Mid-regional pro-atrial natriuretic peptide independently predicts short-term mortality in COVID-19.

BACKGROUND: Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a strong prognostic marker in several inflammatory, respiratory and cardiovascular conditions, but has not been studied in COVID-19 yet. METHODS: This prospective, observational study of patients with COVID-19 infection was conducted from 6 June to 26 November 2020 in different wards of a tertiary hospital. MR-proANP, N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitive cardiac troponin I levels on admission were collected and tested for their association with disease severity and 28-day mortality. RESULTS: A total of 213 eligible patients with COVID-19 were included in the final analyses of whom 13.2% (n = 28) died within 28 days. Median levels of MR-proANP at admission were significantly higher in nonsurvivors (307 pmol/L IQR, [161 - 532] vs 75 pmol/L [IQR, 43 - 153], P < .001) compared to survivors and increased with disease severity and level of hypoxaemia. The area under the ROC curve for MR-proANP predicting 28-day mortality was 0.832 (95% CI 0.753 - 0.912, P < .001). An optimal cut-off point of 160 pmol/L yielded a sensitivity of 82.1% and a specificity of 76.2%. MR-proANP was a significant predictor of 28-day mortality independent of clinical confounders, comorbidities and established prognostic markers of COVID-19 (HR 2.77, 95% CI 1.21 - 6.37; P = .016), while NT-proBNP failed to independently predict 28-day mortality and had a numerically lower AUC compared to MR-proANP. CONCLUSION: Higher levels of MR-proANP at admission are associated with disease severity of COVID-19 and act as a powerful and independent prognostic marker of 28-day mortality.

Immature cell fractions after cessation of chronic P2Y12-inhibition in patients with coronary artery diseases.

Changes in circulating cell populations may promote ischemic events that occur soon after discontinuation of P2Y12-inhibition. The aim of the study was to track the course of thrombopoietic and erythropoietic cells in patients with coronary artery diseases (CAD) after planned and physician-driven cessation of chronic P2Y12-inhibition (clopidogrel 75 mg OD, or prasugrel 10 mg OD, or ticagrelor 90 mg BID). Cell fractions were determined in 62 patients at baseline (the last day of P2Y12-inhibitor intake), on day-10, day-30, and day-180 thereafter. Immature platelet fraction (IPF), immature reticulocyte fraction (IRF), reticulocyte hemoglobin content (Ret-Hb) and red blood cell count (RBC) significantly increased from baseline to day-180 (IPF: p = .003; IRF: p = .013; Ret-Hb: p < .001; RBC: p = .044). Platelet count, leucocyte count and immature granulocyte fraction did not change over time (p = .561, p = .869, and p = .161, respectively). Fibrinogen levels significantly declined over time (p = .011), thrombopoietin levels increased in a non-significant manner (p = .379). We did not observe any significant interaction with choice of P2Y12-inhibitor, therefore suggesting a drug class-effect. Our data shows, that discontinuation of dual antiplatelet therapy is associated with raised thrombopoietic and erythropoietic activity in the bone marrow, without significant upregulation of thrombopoietin. This provides further evidence for a direct stimulation of precursor cells by P2Y12-inhibitors.

Effect of marathon and ultra-marathon on inflammation and iron homeostasis.

The physiological response to high-level endurance exercise, such as running a marathon, poses several beneficial but also potentially harmful metabolic changes. The objective of this study was to determine the impact of marathon (M) and ultra-marathon (UM) on inflammation and iron homeostasis in paired samples. Fifteen well-trained, non-professional endurance athletes (14 males, 1 female) performed both a 130 km ultra-marathon and a traditional 42.195 km marathon. We determined markers of inflammation and iron homeostasis before, immediately after, and within 5 days after finishing each run, respectively. Biomarkers of inflammation (leucocytes, neutrophil granulocytes, monocytes, and c-reactive protein [CRP]) increased significantly after both marathon and ultra-marathon with higher levels of CRP after ultra-marathon compared with marathon both immediately after the race (18.15 ± 12.41 vs 5.58 ± 9.65 mg/L, P < .001) and at follow-up (15.67 ± 16.97 vs 7.19 ± 7.75 mg/L, P = .045) Concentrations of ferritin also increased significantly after both races and remained high at follow-up. Higher levels of ferritin immediately after the race (111.5 ± 103.2 vs 84.8 ± 86.3, P = .001) and at follow-up (102.7 ± 79.5 vs 74.6 ± 65.6, P = .001) were found in ultra-marathon finishers. The observed increase of serum iron and transferrin saturation (TSAT) after marathon and the decrease of serum iron and TSAT after ultra-marathon resulted in a significant absolute difference between the two races. The present data suggest a higher degree of inflammation after ultra-marathon compared with marathon. Markers of iron homeostasis also showed different response patterns with regard to running distance.

Impact of platelet turnover on long-term adverse cardiovascular outcomes in patients undergoing percutaneous coronary intervention.

BACKGROUND: Increased platelet turnover and high platelet reactivity are associated with short-term major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) or stable coronary artery disease (SCAD). We investigated the impact of platelet turnover on long-term MACE. METHODS: Consecutive patients presenting with ACS or SCAD undergoing PCI between 2009 and 2010 were included. All patients received clopidogrel and aspirin as dual antithrombotic therapy regimen. Multivariable Cox proportional hazard models were applied to assess the prognostic impact of platelet turnover (reticulated platelet count [RPC], mean platelet volume [MPV]) and function on long-term MACE, a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. RESULTS: In total, 477 patients were eligible. Mean age was 64.3 ± 12.7 years, 68.8% were male. Median follow-up was 5.8 (IQR 4.2-6.5) years. Median RPC was 7.6 (IQR 5.6-10.4) g/L and median MPV was 10.7 (IQR 10.1-11.3) fL. In univariable analysis, RPC was associated with MACE, both as continuous (HR 1.064 [95%CI 1.021-1.111]; P = .006) and dichotomized (HR 1.693 [95%CI 1.156-2.481]; P = .006) variable. After adjustment, continuous RPC (HR 1.055 [95%CI 1.012-1.099]; P = .010) and dichotomized RPC (HR 1.716 [95%CI 1.152-2.559]; P = .007) remained significantly associated with MACE. Neither MPV nor platelet function testing was associated with long-term adverse outcome. CONCLUSION: Increased platelet turnover is associated with long-term adverse outcome in patients with coronary artery disease undergoing PCI. Platelet turnover represents a new marker of atherothrombotic risk and might help to guide composition or duration of antiplatelet therapy.

Twenty-four-hour time dependency of clopidogrel effects in patients with acute coronary syndromes: The CiCAD-Study.

Long-term evidence shows an increased risk of cardiovascular events in the morning hours and recent studies in aspirin-treated patients have shown increased platelet reactivity at the end of the dosing interval. Similar pharmacodynamic analyses of adenosine-diphosphate (ADP) receptor inhibitors are scarce. We therefore investigated changes in clopidogrel-dependent platelet function and activation over 24 h and whether enhanced platelet turnover might explain diurnal variability of platelet function and activation. Twenty-one patients after acute coronary syndromes (ACS) on maintenance doses of clopidogrel (75 mg) and aspirin (100 mg) Once per day (OD) were included. Blood was collected at five time points in 24 h. Platelet function and activation was analyzed by vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P), Verify Now, multiple electrode aggregometry (MEA), and platelet PAC-1 and P-selectin (P-sel) expression. Additionally, platelet count, mean platelet volume (MPV), and reticulated platelet fraction (RPF) were analyzed. There was significant diurnal variability of clopidogrel effects as documented with VASP-P, Verify Now, and PAC-1 and P-sel (all p < 0.05), whereas MEA did not differ over 24 h. Neither MPV nor RPF varied significantly over 24 h. In patients with high RPF, platelet function and activation was significantly higher in all assays, compared to patients with low RPF (all p < 0.05). However, the changes over time in low versus high RPF groups were similar. ADP-dependent platelet function and activation recovers significantly at the end of the 24-h dosing interval in patients with ACS on a maintenance dose of clopidogrel and aspirin. Although platelet function and activation is increased in patients with higher RPF, platelet turnover might not explain the observed diurnal variability.

Determinants of growth differentiation factor 15 in patients with stable and acute coronary artery disease. A prospective observational study.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor ß family and has been associated with inflammation, cancer, aging, diabetes mellitus (DM) and atherosclerosis. Determinants of GDF-15 have been investigated in several conditions. We aimed to investigate determinants of GDF-15 plasma levels in patients with angiographically proven coronary artery disease (CAD). METHODS: Four hundred and seventy three consecutive patients with CAD were investigated between May 2009 and February 2011. Patients were separated into those with stable CAD (SCAD) and with ST-elevation and non-ST-elevation myocardial infarction (STEMI and NSTEMI). Blood samples for determination of GDF-15 were obtained before coronary angiography. Determinant of GDF-15 levels were analyzed by logistic regression analysis in unadjusted and adjusted models. Study endpoints were cardiovascular death (CV-death), myocardial infarction, unstable angina, unplanned revascularization, stent thrombosis and stroke assessed at a mean follow-up of 188 (177.2-243) days. RESULTS: Overall median and (25-27th percentile) GDF-15 level was 1212.8 pg/ml (833.2-1957 pg/ml). GDF-15 was significantly higher in STEMI compared to SCAD and NSTEMI groups (P < 0.0001). In a multivariate regression analysis advanced age, DM, acute hyperglycemia (AHG), CRP and chronic kidney disease (CKD) were independent predictors of elevated GDF-15 levels (P < 0.05). Receiver operating curve analysis of GDF-15 for prediction of CV-death showed an area under the curve of 0.852 with a confidence interval of 0.745-0.960, P < 0.0001. The estimated cut-off was 2094.6 pg/ml with a sensitivity of 76 % and specificity of 80 %. CONCLUSION: In patients with CAD undergoing PCI with stent implantation, GDF-15 is determined by advanced age, acute and chronic hyperglycemia, inflammation and CKD. GDF-15 is a valuable predictor of CV-death in a population of CAD patients after PCI.

Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention.

AIMS: Although platelet reactivity during P2Y12-inhibitors is associated with stent thrombosis (ST) and bleeding, standardized and clinically validated thresholds for accurate risk stratification after percutaneous coronary intervention (PCI) are lacking. We sought to determine the prognostic value of low platelet reactivity (LPR), optimal platelet reactivity (OPR), or high platelet reactivity (HPR) by applying uniform cut-off values for standardized devices. METHODS AND RESULTS: Authors of studies published before January 2015, reporting associations between platelet reactivity, ST, and major bleeding were contacted for a collaborative analysis using consensus-defined, uniform cut-offs for standardized platelet function assays. Based on best available evidence for each device (exploratory studies), LPR-OPR-HPR categories were defined as <95, 95-208, and >208 PRU for VerifyNow, <19, 19-46, and >46 U for the Multiplate analyser and <16, 16-50, and >50% for VASP assay. Seventeen studies including 20 839 patients were used for the analysis; 97% were treated with clopidogrel and 3% with prasugrel. Patients with HPR had significantly higher risk for ST [risk ratio (RR) and 95% CI: 2.73 (2.03-3.69), P < 0.00001], yet a slight reduction in bleeding [RR: 0.84 (0.71-0.99), P = 0.04] compared with those with OPR. In contrast, patients with LPR had a higher risk for bleeding [RR: 1.74 (1.47-2.06), P < 0.00001], without any further benefit in ST [RR: 1.06 (0.68-1.65), P = 0.78] in contrast to OPR. Mortality was significantly higher in patients with HPR compared with other categories (P < 0.05). Validation cohorts (n = 14) confirmed all results of exploratory studies (n = 3). CONCLUSIONS: Platelet reactivity assessment during thienopyridine-type P2Y12-inhibitors identifies PCI-treated patients at higher risk for mortality and ST (HPR) or at an elevated risk for bleeding (LPR).

Variability of on-treatment platelet reactivity in patients on clopidogrel.

Response to clopidogrel therapy is subject to inter-individual variability. However, data with regard to on-treatment platelet reactivity over time in patients undergoing coronary stenting are scarce. For this prospective observational study, 102 consecutive patients on dual antiplatelet therapy undergoing coronary stenting due to stable coronary artery disease (CAD; n = 29), non ST-elevation acute coronary syndrome (NSTE-ACS; n = 45) and ST-elevation myocardial infarction (STEMI; n = 28) were enrolled. Vasodilator-stimulated phosphoprotein-phosphorylation assay was performed at baseline, as well as 1, 3 and 6 months thereafter. Platelet reactivity index (PRI) measured after 1, 3 and 6 months was lower compared to baseline values (p < 0.001). Variables responsible for reduced response to clopidogrel at baseline (reticulated platelet fraction, simvastatin therapy) and during steady-state phase (body mass index, blood glucose concentrations, cholesterol/HDL-ratio and quality of life score) were different. High on-treatment platelet reactivity (HTPR)-phenotype (cut-off = 50% PRI) within the first month changed in 31% of stable CAD, 33% of NSTE-ACS and 39% of STEMI patients, respectively. HTPR-phenotype in the steady-state phase (month 1 to 6) changed in 45% of stable CAD, 33% of NSTE-ACS and 25% of STEMI patients. Response to clopidogrel and accordingly platelet function might vary over time, especially when a cut-off based approach, is used. There was a significant reduction of on-treatment platelet reactivity within the first month after percutaneous coronary intervention with stenting which was maintained for up to 6 months. Variables associated with reduced response to clopidogrel at baseline and during steady-state phase were different, as the latter mainly reflected an unfavorable metabolic profile, comprising elevated BMI, blood glucose levels as well as cholesterol/HDL-ratio.

Impact of an Ultra-Endurance Marathon on Cardiac Function in Association with Cardiovascular Biomarkers.

BACKGROUND: Participation in ultra-endurance races may lead to a transient decline in cardiac function and increased cardiovascular biomarkers. This study aims to assess alterations in biventricular function immediately and five days after the competition in relation to elevation of high-sensitivity cardiac Troponin I (hs-cTnI) and N-terminal-pro-brain-natriuretic-peptide (NT-proBNP). METHODS AND RESULTS: Fifteen participants of an ultramarathon (UM) with a running distance of 130 km were included. Transthoracic echocardiography and quantification of biomarkers was performed before, immediately after and five days after the race. A significant reduction in right ventricular fractional area change (FAC) was observed after the race (48.0 ± 4.6% vs. 46.7 ± 3.8%, p = 0.011) that persisted five days later (48.0 ± 4.6% vs. 46.3 ± 3.9%, p = 0.027). No difference in left ventricular ejection fraction (LVEF) was found (p = 0.510). Upon stratification according to biomarkers, participants with NT-proBNP above the median had a significantly reduced LVEF directly (60.8 ± 3.6% vs. 56.9 ± 4.8%, p = 0.030) and five days after the race (60.8 ± 3.6% vs. 55.3 ± 4.5%, p = 0.007) compared to baseline values. FAC was significantly reduced five days after the race (48.4 ± 5.1 vs. 44.3 ± 3.9, p = 0.044). Athletes with hs-cTnI above the median had a significantly reduced FAC directly after the race (48.1 ± 4.6 vs. 46.5 ± 4.4, p = 0.038), while no difference in LVEF was observed. No alteration in cardiac function was observed if hs-cTnI or NT-proBNP was below the median. CONCLUSION: A slight decline in cardiac function after prolonged strenuous exercise was observed in athletes with an elevation of hs-cTnI and NT-proBNP above the median but not below.

Biomarkers in acute coronary artery disease.

Death from coronary artery disease is by far the leading cause of death worldwide. There is no doubt that a better understanding of atherothrombosis has guided development of improved diagnostic facilities as well as revascularization technologies in combination with current antithrombotic strategies that have altogether impressively reduced acute thromboembolic complications and death from cardiovascular causes within the last decades. However, the rate of ischemic complications even after optimal revascularization and medical therapy remains high. Similarly, morbidity and death associated with chronic ischemic heart disease and ischemic cardiomyopathy respectively are constantly rising. Therefore, there is still a strong need for effective primary prevention strategies, fast and accurate diagnostic procedures as well as for new and smart antithrombotic drugs. The review focuses on cardiac troponins, as relevant markers of myocardial necrosis, currently used in the diagnostic process of acute coronary syndrome. Furthermore, we will discuss the potential role of copeptin, a new marker of acute endogenous stress in acute coronary syndrome patients, as faster diagnosis might lead to faster treatment as well as improved short- and long-term outcome following acute coronary syndrome. Finally, platelets are an old, yet rediscovered biomarker for ischemic cardiovascular outcomes that might be used to estimate the individual bleeding or thrombotic risk and to tailor antiplatelet therapy.

Multisystem inflammatory syndrome in adults in a young male following severe acute respiratory syndrome coronavirus-2 infection: a case report.

BACKGROUND: Multisystem inflammatory syndrome in adults (MIS-A) is a rare but potentially life-threatening condition that may occur during or in the weeks following severe acute respiratory syndrome coronavirus-2 infection. To date, only case reports and small case series have described typical findings and management of patients with MIS-A. The prevalence of MIS-A is largely unknown due to the lack of data. CASE SUMMARY: A 30-year-old male patient presented to the emergency department with new-onset of fever, chest discomfort, macular exanthema, abdominal pain, mild dyspnoea, and coughing. The patient reported a mildly symptomatic recent coronavirus disease-19 (COVID-19). Significantly increased markers of inflammation and a modest increase of cardiac troponin were found upon laboratory work-up at admission. Despite broad-spectrum antibiotics, the patient's clinical status deteriorated continuously. Cardiac work-up, including echocardiography, coronary angiography, and cardiac magnetic resonance imaging, was done and signs of acute myocarditis with mildly reduced left ventricular systolic function were found. The complex multi-organ symptom constellation facilitated the diagnosis of MIS-A following COVID-19 infection. Besides aspirin, intravenous, continuous hydrocortisone treatment was initiated, resulting in a prompt improvement of symptoms and clinical findings. DISCUSSION: We report a case of successfully treated MIS-A in the context of COVID-19, which further adds to the existing literature on this rare but clinically significant condition. Our case highlights the necessity of an interdisciplinary approach to correctly diagnose this complex, multi-organ disease and enable fast and appropriate management of these high-risk patients.

Improvement of outcome prediction of hospitalized patients with COVID-19 by a dual marker strategy using high-sensitive cardiac troponin I and copeptin.

BACKGROUND: COVID-19 has been associated with a high prevalence of myocardial injury and increased cardiovascular morbidity. Copeptin, a marker of vasopressin release, has been previously established as a risk marker in both infectious and cardiovascular disease. METHODS: This prospective, observational study of patients with laboratory-confirmed COVID-19 infection was conducted from June 6th to November 26th, 2020 in a tertiary care hospital. Copeptin and high-sensitive cardiac troponin I (hs-cTnI) levels on admission were collected and tested for their association with the primary composite endpoint of ICU admission or 28-day mortality. RESULTS: A total of 213 eligible patients with COVID-19 were included of whom 55 (25.8%) reached the primary endpoint. Median levels of copeptin and hs-cTnI at admission were significantly higher in patients with an adverse outcome (Copeptin 29.6 pmol/L, [IQR, 16.2-77.8] vs 17.2 pmol/L [IQR, 7.4-41.0] and hs-cTnI 22.8 ng/L [IQR, 11.5-97.5] vs 10.2 ng/L [5.5-23.1], P < 0.001 respectively). ROC analysis demonstrated an optimal cut-off of 19.3 pmol/L for copeptin and 16.8 ng/L for hs-cTnI and an increase of either biomarker was significantly associated with the primary endpoint. The combination of raised hs-cTnI and copeptin yielded a superior prognostic value to individual measurement of biomarkers and was a strong prognostic marker upon multivariable logistic regression analysis (OR 4.274 [95% CI, 1.995-9.154], P < 0.001). Addition of copeptin and hs-cTnI to established risk models improved C-statistics and net reclassification indices. CONCLUSION: The combination of raised copeptin and hs-cTnI upon admission is an independent predictor of ICU admission or 28-day mortality in hospitalized patients with COVID-19.

Neurotensin and Adverse Cardiovascular Outcomes in Patients Undergoing Percutaneous Coronary Intervention.

Background: Neurotensin is involved in fatty acid and glucose metabolism and promotes the development of obesity and diabetes. These associations appear to be more pronounced in women. We investigated the association of neurotensin with long-term major adverse cardiovascular events (MACE) in patients presenting with acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) undergoing percutaneous coronary intervention (PCI). Methods: We included 452 consecutive patients [144 (31.9%) females] undergoing PCI for ACS or CCS. Plasma samples drawn after PCI were analyzed for neurotensin with an enzyme-linked immunoassay. As primary endpoint, a composite of MACE including all-cause death, non-fatal myocardial infarction and non-fatal stroke during 7 years of follow-up was investigated. As secondary endpoint, we investigated all-cause death. Results: Neurotensin levels did not differ between male and female patients (p = 0.560). MACE occurred in 150 (33.2%) patients. Restricted cubic splines demonstrated a U-shaped association of log-transformed neurotensin with the primary and secondary endpoint. Therefore, we dichotomized our cohort according to tertiles of log-transformed neurotensin. In Kaplan-Meier analysis including the total cohort and restricted to male patients log- neurotensin tertiles were not associated with MACE (both p > 0.05). Moreover, in the overall cohort and in male patients multivariable Cox regression analysis log-neurotensin tertiles were not associated with MACE or with all-cause death (all p > 0.05). However, in female patients log-neurotensin was associated with MACE in Kaplan-Meier analysis (log-rank p = 0.013). Also, after multivariable adjustment female patients in the first tertile had a significantly increased risk for MACE compared to female patients in the second tertile [HR 3.84 (95% CI 1.71-8.60), p = 0.001]. There was tendency for increased risk in female patients in the third tertile compared to the second tertile [HR 2.14 (95% CI 0.97-4.73), p = 0.058]. Moreover, in female patients the [first and the third tertile of log- neurotensin were associated with all-cause death 1s vs. 2nd tertile: HR 3.03 (95% CI 1.21-7.63), p = 0.018; 3rd vs. 2nd tertile: HR 3.01 (95% CI 1.22-7.44), p = 0.016]. Conclusion: In female patients with CAD undergoing PCI, neurotensin has a U-shaped relationship with adverse outcomes. These data suggest a sex specific association between neurotensin and long-term adverse events after PCI.

Admission proinsulin is associated with mortality in patients with admission hyperglycemia during acute coronary syndrome: results from a pilot observational study.

BACKGROUND: Acute hyperglycemia (AHG) is associated with mortality in patients with acute coronary syndrome (ACS). The extent to which hyperproinsulinemia contributes to worse clinical outcomes for this specific patient population is unknown. METHODS: We included 308 consecutive ACS patients who underwent coronary angioplasty in this pilot observational study. Patients were separated into 3 groups: patients with proven diabetes mellitus (DM group) (n =55), nondiabetic patients with a normal glucose concentration at admission (NAG group) (n =175), and nondiabetic patients with AHG at presentation (AHG group) (n =78). Blood samples for glucose, insulin, and proinsulin measurements were obtained at admission. The primary end point of the study was all-cause mortality, which was assessed at a mean follow-up of 19 months (interquartile range, 12-28 months). RESULTS: Patients in the AHG and DM groups had significantly (P =0.048) higher all-cause mortality compared with the NAG group. A univariate Cox regression analysis revealed that the proinsulin concentration was significantly associated with all-cause mortality for all study participants (hazard ratio, 1.013; 95% CI, 1.002-1.024; P =0.023). AHG patients with increased proinsulin concentrations showed a mortality rate similar to that of DM patients but had a significantly higher mortality rate than patients with AHG and a low proinsulin concentration (χ² =7.57; P =0.006) and patients with NAG (with or without increased proinsulin) [χ² =7.66 (P =0.006) and 13.98 (P < 0.001), respectively]. A multivariate regression analysis revealed that the concentrations of glucose and proinsulin at admission were significant (P =0.002) predictors of all-cause mortality. CONCLUSIONS: An increased proinsulin concentration may be a marker for mortality in ACS patients with hyperglycemia at admission and without known diabetes. Further studies are needed to evaluate the role of metabolic parameters such as proinsulin.

Von Willebrand Factor and ADAMTS13 and long-term outcomes in patients undergoing percutaneous coronary intervention.

BACKGROUND: Von Willebrand factor (VWF) and its cleaving protease a disintegrin-like and metalloprotease with thrombospondin type I repeats 13 (ADAMTS13) are pivotal mediators of thrombosis and are associated with the progression of atherosclerosis. We investigated the impact of VWF, ADAMTS13 and VWF/ADAMTS13 on long-term major adverse cardiovascular outcomes (MACE) in patients undergoing percutaneous coronary intervention (PCI). METHODS: We analysed 701 patients undergoing PCI between 2003 and 2006. VWF and ADAMTS13 antigen levels were measured before PCI. As primary endpoint, we investigated MACE, a composite of all-cause mortality, myocardial infarction or ischemic stroke during 8 years of follow-up. As secondary endpoint, we investigated all-cause mortality. RESULTS: Mean age was 63.8 years, 496 (70.8%) were male. Acute coronary syndrome (ACS) was diagnosed in 347 (49.5%) patients, stable coronary artery disease (SCAD) in 354 (50.5%). During follow-up 228 (32.5%) patients experienced MACE, and 161 (23.0%) died. In ACS patients, VWF was significantly associated with MACE (HR 1.402 (95%CI 1.003-1.959), p = 0.048), whereas ADAMTS13 and VWF/ADAMTS13 had no predictive value. In SCAD, neither VWF, ADAMTS13, nor VWF/ADAMTS13 correlated with MACE. VWF was significantly associated with all-cause death in ACS patients (HR 1.841 (95%CI 1.187-2.856), p = 0.006), but not in SCAD (1.394 (95%CI 0.856-2.269), p = 0.181). ADAMTS13 and VWF/ADAMTS13 were not correlated with ACS and SCAD, respectively. CONCLUSION: VWF but not ADAMTS13 and VWF/ADAMTS13 was associated with MACE and mortality in patients with ACS but not SCAD. This finding highlights the importance of VWF as an essential marker of risk in patients with ACS.

Impact of ultra-marathon and marathon on biomarkers of myocyte necrosis and cardiac congestion: a prospective observational study.

BACKGROUND: An elevation of cardiac biomarkers is observed after intense or long-lasting physical activity. However, a recent meta-analysis has suggested that there might be an inverse relationship between duration of exercise and degree of biomarker elevation. The objective of this observational study was to investigate the impact of ultra-marathon (UM) vs. marathon (M) on biomarkers of myocyte necrosis and hemodynamic stress/congestion. METHODS: Well-trained endurance athletes were recruited to participate in a 130-km UM and a M run. Troponin I (TnI), creatine kinase (CK), N-terminal pro-brain natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), and copeptin were measured after both events, respectively. RESULTS: Fifteen athletes (14 males, one female) were included. There was no difference in exercise intensity according to the Borg scale (UM 16 [IQR 15-17], M 16 [IQR 14-17]; p = 0.424). Biomarkers of myocyte necrosis both differed significantly with higher levels of TnI (UM 0.056 ng/L [IQR 0.022-0.104), M 0.028 ng/L [IQR 0.022-0.049]; p = 0.016) and CK (UM 6992 U/l [IQR 2886-23038], M 425 U/l [IQR 327-681]; p = 0.001) after UM compared to M. Also, NT-proBNP (UM 723 ng/L [IQR 378-1152], M 132 ng/L [IQR 64-198]; p = 0.001) and MR-proADM (UM 1.012 nmol/L [IQR 0.753-0.975], M 0.877 nmol/L [IQR 0.550-0.985]; p = 0.023) as markers of myocardial congestion were significantly higher after UM. There was a tendency for elevated copeptin levels after M, but did not reach statistical significance (p = 0.078). CONCLUSION: Ultra-marathon is associated with higher levels of biomarkers of myocyte necrosis and cardiac congestion compared to marathon, highlighting the impact of exercise duration on the cardiovascular system.

Neuromuscular electrical stimulation reduces skeletal muscle protein degradation and stimulates insulin-like growth factors in an age- and current-dependent manner: a randomized, controlled clinical trial in major abdominal surgical patients.

OBJECTIVE: To investigate the effect of neuromuscular electrical stimulation (NMES) on skeletal muscle metabolism after major abdominal surgery. SUMMARY BACKGROUND DATA: Protein catabolism associated with surgical interventions leads to reduced muscle strength, increased clinical complications and prolonged convalescence. Immobilization is suggested as a major stimulus for muscle wasting. This study investigates the potency of NMES on skeletal muscle growth factors and degradation processes in surgical patients. METHODS: This observer blind study included 26 patients after major abdominal surgery mainly due to cancer aged 60 +/- 10 years. Starting on the first postoperative day, 1 randomly assigned thigh of each patient was treated on 4 consecutive days with NMES, whereas the other leg was used as sham-stimulated control. Thereafter, muscle biopsies from both legs were performed. Differences in mRNA level, protein expression, and enzyme activity between legs were analyzed by cross-over analysis of variance (Clinical Trial Registration Number: NCT00635440). RESULTS: NMES significantly increased total RNA content and total sarcoplasmatic protein content. NMES significantly reduced ubiquitin-conjugated sarcoplasmatic proteins and proteasome activity. The mechano growth factor mRNA level correlated positively with the applied current and negatively with the body mass index of the patients. The increase in insulin like growth factor-1Ea mRNA after NMES correlated negatively with the age of the patients. CONCLUSIONS: This study shows that NMES significantly increases total RNA content and reduces protein degradation in postoperative patients. Moreover, the induction of growth factors by NMES reveals dependency on body mass index, age, and applied current. We conclude that NMES is a useful clinical tool to reduce protein catabolism in postoperative patients.

Prognostic impact of familial hypercholesterolemia on long-term outcomes in patients undergoing percutaneous coronary intervention.

BACKGROUND: Patients with familial hypercholesterolemia (FH) are at increased risk for premature and subsequent cardiovascular disease. Data on long-term major adverse cardiovascular events (MACE) in patients with FH after percutaneous coronary intervention (PCI) in the era of high-intensity statins are scarce. OBJECTIVE: We assessed the prognostic impact of clinically diagnosed FH on long-term MACE, a composite of all-cause death, myocardial infarction, and ischemic stroke in patients admitted for stable coronary artery disease (SCAD) or acute coronary syndromes (ACSs) undergoing PCI. METHODS: FH was diagnosed according to the Dutch Lipid Clinic Network diagnosis criteria: "Unlikely FH" diagnosis was defined as 0 to 2 points, "possible FH" as 3 to 5 points, and "probable/definite FH" diagnosis as 6 or higher. RESULTS: From a total of 1550 eligible patients (47.4% were admitted for SCAD and 52.6% for ACS), 77 (5.0%) were classified as probable/definite FH, 332 (21.4%) as possible FH, and 1141 (73.6%) as unlikely FH. Mean follow-up was 6.0 ± 2.4 years. After adjustment for possible confounders, patients classified with probable or definite FH (hazard ratio [HR] 1.922 [95% confidence interval (CI) 1.220-2.999]; P = .004), but not patients with possible FH (HR 1.105 [95% CI 0.843-1.447]; P = .470) faced a significant, approximately 2-fold increased risk of MACE compared with patients with unlikely FH. CONCLUSION: After adjustment for confounders, patients with probable or definite FH faced an approximate 2-fold increased risk for long-term MACE compared with patients without FH despite the widespread use of high-intensity statins. The new option of proprotein convertase subtilisin/kexin type 9 gene inhibitors in addition to other current optimal lipid-lowering strategies might help to further improve clinical outcome in patients with probable/definite FH.

Prognostic Impact of Soluble P-Selectin on Long-Term Adverse Cardiovascular Outcomes in Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Soluble P-selectin (sP-selectin), a biomarker of inflammatory pathologies including cardiovascular disease, is known to have pro-atherosclerotic effects such as the ability to increase leukocyte recruitment and modulate thrombotic response. We aimed to assess the impact of sP-selectin on long-term major adverse cardiovascular events (MACE) in patients after coronary stenting for coronary artery disease. METHODS: We analysed 733 patients of a single-centre registry undergoing percutaneous coronary intervention (PCI) between 2003 and 2006. Plasma samples were analysed for sP-selectin antigen concentration with an enzyme-linked immunoassay. The study population was categorized according to sP-selectin quartiles. Endpoint of the study was long-term MACE, a composite of all-cause death, myocardial infarction (MI) and stroke. RESULTS: Of the total patient cohort, 361 (49.2%) patients were admitted for stable coronary artery disease and 372 (50.8%) for acute coronary syndrome. Median age was 64 years and 70.7% were male. After a mean follow-up period of 9.7 years, MACE occurred in 344 (46.9%) patients. The primary endpoint components of all-cause death occurred in 211 (28.8%), MI in 88 (12.0%) and ischaemic stroke in 45 (6.1%) patients. After adjustment for confounders, patients in the 2nd, 3rd and 4th quartile were at higher risk for MACE compared with the 1st quartile (hazard ration [HR], 1.234 [0.899-1.695], p = 0.193; HR, 1.480 [1.085-2.019], p = 0.013; and HR, 1.571 [1.115-2.152], p = 0.004). sP-selectin as continuous variable model was significantly associated with MACE after adjustment (HR per 1 ng/mL increase of 1.009 [95% confidence interval, 1.002-1.017]; p = 0.016). CONCLUSION: Elevated levels of sP-selectin were associated with increased risk for long-term MACE in patients undergoing PCI.