Peripheral blood mononuclear cell hyperresponsiveness in patients with premature myocardial infarction without traditional risk factors.

An increasing number of patients develop an atherothrombotic myocardial infarction (MI) in the absence of standard modifiable risk factors (SMuRFs). Monocytes and macrophages regulate the development of atherosclerosis, and monocytes can adopt a long-term hyperinflammatory phenotype by epigenetic reprogramming, which can contribute to atherogenesis (called "trained immunity"). We assessed circulating monocyte phenotype and function and specific histone marks associated with trained immunity in SMuRFless patients with MI and matched healthy controls. Even in the absence of systemic inflammation, monocytes from SMuRFless patients with MI had an increased overall cytokine production capacity, with the strongest difference for LPS-induced interleukin-10 production, which was associated with an enrichment of the permissive histone marker H3K4me3 at the promoter region. Considering the lack of intervenable risk factors in these patients, trained immunity could be a promising target for future therapy.

Rapid Improvements in Physical Activity and Sedentary Behavior in Patients With Acute Myocardial Infarction Immediately Following Hospital Discharge.

Background Little is known about changes in physical activity (PA) and sedentary behavior (SB) patterns in the acute phase of a myocardial infarction (MI). We objectively assessed PA and SB during hospitalization and the first week after discharge. Methods and Results Consecutively admitted patients hospitalized with an MI were approached to participate in this prospective cohort study. SB, light-intensity PA, and moderate-vigorous intensity PA were objectively assessed for 24 h/d during hospitalization and up to 7 days after discharge in 165 patients. Changes in PA and SB from the hospital to home phase were evaluated using mixed-model analyses, and outcomes were stratified for predefined subgroups based on patient characteristics. Patients (78% men) were aged 65±10 years and diagnosed with ST-segment-elevation MI (50%) or non-ST-segment-elevation MI (50%). Sedentary time was high during hospitalization (12.6 [95% CI, 11.8-13.7] h/d) but substantially decreased following transition to the home environment (-1.8 [95% CI, -2.4 to -1.3] h/d). Furthermore, the number of prolonged sedentary bouts (≥60 minutes) decreased between hospital and home (-1.6 [95% CI, -2.0 to -1.2] bouts/day). Light-intensity PA (1.1 [95% CI, 0.8-1.6] h/d) and moderate-vigorous intensity PA (0.2 [95% CI, 0.1-0.3] h/d) were low during hospitalization but significantly increased following transition to the home environment (light-intensity PA: 1.8 [95% CI, 1.4-2.3] h/d; moderate-vigorous intensity PA: 0.4 [95% CI, 0.3-0.5] h/d; both P<0.001). Improvements in PA and SB were similar across groups, except for patients who underwent coronary artery bypass grafting and who did not improve their PA patterns after discharge. Conclusions Patients with MI demonstrate high levels of SB and low PA volumes during hospitalization, which immediately improved following discharge at the patient's home environment. Registration URL: trialsearch.who.int/; Unique identifier: NTR7646.

Association between engagement in exercise training and peak cardiac biomarker concentrations following ST-elevation myocardial infarction.

Background: Regular exercise training is an important factor in prevention of myocardial infarction (MI). However, little is known whether exercise engagement prior to MI is related to the magnitude of post-MI cardiac biomarker concentrations and clinical outcomes. Objectives: We tested the hypothesis that exercise engagement in the week prior MI is related to lower cardiac biomarker concentrations following ST-elevated MI (STEMI). Methods: We recruited hospitalised STEMI patients and assessed the amount of exercise engagement in the 7 days preceding MI onset using a validated questionnaire. Patients were classified as 'exercise' if they performed any vigorous exercise in the week prior MI, or as 'control' if they did not. Post-MI peak concentrations of high-sensitive cardiac troponin T (peak-hs-cTnT) and creatine kinase (peak-CK) were examined. We also explored whether exercise engagement prior MI is related to the clinical course (duration of hospitalisation and incidence of in-hospital, 30-day and 6-month major adverse cardiac events (reinfarction, target vessel revascularisation, cardiogenic shock or death)). Results: In total, 98 STEMI patients were included, of which 16% (n=16) was classified as 'exercise', and 84% (n=82) as 'control'. Post-MI peak-hs-cTnT and peak-CK concentrations were lower in the exercise group (941 (645-2925) ng/mL; 477 (346-1402) U/L, respectively) compared with controls (3136 (1553-4969) ng/mL, p=0.010; 1055 (596-2019) U/L, p=0.016, respectively). During follow-up, no significant differences were found between both groups. Conclusion: Engagement in exercise is associated with lower cardiac biomarker peak concentrations following STEMI. These data could provide further support for the cardiovascular health benefits of exercise training.

Effects of viscosity on cerebral blood flow after cardiac arrest.

OBJECTIVES: To determine blood viscosity in adult comatose patients treated with mild therapeutic hypothermia after cardiac arrest and to assess the relation between blood viscosity, cerebral blood flow, and cerebral oxygen extraction. DESIGN: Observational study. SETTING: Tertiary care university hospital. PATIENTS: Ten comatose patients with return of spontaneous circulation after out-of-hospital cardiac arrest. INTERVENTION: Treatment with mild therapeutic hypothermia for 24 hours followed by passive rewarming to normothermia. MEASUREMENTS AND MAIN RESULTS: Median viscosity at shear rate 50/s was 5.27 mPa · s (4.29-5.91 mPa · s) at admission; it remained relatively stable during the first 12 hours and decreased significantly to 3.00 mPa · s (2.72-3.58 mPa · s) at 72 hours (p < 0.001). Median mean flow velocity in the middle cerebral artery was low (27.0 cm/s [23.8-30.5 cm/s]) at admission and significantly increased to 63.0 cm/s (51.0-80.0 cm/s) at 72 hours. Median jugular bulb saturation at the start of the study was 61.5% (55.5-75.3%) and significantly increased to 73.0% (69.0-81.0%) at 72 hours. Median hematocrit was 0.41 L/L (0.36-0.44 L/L) at admission and subsequently decreased significantly to 0.32 L/L (0.27-0.35 L/L) at 72 hours. Median C-reactive protein concentration was low at admission (2.5 mg/L [2.5-6.5 mg/L]) and increased to 101 mg/L (65-113.3 mg/L) in the following hours. Median fibrinogen concentration was increased at admission 2,795 mg/L (2,503-3,565 mg/L) and subsequently further increased to 6,195 mg/L (5,843-7,368 mg/L) at 72 hours. There was a significant negative association between blood viscosity and the mean flow velocity in the middle cerebral artery (p = 0.0008). CONCLUSIONS: Changes in blood viscosity in vivo are associated with changes in flow velocity in the middle cerebral artery. High viscosity early after cardiac arrest may reduce cerebral blood flow and may contribute to secondary brain injury. Further studies are needed to determine the optimal viscosity during the different stages of the postcardiac arrest syndrome.

Adherence to guidelines for the prescribing of double and triple combinations of antithrombotic agents.

BACKGROUND: To prevent cardiovascular complications, sometimes double and triple therapy with a vitamin K antagonist (VKA), clopidogrel and/or acetylsalicylic acid (ASA) are indicated. These combinations increase the patient's risk of serious bleeding events. Therefore, adherence to clinical guidelines is of the utmost importance when these high-risk therapies are prescribed. METHODS: We performed a retrospective cohort study of 238 cases in a community pharmacy that were treated with a combination of VKA, clopidogrel and/or ASA between January 2006 and December 2009. Hospital records and community pharmacy records were used to obtain the indication(s), the duration of combination therapy, the presence of risk-increasing and risk-decreasing co-medications and any relevant co-morbidities. The cardiologists' attitudes towards the prescribing of antithrombotic combinations and their self-reported adherence to guidelines were assessed by a brief questionnaire. RESULTS: We found there was no guideline-based indication for 22 of the 146 cases (14%) on ASA plus clopidogrel and 19 of the 82 cases (23%) on VKA plus ASA. Of the 238 cases given antithrombotic combination therapies, 77 (32%) were placed at an additional increased risk of serious gastrointestinal events, yet 43 (56%) of these did not receive adequate gastric protection. Out of the 19 of 60 cardiologists (32%) who responded to our questionnaire; 17 (90%) and 13 (68%) stated that a strict indication is very important when initiating therapy with ASA plus clopidogrel or ASA plus VKA, respectively. CONCLUSIONS: There is room to further develop adherence to guideline-based prescribing of antithrombotic combination therapies and to improve prescription of gastric protection for patients receiving these high-risk combinations.

Highly sensitive cardiac troponin T and long-term mortality in a population of community-derived perimenopausal women: nested case-control study.

OBJECTIVE: To assess the association between baseline levels of highly sensitive cardiac troponin T (hs-cTnT) and long-term mortality in perimenopausal women of the general community using a gender specific 99th percentile reference limit. DESIGN: Nested case control. SETTING: The present study was conducted within the Eindhoven Perimenopausal Osteoporosis Study which is a large prospective cohort of 8503 community-derived women of the city of Eindhoven, The Netherlands. PARTICIPANTS: Cases were defined as Eindhoven Perimenopausal Osteoporosis Study participants who provided an adequate baseline blood sample and subsequently experienced death during follow-up between 1994 and 2003. In total, 123 cases were identified. For each case two matched controls were selected using age, body mass index and hypertension as matching factors. The gender specific 99th percentile reference limit determined in the 246 controls was 8.0 ng/l. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: Hs-cTnT was significantly higher in the cases: 3.0 ng/l versus 2.3 ng/l (p=0.04). After adjustment for matching and clinical risk factors, each 1 SD increase of the level of hs-cTnT was significantly associated with mortality (OR 1.3, 95% CI 1.1 to 1.7, p=0.018). With amino-terminal pro-B-type natriuretic peptide (NT-proBNP) in the multivariable model as a continuous variable the association of hs-cTnT with mortality was lost. With both hs-cTnT and NT-proBNP as dichotomous variables, the gender specific 99th percentile reference limit (8.0 ng/l) was associated with mortality, independent of NT-proBNP (OR 3.7, 95% CI 1.0 to 13.2, p=0.048). CONCLUSIONS: In this study of community-derived perimenopausal women, hs-cTnT was associated with long-term mortality, independent of clinical risk factors. With the use of easily applicable cut-off levels, the gender specific reference limit of hs-cTnT had a prognostic impact that was independent of NT-proBNP.

On-line blood viscosity monitoring in vivo with a central venous catheter, using electrical impedance technique.

Blood viscosity is an important determinant of microvascular hemodynamics and also reflects systemic inflammation. Viscosity of blood strongly depends on the shear rate and can be characterized by a two parameter power-law model. Other major determinants of blood viscosity are hematocrit, level of inflammatory proteins and temperature. In-vitro studies have shown that these major parameters are related to the electrical impedance of blood. A special central venous catheter was developed to measure electrical impedance of blood in-vivo in the right atrium. Considering that blood viscosity plays an important role in cerebral blood flow, we investigated the feasibility to monitor blood viscosity by electrical bioimpedance in 10 patients during the first 3 days after successful resuscitation from a cardiac arrest. The blood viscosity-shear rate relationship was obtained from arterial blood samples analyzed using a standard viscosity meter. Non-linear regression analysis resulted in the following equation to estimate in-vivo blood viscosity (Viscosity(imp)) from plasma resistance (R(p)), intracellular resistance (R(i)) and blood temperature (T) as obtained from right atrium impedance measurements: Viscosity(imp)=(-15.574+15.576R(p)T)SR ((-.138RpT-.290Ri)). This model explains 89.2% (R(2)=.892) of the blood viscosity-shear rate relationship. The explained variance was similar for the non-linear regression model estimating blood viscosity from its major determinants hematocrit and the level of fibrinogen and C-reactive protein (R(2)=.884). Bland-Altman analysis showed a bias between the in-vitro viscosity measurement and the in-vivo impedance model of .04 mPa s at a shear rate of 5.5s(-1) with limits of agreement between -1.69 mPa s and 1.78 mPa s. In conclusion, this study demonstrates the proof of principle to monitor blood viscosity continuously in the human right atrium by a dedicated central venous catheter equipped with an impedance measuring device. No safety problems occurred and there was good agreement with in-vitro measurements of blood viscosity.

Multicolor flow cytometry for evaluation of platelet surface antigens and activation markers.

INTRODUCTION: Flow cytometry allows the analysis of multiple antigens in a single tube at a single cell level. We present a rapid and sensitive two tube flow cytometric protocol for the detection of multiple platelet antigens and activation markers gated on a pure platelet population. MATERIALS AND METHODS: The presence of platelet specific antigens was analyzed in citrated whole blood of normal platelets and from patients diagnosed with platelet abnormalities. Quiescent platelets as well as stimulated platelets were analyzed using a gating strategy based on ubiquitously expressed platelet membrane markers. A ubiquitously expressed platelet marker was combined with antibodies against the activated alpha2b-beta3 (PAC-1), Lysosomal Activated Membrane Protein (CD63) and P-selectin (CD62P). RESULTS: We were able to detect the platelet antigens CD36, CD41, CD42a, CD42b and CD61 in one single tube. Our approach allowed the single tube determination of PAC-1, CD63 and CD62P after activation of platelets by thrombin, collagen, ADP and PAR-1, and determination of platelet abnormalities. CONCLUSIONS: Our two tube multi-parameter screening protocol is suited for the analysis of platelet antigens expressed on quiescent and activated platelets and allows the detection of aberrancies as found in blood of patients with thrombocytopathy such as Glanzmann Thrombasthenia, storage pool disease with diminished granule content and patients treated with clopidogrel and acetylsalicylic acid.

Safety of the combination of intensive cholesterol-lowering therapy with oral anticoagulation medication in elderly patients with atrial fibrillation: a randomized, double-blind, placebo-controlled study.

BACKGROUND: The incidence of atrial fibrillation (AF) is very high in the elderly, and often oral anticoagulation (OAC) is indicated to prevent thromboembolism. OBJECTIVE: The aim of this study was to evaluate the safety of combining intensive cholesterol-lowering therapy with OAC in elderly patients with AF. METHODS: In a randomized, double-blind trial, 34 patients received OAC plus atorvastatin 40 mg/day and ezetimibe 10 mg/day versus placebo over 1 year. Dose adjustments of OAC served as an indicator of an interaction between HMG-CoA reductase inhibitors (statins) and OAC. Safety was evaluated by the occurrence of bleeding and a rise in AST, ALT and creatine phosphokinase. RESULTS: Compared with a 6-month pre-intervention period, the mean daily dose +/- standard error of OAC was 4.4 +/- 1.5% lower in the treatment group (p = 0.003) and virtually the same in the placebo group (change from baseline: -0.1 +/- 1.3%, p = 0.96). The mean daily dose of OAC stabilized after 3 months. In the 6-month post-intervention period, OAC dosing showed no statistically significant change from baseline: -1.9 +/- 1.9% in the placebo arm and -2.6 +/- 2.1% in the intervention arm. CONCLUSION: We conclude that in elderly AF patients treated with OAC, intensive cholesterol-lowering therapy (atorvastatin 40 mg/day and ezetimibe 10 mg/day) is well tolerated. No increased risk in bleeding was found.

Conductivity-based hematocrit measurement during cardiopulmonary bypass.

OBJECTIVE: In a recent clinical study on the reliability of a point-of-care (POC) analyzer, we described a downward bias in hematocrit measurement during cardiopulmonary bypass leading potentially to overtreatment with packed red cells. We hypothesized that the detected deviation is caused by variations in electrolyte concentration rather than by colloids used. METHODS: Blood was sampled from patients before cardiac surgery to obtain undiluted anticoagulated whole blood samples (n = 53). From each sample, four dilution series covering a hematocrit range of 15-30% were made using NaCl (0.9%), modified gelatine (4%), hydroxyethylstarch (6%), or a potassium-based (16 mEq/l) solution, respectively. In each dilution series, hematocrit was measured by POC and via the "golden standard" microcentrifugal method to determine whether the deviation of the POC-analyzer to the microcentrifuge was dependent on the type and dilution level of the solution used. RESULTS: In contrast to the colloid-based dilution series, the crystalloids revealed a significant downward bias of the POC-analyzer with respect to the microcentrifuge (p < 0.05). Due to the correction algorithm for sodium in the POC-analyzer, this deviation was nearly constant for NaCl (mean of difference: -1.8 +/- 0.1%), but increased significantly in case of the potassium-based solution (up to -8.2 +/- 0.4% after 1.5-times dilution). The starch- and gelatine-based solutions led to a significant upward bias (p < 0.05) that increased with progressing dilution (up to 1.2 +/- 0.1% for hydroxyethylstarch and up to 1.3 +/- 0.1% for modified gelatine after 1.5-times dilution). CONCLUSIONS: Conductivity-based POC hematocrit measurement suffers from biases due to changes of the plasma constituents. The downward bias in hematocrit as often seen during cardiopulmonary bypass is driven by changes of different electrolyte concentration rather than by colloids used per se.

Troponin I release at rest and after exercise in patients with hypertrophic cardiomyopathy and the effect of betablockade

PURPOSE OF THE WORK: In patients with hypertrophic cardiomyopathy ischemia may occur due to massive heart weight, myocyte disarray or small vessel disease. We detected elevated troponin levels in some of these patients and hypothesized that troponin release would rise after exercise and diminish after betablockade. METHODS AND RESULTS: In 5 of 7 young patients (6 males) with hypertrophic cardiomyopathy and no overt coronary artery disease we found elevated troponin levels after physical exercise; the peak was between 6 and 9 hours and levels returned to pre-exercise values within 24 hours. Troponin release was consistently diminished after use of a betablocker. CONCLUSIONS: Increased troponin release may be present in patients with hypertrophic cardiomyopathy and is temporarily enhanced by exercise and diminishes with betablockade.

Troponin I release at rest and after exercise in patients with hypertrophic cardiomyopathy and the effect of betablockade.

PURPOSE OF THE WORK: In patients with hypertrophic cardiomyopathy ischemia may occur due to massive heart weight, myocyte disarray or small vessel disease. We detected elevated troponin levels in some of these patients and hypothesized that troponin release would rise after exercise and diminish after betablockade. METHODS AND RESULTS: In 5 of 7 young patients (6 males) with hypertrophic cardiomyopathy and no overt coronary artery disease we found elevated troponin levels after physical exercise; the peak was between 6 and 9 hours and levels returned to pre-exercise values within 24 hours. Troponin release was consistently diminished after use of a betablocker. CONCLUSIONS: Increased troponin release may be present in patients with hypertrophic cardiomyopathy and is temporarily enhanced by exercise and diminishes with betablockade.

Dual site coronary sinus pacing in a patient with an artificial tricuspid valve prosthesis.

For safety reasons, two leads for left ventricular pacing were implanted in the coronary sinus of a pacemaker dependent patient with an artificial tricuspid valve prosthesis.