Alistair S. Hall

A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.

The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

Ischaemic heart disease in women: are there sex differences in pathophysiology and risk factors?Position Paper from the Working Group on Coronary Pathophysiology and Microcirculation of the European Society of Cardiology

Cardiovascular disease (CVD) is the leading cause of death in women, and knowledge of the clinical consequences of atherosclerosis and CVD in women has grown tremendously over the past 20 years. Research efforts have increased and many reports on various aspects of ischaemic heart disease (IHD) in women have been published highlighting sex differences in pathophysiology, presentation, and treatment of IHD. Data, however, remain limited. A description of the state of the science, with recognition of the shortcomings of current data, is necessary to guide future research and move the field forward. In this report, we identify gaps in existing literature and make recommendations for future research. Women largely share similar cardiovascular risk factors for IHD with men; however, women with suspected or confirmed IHD have less coronary atherosclerosis than men, even though they are older and have more cardiovascular risk factors than men. Coronary endothelial dysfunction and microvascular disease have been proposed as important determinants in the aetiology and prognosis of IHD in women, but research is limited on whether sex differences in these mechanisms truly exist. Differences in the epidemiology of IHD between women and men remain largely unexplained, as we are still unable to explain why women are protected towards IHD until older age compared with men. Eventually, a better understanding of these processes and mechanisms may improve the prevention and the clinical management of IHD in women.

Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: the GEOSTAT-1 Study.

Background—Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results—The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415). Conclusion—The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration—URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.

Gender Bias in Acute Coronary Syndromes

The major aim of this review was to ascertain whether effective evidence-based treatments for acute coronary syndromes (ACS) are underutilized in women in various geographic areas compared with men. The focus of our review was the relative use of effective treatments in patients with coronary angiographic evidence of obstructive coronary disease, defined as a lumen stenosis >50% of the adjacent non-diseased arterial diameter. We searched MEDLINE, and the Cochrane Database between January 1998 and May 2008. Only a few of the published clinical registries on ACS provide data on treatments dichotomized by confirmed coronary angiographic disease. Consequently, we also accessed individual patient-level data from 3 established ACS registries: the Finnish TACOS (Tampere Acute COronary Syndrome), the British EMMACE 2 (Evaluation of Methods and Management of Acute Coronary Events) and the Argentine PACS-ITALSIA (Prognosis in Acute Coronary Syndromes and the ITALian hospital Sindrome Isquemico Agudo). Despite presenting with higher risk characteristics and having higher in-hospital and 6 months risk of death, women with ACS and obstructive coronary artery disease were apparently treated less aggressively with secondary preventive drugs than were men, being less likely to receive aspirin, beta-blockers and statins at discharge. Overall, coronary revascularization appears to be performed in a similar proportion of women and men - once angiography has been performed and the coronary anatomy is known. However, substantial geographic variation exists in the relative rate of coronary angiography in men and women. In United Kingdom coronary revascularization tends to be done less frequently in women. Our study, therefore, demonstrates a gender bias in the delivery of secondary drug treatments for ACS, even for patients with documented significant coronary disease.

Left ventricular volume reduction without ventriculectomy

Partial left ventriculectomy (the Batista procedure) to achieve left ventricular volume reduction (LVVR) has been advocated as an alternative to cardiac transplantation in patients with end-stage dilated left ventricles. Here, we describe a new technique of LVVR that uses realignment of the papillary muscles, thus avoiding ventriculectomy, and report preliminary results. Eight patients (all male, mean age 49.3 [range 38 to 70] years) underwent LVVR between October 1998 and March 2000 as an adjunct to surgical coronary revascularization. Five were assessed with echocardiography and cardiopulmonary exercise testing before and after (mean follow-up time 267 [range 94 to 416] days) the operation. LVVR significantly improved left ventricular end-diastolic volume (254 +/- 32 to 218 +/- 36 mL, p = 0.03), left ventricular ejection fraction (20.14% +/- 1.36% to 31.28% +/- 2.32%, p = 0.007), and exercise duration (from 394 +/- 88 to 611 +/- 79 seconds, p = 0.03). A nonsignificant improvement in maximal oxygen consumption was also observed. This technique of LVVR is relatively simple to perform and is accomplished through a small apical cardiotomy. Preliminary results show an encouraging functional improvement following surgery. Future controlled studies are required to assess this novel technique further.

Hyperglycaemia, in relation to sex, and mortality after acute coronary syndrome:

Aims Both diabetes mellitus (DM) and hyperglycaemia are known to predict outcome after acute coronary syndrome (ACS). Recent work has suggested women with DM have greater baseline cardiovascular risk and poorer outcome after ACS. The interaction between sex and abnormal glucose homoeostasis in patients without diabetes is unexplored; we aimed to assess this relationship. Methods and results Retrospective analysis of data from a prospective cohort study of 1575 patients with a confirmed ACS and no previous diagnosis of DM in 11 UK hospitals. Multivariable analysis was performed to assess the value of clinical variables, including hyperglycaemia and sex, in predicting 2 year all-cause mortality. Sex and hyperglycaemia interacted in predicting mortality. In men, mortality risk increased more steeply with incremental levels of glycaemia than in women (glucose ≥ 11.1 mmol/l, hazard ratio, 2.19; 95% confidence interval, 1.2-4.0). In both sex groups increasing glycaemia predicted mortality at levels currently not recommended for acute therapeutic intervention (7.8-11.0 mmol/l). Conclusions In patients not known to have diabetes, hyperglycaemia is a concentration-dependent predictor of long-term mortality after ACS; this predictive value is stronger in men than women. Eur J Cardiovasc Prev Rehabil 14:666-671

Serum 99th centile values for two heart-type fatty acid binding protein assays

Background We have previously demonstrated that heart-type fatty acid binding protein (H-FABP) is an independent prognostic marker for survival after acute coronary syndrome (ACS). This study aimed to define the 99th centile values for H-FABP as determined with two different assays, and to study the relationship with age, gender and renal function. Methods H-FABP was measured on redundant routine outpatient samples using the MARKIT-M (Dainippon) and the Evidence Investigator (Randox) assays. Results Two hundred and forty-two subjects with Siemens Ultra-TnI value <0.045 μg/L (99th centile) were studied. In all, 174 subjects had estimated glomerular filtration rate (eGFR) >60 mL/min. The 99th centile values for subjects with eGFR >60 mL/min for the Evidence Investigator H-FABP were 5.3 and 5.8 μg/L and for the MARKIT-M H-FABP were 8.3 and 9.1 μg/L in female and male subjects, respectively. There is an increase in H-FABP with age in subjects with normal renal function for both assays. Gender comparison showed no significant difference for either assay. Comparison of samples showed that subjects with eGFR <60 mL/min showed a median increase of 0.71 μg/L with Evidence Investigator assay and 1.09 μg/L with MARKIT-M assay compared with subjects with eGFR >60 mL/min. Calibration differences were confirmed by cross measurement of calibrators and recombinant H-FABP. Conclusions We have defined the 99th centile values for H-FABP in a population of primary and secondary care outpatients that can be used to risk stratify patients with ACS. We have confirmed that H-FABP increases with renal dysfunction and age, but have not confirmed the gender difference previously reported.

A randomized, controlled trial of simvastatin versus rosuvastatin in patients with acute myocardial infarction: the Secondary Prevention of Acute Coronary Events – Reduction of Cholesterol to Key European Targets Trial

Aims We sought to evaluate reports that rosuvastatin 10 mg is a more efficacious treatment of hyperlipidaemia than is simvastatin 40 mg, hoping to assess this issue in the previously unstudied context of acute myocardial infarction. Methods and results The Secondary Prevention of Acute Coronary Events - Reduction of Cholesterol to Key European Targets (SPACE ROCKET) Trial was an investigator-led, open-label, blinded-endpoint, multicentre, randomized, controlled trial assessing the proportion of patients, at 3 months, achieving European Society of Cardiology 2003 (ESC-03) lipid targets of total cholesterol (TC) less than 4.5 mmol/l (174 mg/dl) or low-density lipoprotein cholesterol (LDLc) less than 2.5 mmol/l (97 mg/dl). Of 1263 patients randomized, 77.6% simvastatin versus 79.9% rosuvastatin achieved ESC-03 targets [odds ratio (OR): 1.16; 95% confidence interval (CI): 0.88–1.53; P = 0.29]. There were statistically significant differences for simvastatin versus rosuvastatin, respectively, for mean LDLc 2.03 mmol/l (78 mg/dl) versus 1.94 mmol/l (75 mg/dl; P =0.009) and also mean TC 3.88 mmol/l (150 mg/dl) versus 3.75 mmol/l (145 mg/dl; P =0.005). A post-hoc analysis showed higher achievement of the new ESC, American Heart Association and American College of Cardiology optimal lipid target of LDLc less than 1.81 mmol/l (70 mg/dl) with rosuvastatin (45.0%) compared with simvastatin (37.8%; OR: 1.37; 95% CI: 1.09–1.72; P = 0.007). The proportion of patients achieving the Fourth Joint Task Force European Guidelines (2007) of TC less than 4.0 mmol/l (155 mg/dl) and LDLc less than 2.0 mmol/l (77 mg/dl) was 38.7% for simvastatin 40 mg and 47.7% for rosuvastatin 10 mg (OR: 1.48; 95% CI: 1.18–1.86; P = 0.001). Conclusion We observed no superiority of either treatment for the ESC-03 lipid targets. Rosuvastatin 10 mg lowered mean cholesterol more effectively than simvastatin and achieved better results for the latest, more stringent, ESC target.

Diabetes Mellitus and Mortality after Acute Coronary Syndrome as a First or Recurrent Cardiovascular Event

Background Diabetes Mellitus (DM) is associated with adverse cardiovascular prognosis. However, the risk associated with DM may vary between individuals according to their overall cardiovascular risk burden. Therefore, we aimed to determine whether DM is associated with poor outcome in patients presenting with Acute Coronary Syndrome (ACS) according to the index episode being a first or recurrent cardiovascular event. Methods and Findings We conducted a retrospective analysis of a prospective cohort study involving 2499 consecutively admitted patients with confirmed ACS in 11 UK hospitals during 2003. Usual care was provided for all participants. Demographic factors, co-morbidity and treatment (during admission and at discharge) factors were recorded. The primary outcome was all cause mortality (median 2 year follow up), compared for cohorts with and without DM according to their prior cardiovascular disease (CVD) disease status. Adjusted analyses were performed with Cox proportional hazards regression analysis. Within the entire cohort, DM was associated with an unadjusted 45% increase in mortality. However, in patients free of a history of CVD, mortality of those with and without DM was similar (18.8% and 19.7% respectively; p = 0.74). In the group with CVD, mortality of patients with DM was significantly higher than those without DM (46.7% and 33.2% respectively; p<0.001). The age and sex adjusted interaction between DM and CVD in predicting mortality was highly significant (p = 0.002) and persisted after accounting for comorbidities and treatment factors (p = 0.006). Of patients free of CVD, DM was associated with smaller elevation of Troponin I (p<0.001). However in patients with pre-existing CVD Troponin I was similar (p = 0.992). Conclusions DM is only associated with worse outcome after ACS in patients with a pre-existing history of CVD. Differences in the severity of myocyte necrosis may account for this. Further investigation is required, though our findings suggest that aggressive primary prevention of CVD in patients with DM may have beneficially modified their first presentation with (and mortality after) ACS.

Effects of Angiotensin-Converting Enzyme Inhibitors and Beta Blockers on Clinical Outcomes in Patients With and Without Coronary Artery Obstructions at Angiography (from a Register-Based Cohort Study on Acute Coronary Syndromes)

We sought to determine the effectiveness of angiotensin-converting enzyme (ACE) inhibition and β-blocker treatment as a function of the degree of coronary artery disease (CAD) obstruction at angiography. The Evaluation of Methods and Management of Acute Coronary Events registry enrolled patients who had been hospitalized for an acute coronary syndrome. There were 1,602 patients who had cardiac catheterization that were used for this analysis. The main outcome measures were evidence-based therapies prescribed at discharge and 6-month incidence of all-cause mortality. The cohort consisted of 1,252 patients with obstructive CAD (>50% luminal diameter obstructed) and 350 patients with nonobstructive CAD. Multivariate logistic regression analysis adjusted for further medications and other clinical factors was performed. Patients with nonobstructive CAD had significantly (p <0.001) higher rates of β-blocker (77.8% vs 63.3%) and lower rates of ACE-inhibitor (57.7% vs 66.4%) prescriptions. In patients with nonobstructive CAD, ACE-inhibitor therapy was clearly associated with a lower 6-month mortality (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.03 to 0.78, p = 0.004). No significant association between β-blocker use and death was found. In patients with obstructive CAD, both β blockers (OR 0.47, 95% CI 0.32 to 0.67, p <0.001) and ACE inhibitors (OR 0.47, 95% CI 0.26 to 0.87, p = 0.01) were significantly associated with a reduced risk of 6-month mortality. In conclusion, ACE-inhibitor therapy seems to be an effective first-line treatment for preventing the occurrence of mortality in patients with nonobstructive CAD.