed the predictive power of 135 novel biomarkers for long-term mortality in patients with stable CAD. DESIGN, SETTING AND SUBJECTS We included 1275 patients with stable CAD from the LUdwigshafen RIsk and Cardiovascular health study with a median follow-up of 9.8 years to investigate whether the predictive power of the VILCAD score could be improved by the addition of novel biomarkers. Additional biomarkers were selected in a bootstrapping procedure based on Cox regression to determine the most informative predictors of mortality. RESULTS The final multivariable model encompassed nine clinical and biochemical markers: age, sex, left ventricular ejection fraction (LVEF), heart rate, N-terminal pro-brain natriuretic peptide, cystatin C, renin, 25OH-vitamin D3 and haemoglobin A1c. The extended VILCAD biomarker score achieved a significantly improved C-statistic (0.78 vs. 0.73; P = 0.035) and net reclassification index (14.9%; P < 0.001) compared to the original VILCAD score. Omitting LVEF, which might not be readily measureable in clinical practice, slightly reduced the accuracy of the new BIO-VILCAD score but still significantly improved risk classification (net reclassification improvement 12.5%; P < 0.001). CONCLUSION The VILCAD biomarker score based on routine parameters complemented by novel biomarkers outperforms previous risk algorithms and allows more accurate classification of patients with stable CAD, enabling physicians to choose more personalized treatment regimens for their patients.

Hemoglobin, iron metabolism and angiographic coronary artery disease (The Ludwigshafen Risk and Cardiovascular Health Study).

BACKGROUND Anemia has been shown to be a risk factor for coronary artery disease and mortality. The involvement of body iron stores in the development of CAD remains controversial. So far, studies that examined hemoglobin and parameters of iron metabolism simultaneously do not exist. METHODS AND RESULTS Hemoglobin and iron status were determined in 1480 patients with stable angiographic coronary artery disease (CAD) and in 682 individuals in whom CAD had been ruled out by angiography. The multivariate adjusted odds ratios (OR) for CAD in the lowest quartiles of hemoglobin and iron were 1.62 (95%CI: 1.22-2.16), and 2.05 (95%CI: 1.51-2.78), respectively compared to their highest gender-specific quartiles. The fully adjusted ORs for CAD in the lowest quartiles of transferrin saturation, ferritin (F) and soluble transferrin receptor (sTfR)/log10F index were 1.69 (95%CI: 1.25-2.27), 1.98 (95%CI: 1.48-2.65), and 1.64 (95%CI: 1.23-2.18), respectively compared to their highest gender-specific quartiles. When adjusting in addition for iron and ferritin the OR for CAD in the lowest quartiles of hemoglobin was still 1.40 (95%CI: 1.04-1.90) compared to the highest gender-specific quartiles. Thus, the associations between either iron status or low hemoglobin and CAD appeared independent from each other. The sTfR was only marginally associated with angiographic CAD. CONCLUSIONS Both low hemoglobin and iron depletion are independently associated with angiographic CAD.

Minimized extracorporeal circulation does not impair cognitive brain function after coronary artery bypass grafting

OBJECTIVES Objective evaluation of the impact of minimized extracorporeal circulation (MECC) on perioperative cognitive brain function in coronary artery bypass grafting (CABG) by electroencephalogram P300 wave event-related potentials and number connection test (NCT) as metrics of cognitive function. METHODS Cognitive brain function was assessed in 31 patients in 2013 with a mean age of 65 years [standard deviation (SD) 10] undergoing CABG by the use of MECC with P300 auditory evoked potentials (peak latencies in milliseconds) directly prior to intervention, 7 days after and 3 months later. Number connection test, serving as method of control, was performed simultaneously in all patients. RESULTS Seven days following CABG, cognitive P300 evoked potentials were comparable with preoperative baseline values [vertex (Cz) 376 (SD 11) ms vs 378 (18) ms, P = 0.39; frontal (Fz) 377 (11) vs 379 (21) ms, P = 0.53]. Cognitive brain function at 3 months was compared with baseline values [(Cz) 376 (11) ms vs 371 (14 ms) P = 0.09; (Fz) 377 (11) ms vs 371 (15) ms, P = 0.04]. Between the first postoperative measurement and 3 months later, significant improvement was observed [(Cz) 378 (18) ms vs 371 (14) ms, P = 0.03; (Fz) 379 (21) vs 371 (15) ms, P = 0.02]. Similar clearly corresponding patterns could be obtained via the number connection test. Results could be confirmed in repeated measures analysis of variance for Cz (P = 0.05) and (Fz) results (P = 0.04). CONCLUSIONS MECC does not adversely affect cognitive brain function after CABG. Additionally, these patients experience a substantial significant cognitive improvement after 3 months, evidentiary proving that the concept of MECC ensures safety and outcome in terms of brain function.

A novel blood-sparing agent in cardiac surgery? First in-patient experience with the synthetic serine protease inhibitor MDCO-2010: a phase II, randomized, double-blind, placebo-controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass

BACKGROUND Antifibrinolytics have been used for 2 decades to reduce bleeding in cardiac surgery. MDCO-2010 is a novel, synthetic, serine protease inhibitor. We describe the first experience with this drug in patients. METHODS In this phase II, double-blind, placebo-controlled study, 32 patients undergoing isolated primary coronary artery bypass grafting with cardiopulmonary bypass were randomly assigned to 1 of 5 increasing dosage groups of MDCO-2010. The primary aim was to evaluate pharmacokinetics (PK) with assessment of plasmatic concentrations of the drug, short-term safety, and tolerance of MDCO-2010. Secondary end points were influence on coagulation, chest tube drainage, and transfusion requirements. RESULTS PK analysis showed linear dosage-proportional correlation between MDCO-2010 infusion rate and PK parameters. Blood loss was significantly reduced in the 3 highest dosage groups compared with control (P = 0.002, 0.004 and 0.011, respectively). The incidence of allogeneic blood product transfusions was lower with MDCO-2010 4/24 (17%) vs 4/8 (50%) in the control group. MDCO-2010 exhibited dosage-dependent antifibrinolytic effects through suppression of D-dimer generation and inhibition of tissue plasminogen activator-induced lysis in ROTEM analysis as well as anticoagulant effects demonstrated by prolongation of activated clotting time and activated partial thromboplastin time. No systematic differences in markers of end organ function were observed among treatment groups. Three patients in the MDCO-2010 groups experienced serious adverse events. One patient experienced intraoperative thrombosis of venous grafts considered possibly related to the study drug. No reexploration for mediastinal bleeding was required, and there were no deaths. CONCLUSIONS This first-in-patient study demonstrated dosage-proportional PK for MDCO-2010 and reduction of chest tube drainage and transfusions in patients undergoing primary coronary artery bypass grafting. Antifibrinolytic and anticoagulant effects were demonstrated using various markers of coagulation. MDCO-2010 was well tolerated and showed an acceptable initial safety profile. Larger multi-institutional studies are warranted to further investigate the safety and efficacy of this compound.

Off-pump compared to minimal extracorporeal circulation surgery in coronary artery bypass grafting.

OBJECTIVE Coronary artery bypass grafting (CABG) using extracorporeal circulation (ECC) is still the gold standard. However, alternative techniques have been developed to avoid ECC and its potential adverse effects. These encompass minimal extracorporeal circulation (MECC) or off-pump coronary artery bypass grafting (OPCAB). However, the prevailing potential benefits when comparing MECC and OPCABG are not yet clearly established. METHODS In this retrospective study we investigated the potential benefits of MECC and OPCABG in 697 patients undergoing CABG. Of these, 555 patients had been operated with MECC and 142 off-pump. The primary endpoint was Troponin T level as an indicator for myocardial damage. RESULTS Study groups were not significantly different in general. However, patients undergoing OPCABG were significantly older (65.01 years ± 9.5 vs. 69.39 years ± 9.5; p value <0.001) with a higher Logistic EuroSCORE I (4.92% ± 6.5 vs. 5.88% ± 6.8; p value = 0.017). Operating off pump significantly reduced the need for intra-operative blood products (0.7% vs. 8.6%; p-value <0.001) and the length of stay in the intensive care unit (ICU) (2.04 days ± 2.63 vs. 2.76 days ± 2.79; p value <0.001). Regarding other blood values a significant difference could not be found in the adjusted calculations. The combined secondary endpoint, major cardiac or cerebrovascular events (MACCE), was equal in both groups as well. CONCLUSIONS Coronary artery bypass grafting using MECC or OPCABG are two comparable techniques with advantages for OPCABG regarding the reduced need for intra-operative blood products and shorter length of stay in the ICU. However serological values and combined endpoint MACCE did not differ significantly in both groups.

Aortic valve replacement and concomitant procedures with the Perceval valve: results of European trials.

BACKGROUND The Perceval (Sorin Group, Milan, Italy) is a self-anchoring sutureless aortic valve prosthesis. We report the short- to midterm results of combined aortic valve replacement (AVR) with concomitant procedures in elderly patients undergoing operation as part of 3 consecutive prospective multicenter European studies. METHODS From April 2007 to February 2013, 243 patients (mean age, 79.7 ± 5.1 years; female patients, 61%; median EuroSCORE, 9%) underwent AVR with concomitant procedures. The concomitant procedures were coronary artery bypass grafting (CABG) (182 cases), septal myectomy (21 cases), CABG + other procedures (18 cases), and 22 other procedures. Primary and secondary end points included implant feasibility and safety (for mortality and morbidity) and efficacy (New York Heart Association [NYHA] class improvement and hemodynamic results) of the prosthesis at the different follow-up periods. Data were expressed as mean ± standard deviation. Kaplan-Meier analysis was performed for survival analysis. RESULTS Mean aortic cross-clamp and extracorporeal circulation (ECC) times were 50.7 ± 22.8 minutes and 78.9 ± 32.3 minutes, respectively. Thirty-day mortality was 2.1%. Mean postoperative gradient and effective orifice area were 10.1 ± 4.7 mm Hg and 1.5 ± 0.4 cm(2) and 8.9 ± 5.6 mm Hg and 1.6 ± 0.4 cm(2), respectively, at 1 year. There were early explantations, 4 of which resulted from paravalvular leaks. One additional valve explantation resulted from aortic root bleeding, probably caused by excessively extensive decalcification. In the late period, there was 1 mild paravalvular leak and no intravalvular insufficiency. No migration, dislodgement, or degeneration of the valve occurred during follow-up. Median follow-up was 444 days. CONCLUSIONS These trials confirm the safety and efficacy of the Perceval sutureless aortic valve, especially in elderly patients requiring AVR + concomitant procedures. In this patient group, sutureless valves may be advantageous compared to transcatheter valve implantations as concomitant procedures other than percutaneous coronary artery angioplasty are not always possible in the latter.

Change in physical activity after smoking cessation: the Coronary Artery Risk Development in Young Adults (CARDIA) study

AIMS To estimate physical activity trajectories for people who quit smoking, and compare them to what would have been expected had smoking continued. DESIGN, SETTING AND PARTICIPANTS A total of 5115 participants in the Coronary Artery Risk Development in Young Adults Study (CARDIA) study, a population-based study of African American and European American people recruited at age 18-30 years in 1985/6 and followed over 25 years. MEASUREMENTS Physical activity was self-reported during clinical examinations at baseline (1985/6) and at years 2, 5, 7, 10, 15, 20 and 25 (2010/11); smoking status was reported each year (at examinations or by telephone, and imputed where missing). We used mixed linear models to estimate trajectories of physical activity under varying smoking conditions, with adjustment for participant characteristics and secular trends. FINDINGS We found significant interactions by race/sex (P = 0.02 for the interaction with cumulative years of smoking), hence we investigated the subgroups separately. Increasing years of smoking were associated with a decline in physical activity in black and white women and black men [e.g. coefficient for 10 years of smoking: -0.14; 95% confidence interval (CI) = -0.20 to -0.07, P < 0.001 for white women]. An increase in physical activity was associated with years since smoking cessation in white men (coefficient 0.06; 95% CI = 0 to 0.13, P = 0.05). The physical activity trajectory for people who quit diverged progressively towards higher physical activity from the expected trajectory had smoking continued. For example, physical activity was 34% higher (95% CI = 18 to 52%; P < 0.001) for white women 10 years after stopping compared with continuing smoking for those 10 years (P = 0.21 for race/sex differences). CONCLUSIONS Smokers who quit have progressively higher levels of physical activity in the years after quitting compared with continuing smokers.

Sex- and gender-related risk factor burden in patients with premature acute coronary syndrome

BACKGROUND Few contemporary data exist on traditional (TRF) and non-TRF (NTRF) burden in patients with premature acute coronary syndrome (ACS). METHODS Prevalence of TRFs and NTRFs were measured in 1015 young (55 years old or younger) ACS patients recruited from 26 centres in Canada, the United States, and Switzerland. Risk factors were compared across sex and family history categories, and against a sample of the general Canadian population based on the 2000-2001 Canadian Community Health Survey. The 10- and 30-year risks of cardiovascular disease (CVD) were estimated using Framingham Risk Scores. RESULTS Risk factors were more prevalent in premature ACS patients compared with the general population. Young women with a family history of coronary artery disease showed the greatest risk factor burden including TRFs of hypertension (67%), dyslipidemia (67%), obesity (53%), smoking (42%), and diabetes (33%), and NTRFs of anxiety (55%), low household income (44%), and depression (37%). The estimated median 10-year risk of CVD was 7% (interquartile range [IQR], 3%-9%) in women and 13% (IQR, 7%-17%) in men, whereas the 30-year risk of CVD was 36% (IQR, 22%-49%) in women and 44% (IQR, 31%-57%) in men. CONCLUSIONS Patients with premature ACS, especially women with a positive family history, are characterized by a very high risk factor burden that is poorly captured by 10-year risk estimates but better captured by 30-year estimates. Consideration of NTRFs and use of 30-year risk estimates might better estimate risk in young individuals and improve the prevention of premature ACS.