Mon2 predicts poor outcome in ST-elevation myocardial infarction.

AIMS: There are limited data on the role of human monocyte subsets in ST-elevation myocardial infarction (STEMI). The study aimed to establish the relationship between monocyte subsets, their phagocytic and nuclear factor κB (NFκB) activity and outcomes in STEMI. METHODS: Monocyte subsets and their phagocytic activity and intracellular levels of inhibitory κB kinase ß (IKKß, marker of NFκB activity) were measured by flow cytometry in 245 patients with STEMI, median follow-up of 46 months. RESULTS: Mon2 (CD14++CD16+CCR2+) counts were independently predictive of major adverse cardiovascular events (MACE) [4th quartile HR 3.42 (95% CI 1.43-8.16), P = 0.006 and 3rd quartile HR 2.88 (95% CI 1.19-7.00), P = 0.02 vs. 1st quartile]. Mon2 subset was the only subset associated with higher occurrence of heart failure (4th quartile vs. 1st quartile, sevenfold, P = 0.001 on univariate analysis; fivefold, P = 0.04 on multivariable analysis). On receiver operating characteristic, analysis including of Mon2 improved prognostic value of troponin T and creatine kinase for MACE and heart failure (HF). Higher intracellular Mon2 IKKß levels were associated with 10-fold lower occurrence of HF on multivariable analysis (4th vs. 1st quartiles, P = 0.03). Abnormal Mon1 and Mon2 phagocytic capacities were related to HF development, but the association was dependent on the infarct size and other prognosticators. High Mon2 levels were associated with lower ejection fraction after STEMI onset (P = 0.001) and at 6-month follow-up (P < 0.001). CONCLUSIONS: Abnormal Mon2 characteristics have a unique association with poor outcome in patients with STEMI. The relation of Mon2 with occurrence of HF is strongly and independently related to their functional status, which may have potential therapeutic implications.

Clinical Stroke prevention in atrial fibrillation.

Oral anticoagulation therapy has reduced the risk of ischaemic stroke and improved the outcomes for patients with atrial fibrillation considerably. The emergence of the non-vitamin K oral anticoagulants as alternatives to vitamin K antagonists has significantly changed the practice of stroke prevention in atrial fibrillation. As the main complication with antithrombotic therapy is bleeding, physicians should always balance the risk of ischaemic stroke against intracranial haemorrhage and intervene where appropriate to reduce both risks. Individual approach is often mandatory due to heterogeneity of the risks and patient preferences. The purpose of this review is to summarise the current knowledge of the oral anticoagulation therapy in atrial fibrillation patients and guide physicians with the management of anticoagulants based on data from clinical trials and systematic reviews.

Renal dysfunction and diastolic impairment among British ethnic minorities with hypertension: the Ethnic-Echocardiographic Heart of England Screening Study.

Renal dysfunction is frequently associated with left ventricular (LV) hypertrophy and diastolic dysfunction in hypertensive patients. Limited data exist on renal dysfunction and diastolic impairment among British ethnic minorities with hypertension. We studied associations between renal impairment and diastolic dysfunction in hypertensive subjects of African-Caribbean and South Asian origin. Five hundred and ten hypertensive subjects with ejection fraction ⩾55% and with no history of ischaemic heart disease/valve pathology were included from the original population of the Ethnic-Echocardiographic Heart of England Screening Study (E-ECHOES). Diastolic function and cardiac remodelling were measured by echocardiography. LV hypertrophy was common and present in 62% of patients with normal estimated glomerular filtration rate (eGFR, >90 ml min-1 per 1.73 m2), 73% in those with eGFR 60-89 ml min-1 per 1.73 m2 and 87% with eGFR <60 ml min-1 per 1.73 m2. On both univariate and multivariable linear regression, reduced eGFR was associated with higher LV mass index (LVMI, P=0.01 and P=0.039, respectively). On multivariable analyses, increased LVMI (but not eGFR) was an independent predictor of echocardiographic parameters of diastolic dysfunction. Higher LVMI was an independent predictor of all-cause or cardiovascular death on multivariable analyses (both P=0.002), but not eGFR. LV hypertrophy is common in minority ethnic groups with hypertension, especially in the presence of renal dysfunction. Increased LVMI rather than renal impairment per se is a major determinant of diastolic dysfunction and increased risk of cardiovascular or all-cause death among hypertensive patients without end-stage renal failure.

Safety and efficacy of abciximab in older adults undergoing percutaneous coronary intervention.

BACKGROUND: As a result of increased cost and bleeding concerns, older patients receive abciximab during percutaneous coronary intervention (PCI) less often than younger patients. OBJECTIVE: The aim of this was to evaluate the safety and efficacy of abciximab in older adults undergoing PCI. DESIGN: Retrospective, observational single centre cohort study. METHODS: The British Cardiovascular Intervention Society (BCIS) database was used to establish the impact of abciximab in people with advanced age (≥ 75 years) on in-hospital bleeding and ischaemic events and all-cause mortality in 5727 consecutive patients undergoing PCI between January 2008 and June 2014. RESULTS: Older patients represented 23% of the study population (n = 1298). Abciximab was used in 198 (15%) older patients and 970 (22%) younger patients (p < 0.001). Unadjusted bleeding and mortality rates were 1.2% and 5.6%, respectively, vs. 0.4% and 1.7% in younger patients (p = 0.001 and p < 0.001 respectively). On multivariate analysis older subjects were at higher risk of bleeding [odds ratio (OR) 2.76, 95% confidence interval (CI) 1.26-6.04, p = 0.011] and had higher in-hospital mortality (OR 2.36, 95% CI 1.48-3.74, p < 0.001). The use of abciximab in older patients was not significantly associated with excess bleeding (adjusted OR 1.86, 95% CI 0.58-5.93, p = 0.3), ischaemic outcomes (adjusted OR, 95% CI, p = 0.12) or in-hospital mortality (adjusted OR, 95% CI, p = 0.11). Older patients having primary PCI had higher risk of bleeding irrespective of abciximab use (adjusted p = 0.042). CONCLUSION: Abciximab may not be associated with excess bleeding complications in older patients compared with younger individuals and may be safe to use in older people if indicated.

Simultaneous computerised activation of the primary percutaneous coronary intervention pathway reduces out-of-hours door-to-balloon time but not mortality.

BACKGROUND: In 2009 activation of out of hours (OOH) primary percutaneous coronary intervention (PPCI) in our institution changed from separate telephone calls to a simultaneous computerised alert. We assessed the impact of this protocol change on door-to-balloon (DTB) time, in hospital and 1 year mortality. METHODS: Retrospective survey of our Myocardial Ischaemia National Audit Project (MINAP) database. OOH patients were categorized--pre- (Group 1) and post- (Group 2) introduction of the computerised alert protocol. RESULTS: OOH PPCI was performed for 793 patients (mean age 61, 73.4% male)--295 in Group 1 and 498 in Group 2. Median DTB times were 92 min (interquartile range [IQR] 75-111) for Group 1 and 76 min (IQR 64-97) for Group 2 (p < 0.0001). Forty-eight percent achieved DTB in ≤ 90 min in Group 1 compared to 70% in Group 2 (p < 0.0001). Computerised alert was associated with a shorter DTB time on multivariate analysis (beta coefficient -0.09, p = 0.03 for linear regression and OR 2.8, 95% CI 1.6-5.0, p < 0.0001 for logistic regression). In hospital mortality was 4.1% in Group 1 and 5% in Group 2 (p = 0.60). All-cause mortality at 1 year was 6.1% in Group 1 and 9.9% in Group 2 (p = 0.09). CONCLUSIONS: Simultaneous computerised activation for OOH PPCI reduced DTB times, increased the number of patients achieving target DTB times but did not affect mortality.

Gender differences in stroke prevention in atrial fibrillation in general practice: using the GRASP-AF audit tool.

BACKGROUND: Women represent a large proportion of patients with atrial fibrillation (AF) and tend to have higher risk of stroke. AIMS: This study examines gender differences in the utilisation of oral anticoagulation (OAC) and prognosis (i.e. stroke and death) in AF patients in UK general practice. DESIGN: Retrospective observational study. METHODS: The Guidance on Risk Assessment and Stroke Prevention in Atrial Fibrillation (GRASP-AF) tool was employed to identify AF patients from 11 general practices in Darlington, England. RESULTS: Two thousand two hundred and fifty-nine AF patients (mean±SD age 76 ± 12 years; 46% female) were identified. Based on CHA2 DS2 -VASc score 95% of women and 90% of men were at moderate-high risk of stroke. Women with moderate-high risk of stroke were treated with OAC less frequently than men (47% vs. 52%, p = 0.006). Overall rates of stroke and all-cause mortality were higher among women than men (p = 0.02 and p < 0.001). However, there was no significant gender difference in these outcomes in patients receiving OAC (p = 0.52 for stroke, p = 0.18 for death). Among people not receiving OAC where indicated, female gender was associated with an increased risk of stroke before (p = 0.01), and after (p = 0.04), adjustment for stroke risk factors. Women not receiving OAC had a higher risk of death on univariate regression analysis (p = 0.002), but not after adjustment for stroke risk factors (p = 0.53). CONCLUSION: Women with AF are at higher risk of stroke than men without OAC. The gender-related differences in risk of stroke disappear if OAC is used. Despite this, women are more likely not to receive OAC.

TLR4 expression on monocyte subsets in myocardial infarction.

BACKGROUND: Monocyte toll-like receptor 4 (TLR4) has been implicated in the pathogenesis of atherosclerosis with increased levels in myocardial infarction. The aim of this study was to assess the numbers of TLR4(+) monocytes in each monocyte subset in MI, the expression of TLR4 and association with markers of monocyte activation, inflammation, myocardial damage and postmyocardial infarction (MI) cardiac contractility. METHODS: Surface expression of TLR4 and numbers of TLR4-expressing monocytes were quantified by flow cytometry of venous blood in 50 patients with ST-elevation MI (STEMI), 48 with non-STEMI (NSTEMI) and 40 with stable coronary artery disease (CAD). These parameters were measured on days 1, 3, 7 and 30 post-MI in STEMI patients. Three monocyte subsets were defined as CD14(++) CD16(-) CCR2(+) (Mon1), CD14(++) CD16(+) CCR2(+) (Mon2) and CD14(+) CD16(++) CCR2(-) (Mon3). Plasma inflammatory cytokines were assessed using cytometric bead arrays. RESULTS: There was a significant increase in counts of TLR4(+) Mon1 and Mon2 in STEMI patients and TLR4(+) Mon2 in NSTEMI patients compared with controls with CAD. Monocyte TLR4(+) expression was similar between the groups, and was not changed during follow-up in STEMI patients. Plasma interleukin-6 (IL6) levels correlated positively with TLR4(+) Mon2 count (r = 0.54, P < 0.001), but negatively with TLR4 expression on Mon2 (r = -0.33, P = 0.021). CONCLUSION: Following treatment of acute MI, TLR4 expression by individual monocyte subsets is unchanged. An increase in TLR4(+) Mon1 and Mon2 count in patients with STEMI and TLR(+) Mon2 count in those with NSTEMI is due to an increase in monocyte subset count and not to changes in TLR4 expression. Monocyte counts but not TLR4 expression correlate positively with plasma IL6 levels. We suggest that TLR4 expression may not be a reliable marker of monocyte activation in MI.

Monocyte-derived and CD34+/KDR+ endothelial progenitor cells in heart failure.

BACKGROUND: Endothelial progenitor cells (EPCs) are known to be altered in heart failure (HF), but monocyte-derived EPCs in HF have not been assessed. We aimed to characterize monocyte-derived EPCs in systolic HF. METHODS AND RESULTS: We recruited 128 subjects with systolic HF: 50 South Asian (SA), 50 white, and 28 African-Caribbean (AC), for interethnic comparisons. Additionally, SAs with HF were compared with 40 SAs with coronary artery disease (CAD) without HF (disease controls [DCs]) and 40 SA healthy controls (HCs). Counts of CD34(+) and kinase domain receptor (KDR)(+) monocytes attributed to specific monocyte subsets (CD14(++) /CD16(-) [Mon1], CD14(++)/CD16(+) [Mon2], and CD14(+)/CD16(++) [Mon3]) and monocyte expression of vascular endothelial growth factor (VEGF) receptor 1 were analyzed by flow cytometry. We also enumerated CD34(+)/KDR(+) EPCs derived from mononuclear cells ('classic' EPC definition). RESULTS: SAs with HF had significantly reduced counts of CD34(+) monocytes, attributed to the Mon1 and Mon2 subsets. KDR(+) Mon1 counts were 4.5-fold increased in DCs as compared with HCs, but significantly reduced in HF subjects vs. DCs. VEGF receptor type 1 expression on Mon1 and Mon2 cells was significantly reduced in HF patients as compared with DCs. Also, CD34(+)/KDR(+) EPC numbers were reduced in HF subjects. Whites had significantly fewer KDR(+) Mon3 cells than ACs, but significantly more CD34(+) Mon2 cells than SAs and ACs. VEGF receptor type 1 expression by Mon1 cells was predictive for left ventricular ejection fraction after adjustment for ethnicity (ß = - 0.25. P = 0.039). CD34(+) Mon2 counts correlated with measures of microvascular endothelial function, and were predictive of the future risk of hospital admission. CONCLUSIONS: Circulating counts of monocyte-derived EPCs are significantly altered in HF, with significant ethnic differences in the levels of monocyte-derived EPCs.

The CD14++CD16+ monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction.

AIM: Monocytes contribute to both myocardial damage and repair by virtue of subset heterogeneity. The dynamics and functional characteristics of the three human monocyte subsets, including the unique CD14++CD16+ subset, and their contributions to monocyte platelet aggregates (MPAs) following ST-elevation myocardial infarction (STEMI) are unknown. We aimed to examine dynamic changes and relation to left ventricular ejection fraction (LVEF) of the three human monocyte subsets and their aggregates with platelets following STEMI. METHODS: Three monocyte subsets, CD14++CD16-CCR2+ ('classical', Mon1), CD14++CD16+CCR2+ ('intermediate', Mon2) and CD14+CD16++CCR2- ('non-classical', Mon3), and their contribution to MPAs were analyzed by flow cytometry in 50 patients with STEMI, 40 patients with stable coronary artery disease (CAD) and 40 healthy volunteers. Study parameters were measured within 24 h of primary percutaneous coronary intervention (PCI) (day1) and on days 3, 7 and 30. Monocyte activation was assessed by measuring the nuclear factor κB (NFκB) pathway. LVEF was assessed 6 weeks after STEMI. Correlations between monocyte subsets/MPAs and plasma cytokines and troponin were assessed. RESULTS: We observed marked differences in subset dynamics, with a prominent increase in Mon2 (P < 0.0001) but no changes in Mon3. Significant increases in Mon2 CD14 (P = 0.002) and CCR2 (P < 0.0001) expression, and reduction in CD16 expression (P = 0.001) were seen. NFκB pathway activity increased most prominently in Mon2 (P = 0.007). Mon2 count correlated with peak troponin (r = 0.31, P = 0.04) and plasma interleukin (IL)-6 (r = 0.65, P < 0.0001) and IL-10 (r = 0.34, P = 0.017). Mon1 correlated with IL-6 (r = 0.55, P < 0.0001). Reduced Mon2 expression of CD16 on day 1 was independently predictive of higher LVEF (ß = -0.37, P = 0.013). The increase in MPA count following STEMI persisted at 1 month. CONCLUSION: The Mon2 'intermediate' subset has unique dynamic and functional characteristics following STEMI and significant correlations with troponin, plasma cytokines and convalescent left ventricular function. The persistent increase in MPA count 30 days after STEMI may affect monocyte subset functional activity.

Systolic heart failure in South Asians.

Heart failure (HF) is a common condition leading to an unfavourable prognosis and impaired quality of life. In this review, we provide an overview of published literature on possible epidemiological and pathophysiological differences between patients with systolic HF of South Asian origin and those from other ethnic groups (mainly White). Systolic HF tends to manifest earlier among South Asians and with frequent hospital admissions. However, survival for such patients appears to be significantly better compared with the White group, which might be associated with different patterns of HF. For example, this could be attributed to a lower prevalence of left ventricular systolic dysfunction in South Asian subjects. Indeed, the high prevalence of hypertension and diabetes among South Asians may predispose to diastolic HF with preserved systolic function. In addition, because of underrepresentation of South Asians in clinical trials, there are little data on optimal management of this ethnic group.

Immunophenotypic characterization of human monocyte subsets: possible implications for cardiovascular disease pathophysiology.

OBJECTIVES: Monocytes include several subsets with different and sometimes divergent roles in immunity, atherogenesis and reparative processes. OBJECTIVES: We aimed to perform detailed immunophenotypic and functional characterization of human monocyte subsets. PATIENTS/METHODS: Analysis of surface markers of blood and bone marrow monocyte subsets and functional characterization of blood monocyte subsets in healthy volunteers was performed using flow cytometry. RESULTS: In the present study, we show the presence of three subsets which could be unequivocally distinguished by surface expression of CD14, CD16 and CCR2 as CD14(+)CD16(-)CCR2(+) (Mon1), CD14(+)CD16(+)CCR2(+) (Mon2) and CD14(low)CD16(+)CCR2(-) (Mon3) subsets. In comparison with the classic Mon1, the Mon2 subset had the highest expression of Tie2, CXCR4, CD163, CD115, receptors to inter-cellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF), and the highest surface levels of apolipoprotein B and ferritin. In contrast, Mon3 had maximal expression of VCAM-1 receptors and CD204. The Mon2 and Mon3 subsets had significantly lower activity of the NFκB pathway than Mon1. Mon1 and Mon2 had similar phagocytic activity, which was significantly higher compared with Mon3. All three subsets were present in bone marrow, although the relative proportion of Mon2 in bone marrow was about 2.5-fold higher compared with that seen in blood. Significant differences in cytokine production in response to endotoxin stimulation were observed between the three monocyte subsets. CONCLUSION: Given their immunophenotypic similarity, the newly characterized Mon2 population may represent the previously reported pluripotent progenitor/pro-angiogenic monocytes.

Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis.

The complex and multifactorial nature of atherogenesis and development of atherothrombotic complications involves numerous interactions between various cell types inside the vascular wall (e.g. macrophages and smooth muscle cells) and in the blood (e.g. leukocytes and platelets). One relatively recent advance in this area is the discovery of circulating microparticles and their role in endothelial damage, platelet activation, hypercoagulability and regulation of inter-cellular interactions. Microparticles are small anucleoid phospholipid vesicles released from different cells, such as platelets, erythrocytes, leukocytes and endothelial cells. Microparticles carry surface proteins and include cytoplasmic material of the parental cells responsible for the exertion of microparticle-mediated biological effects. About 25% of the procoagulant activity of stimulated platelet suspensions is associated with microparticles released upon platelet activation and their surface may be approximately 50-100-fold more procoagulant than the surface of activated platelets per se. The available lines of evidence indicate that shedding of microparticles from the parental cells is not just a passive process accompanying cellular dysfunction and apoptosis, but a tightly regulated mechanism implicated in the interactions between various cell types. The role of microparticles as biological messengers is supported by their differential and specific involvement in the pathophysiology of different cardiovascular disorders, including atherogenesis and thrombosis.

The effects of exercise stress testing, diurnal variation and temporal decline on circulating progenitor cells.

Endothelial damage/dysfunction is involved in numerous cardiovascular disease processes. Given that the mature endothelial cells have limited capacity for self regeneration, circulating progenitor cells (CPCs) may modulate the balance between vascular damage and regeneration. The three aims of the present study were 1) to define the influence of exercise treadmill testing (ETT) on peripheral CPC levels; 2) to assess the diurnal variation of CPC counts; and 3) to investigate the rate of temporal decline in CPCs once ex vivo . The dynamics of CPC count changes following an ETT were assessed on consecutive 20 patients referred to our 'rapid-access' chest pain clinic (70% male, age 69.9 +/- 7.8) with venous blood samples taken pre-exercise, immediately post-exercise and at 30 minutes post-exercise. Diurnal variation in CPCs was assessed in 13 stable in-hospital patients (46% male, age 69.1 +/- 7.5 years) with blood samples were taken five times every 6 hours. To investigate the temporal decline, blood samples from 12 patients (58.3% male, age 69.9 +/- 7.9 years) were reprocessed for CPC counts at 4 hours and at 24 hours after sample collection. Plasma levels of von Willebrand factor (vWf) and soluble E-selectin (sE-selectin) were assessed by ELISA. CPCs were enumerated with flow cytometry as CD34+, CD133+, CD45dim events. Exercise led to significant increases in vWF and sE-selectin levels, but no significant influence on CPC counts were observed. Baseline CPC numbers demonstrated a negative correlation with vWf (r=-0.551, p=0.012) and sE-selectin levels (r=-0.494, p=0.027). CPC counts showed a significant diurnal variation, being significantly higher at 12 a.m. compared to 12 p.m. (p=0.046) and 6 p.m. (p=0.023). A 4 hour delay in sample preparation did not affect CPCs counts, but there was a significant decline in CPC recovery when sample processing was delayed by 24 hours (p<0.05). Routine exercise stress testing does not significantly affect CPC counts. Peripheral CPC levels showed a significant diurnal variation. Delays in sample preparation for CPC counts should be avoided as they may influence the accuracy of the test by resulting in a significant decline in CPC recovery. Thus, various factors may affect accuracy of CPC enumeration that may limit their role as a reliable clinical marker and biomarker of endothelial damage.