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The extent of myocardial injury during coronary artery bypass surgery (CABG) is associated with subsequent patient morbidity and mortality. One potential way to limit this damage is by the use of remote ischaemic preconditioning, whereby several brief episodes of ischaemia in one region or organ protects other tissues or organs, such as the heart, from a subsequent sustained episode of ischaemia. Studies to date have shown that brief ischaemia of non‐cardiac tissues such as the kidney, intestine or skeletal muscle may also protect the myocardium. Hausenloy et al aimed at assessing whether transient episodes of ischaemia in one arm could reduce myocardial injury in adults with coronary artery disease undergoing elective CABG.
Fifty‐seven adult patients undergoing elective CABG were randomly assigned to receive intervention, defined as three 5‐minute cycles of right upper arm ischaemia by inflating a blood pressure cuff up to 200 mm Hg, or control treatment, where a deflated cuff was placed on the right upper arm for 30 minutes. The remote ischaemic preconditioning intervention was applied after the induction of anaesthesia and before surgery started, therefore both the patient and surgeon were unaware of the treatment allocation. Serum troponin‐T concentration was then measured before surgery and at 6, 12, 24, 48 and 72 hours after surgery. Compared with patients undergoing control treatment, remote ischaemic preconditioning significantly reduced overall serum troponin‐T release at 6, 12, 24 and 48 hours after surgery. The total area under the curve decreased by 43%, from a mean (SD) of 36.12 (26.08) μg/l in the control group to 20.58 (9.58) μg/l in the remote ischaemic preconditioning group (mean difference 15.55 (5.32) μg/l; 95% CI 4.88 to 26.21; p=0.005).
Therefore in this single‐centre study, adults undergoing elective CABG seemed to have less myocardial damage during surgery, as assessed by troponin‐T release. Although the actual mechanism by which remote ischaemic preconditioning protects the myocardium remains unclear, this study shows that the potential clinical benefits are highly significant. The authors are currently performing a further study to investigate whether patients receiving only cardioplegia a the time of CABG show any benefit from this remote ischaemic preconditioning protocol.
Hausenloy DJ, Mwamure PK, Venugopal V, et al Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 2007;370:575–9.
Sixty‐four‐slice computed tomography coronary angiography (CTCA) is increasingly used for the diagnosis of coronary artery disease. However, the exact lifetime attributable risk (LAR) for cancer is not well defined for patients of different age and sex or for different scanning protocols. Einstein et al designed a study to examine the LAR of cancer associated with radiation exposure from a single CTCA study, using the approach suggested in the National Academies Biological Effects of Ionizing Radiation 7th Report (BEIR VII phase 2). In this model the risk of cancer proceeds linearly with no lower threshold. The aim was to determine the LAR of cancer incidence associated with exposure from a single 64‐slice CTCA study and to evaluate the influence of age, sex and scan protocol on cancer risk.
To do this the authors used Monte Carlo simulations, a computerised mathematical model that estimates radiation dose to organs by modelling photon transport from CT through standardised male and female anthropomorphic mathematical phantoms. Eight Monte Carlo simulations were performed to represent different combinations of age, incorporation of electrocardiographically controlled tube current modulation (ECTCM) and inclusion of the aorta. They then worked out a cancer incidence from each age, sex and organ according to the BEIR VII report.
Organ doses ranged from 42 to 91 mSv for the lungs and 50 to 80 mSv for the female breast. Lifetime cancer risks were estimated at 1 in 143 for a 20‐year‐old woman, to 1 in 3261 for an 80‐year‐old man. However, the use of ECTCM decreased these figures to 1 in 219 and 1 in 5017, respectively. For a 60‐year‐old, the estimated cancer risk was 1 in 715 for a woman and 1 in 1911 for a man when using ECTCM. The highest organ LARs were for lung cancer and, in younger women, breast cancer.
These estimates suggest that the use of 64‐slice CTCA is associated with a non‐negligible risk of cancer, which varies and is greatest for women and younger patients. The study is a simplified, theoretical, approach, which is not based on actual epidemiological data. Nonetheless, it implies that in younger patients stress echocardiography, exercise testing or magnetic resonance imaging may be more appropriate first‐choice non‐invasive investigations.
Einstein AJ, Henzlova MJ, Rajagopalan S. Estimating risk of cancer associated with radiation exposure from 64‐slice computed tomography coronary angiography. JAMA 2007;298:317–23.
Data on the prognostic effect of mild thyroid dysfunction in patients with cardiac disease have to date been limited and conflicting. Iervasi et al therefore developed a large prospective study to test the hypothesis that a mildly altered thyroid status is associated with an increased risk of mortality in patients with diagnosed ischaemic or non‐ischaemic cardiac disease.
A total of 3121 patients with all forms of heart disease were followed up for a mean of 32 months and divided into four different groups: euthyroid; subclinical hypothyroidism (SCH); subclinical hyperthyroidism (SCT), and low tri‐iodothyronine syndrome (low T3). Overall, there were 65 cardiac deaths out of 140 total deaths (3.4% and 7.3%), respectively, in euthyroid patients, 15 and 27 (7.2% and 13.0%) in SCH, 8 and 9 (8.2% and 9.2%) in SCT, and 59 and 119 (6.5% and 13.1%) in low T3. Survival rates for cardiac death were lower in SCH, SCT, and low T3 than in euthyroidism (p<0.001). Survival rates for overall death were lower in SCH and low T3 than in euthyroidism also (p<0.001). After adjusting for common cardiac risk factors, hazard ratios (HRs) for cardiac death were higher in SCH (HR=2.40; p=0.02), SCT (HR=2.32; p=0.02) and low T3 (HR=1.63; p=0.007) than in euthyroidism; HRs for overall death were higher in SCH (HR=2.01; p<0.001) and low T3 (HR=1.57; p<0.001), but not in SCT.
The main finding of this study is that the presence of an unknown mild thyroid disorder is linked to an increased risk of mortality in patients with cardiac disease, particularly those with ischaemic heart disease. The study found that almost 40% of patients had previously unidentified abnormal thyroid function, but the authors do also note that most patients in this study were male and subclinical thyroid disease mainly affects women. Nonetheless, all cardiologist should be aware of the need for regular thyroid function checks in all of their patients.
Iervasi G, Molinaro S, Landi P, et al Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007;167:1526–32.
Although the role of low‐density lipoprotein‐cholesterol (LDL‐C) in the development of atherosclerosis is well documented, an increasing amount of evidence also suggests that higher apolipoprotein (apo) B and lower apo A‐I levels may have a role in the pathogenesis of atherosclerosis. Using data from the Framingham Offspring Study, Ingelsson et al investigated the utility of different lipid measures for predicting coronary heart disease risk in a large prospective cohort of men and women (53%).
Serum total cholesterol (TC), high‐density lipoprotein‐cholesterol (HDL‐C), LDL‐C, non‐HDL‐C, apo A‐I and apo B, and three separate lipid ratios (TC:HDL‐C, LDL‐C:HDL‐C, and apo B:apo A‐I) were all measured. A total of 3322 middle‐aged, white participants who attended the fourth offspring examination cycle between 1987 and 1991 took part.
After a median follow‐up of 15.0 years, 291 participants, 198 of whom were men, developed coronary heart disease (CHD). When a multivariate model was used to adjust for non‐lipid risk factors, the apo B:apo A‐I ratio predicted CHD (hazard ratio (HR) per SD increment, 1.39 in men and 1.40 in women), but risk ratios were similar to that for TC:HDL‐C (HR=1.39 in both men and women), and for LDL‐C:HDL‐C (HR=1.35 in men and 1.36 in women). Furthermore, the apo B:apo A‐I ratio did not predict CHD risk in a model containing all the components of the Framingham risk score which included TC:HDL‐C (p=0.12 in men; p=0.58 in women).
This study suggests that the TC:HDL‐C and the apo B:apo A‐I ratios are fairly comparable, but that apo B:apo A‐I does not seem to improve the ability to predict coronary risk. If nothing else, some clinicians fear that measuring apo B has the potential to suggest that cholesterol is not as important as once thought. Currently, the measurement of LDL, HDL and TC are preferred for lipid management.
Ingelsson E, Schaefer EJ, Contois JH, et al Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007;298:776–85.
Rheumatic heart disease is a major cause of morbidity and mortality in the developing world and is a significant burden on healthcare systems with limited resources. A multinational group representing a partnership between researchers in Mozambique, Cambodia, France and Australia carried out two large population‐based studies of school children in Cambodia and Mozambique, to identify the feasibility of echocardiographic screening and to ascertain whether this technology would provide a more realistic estimate of the prevalence of rheumatic heart disease than clinical assessment alone.
The studies were performed in 2001–2 in Cambodia and 2005 in Mozambique. Echocardiography was performed by technicians who were unaware of the clinical findings. Only left‐sided heart valves were examined for rheumatic heart disease; although frequently identified, neither mild tricuspid regurgitation nor pulmonary regurgitation were regarded as being diagnostic of rheumatic disease. Diagnosis was confirmed by the presence of any definite evidence of mitral or aortic regurgitation seen in two planes by Doppler echocardiography, accompanied by at least two out of three of the following morphological valvular abnormalities: restricted leaflet mobility, focal or generalised valvular thickening or abnormal subvalvular thickening.
A total of 3677 children in Cambodia and 2170 children in Mozambique were randomly screened in the studies which both had >90% power at the 0.01 significance level. Clinical examination detected rheumatic heart disease in eight children in Cambodia (prevalence rate 2.2 cases/1000, 95% CI 0.7 to 3.7) and five children in Mozambique (prevalence rate 2.3 cases/1000, 95% CI 0.3 to 4.3). These findings were confirmed by echocardiography. All children in whom cardiac abnormalities were noted underwent repeat scanning and later videotape analysis by three independent doctors experienced in diagnosing rheumatic heart disease. Echocardiographic screening identified 79 cases of rheumatic heart disease in Cambodia (prevalence rate 21.5 cases/1000, 95% CI 16.8 to 26.2) and 66 cases in Mozambique (prevalence rate 30.4 cases/1000, 95% CI 23.2 to 37.6). The most commonly identified lesion was the mitral valve: 87.3% in Cambodia and 98.4% in Mozambique.
Currently the disease burden of rheumatic heart disease may be underestimated since prevalence data are based on comprehensive clinical examinations rather than echocardiographic screening programmes. The results of these studies suggest that echocardiography may detect up to 10 times as many cases as clinical screening in these population groups. However, even echocardiographic screening in these populations may underestimate the true prevalence. Accurate information on the prevalence of rheumatic fever will allow optimal regional healthcare planning and early identification of people to be targeted for secondary prevention. The observation that 90% of cases of rheumatic heart disease can be clinically silent is a compelling argument for access to portable echocardiographic equipment in the developing world, despite limited financial resources.
Marijon E, Ou P, Celermajer DS, et al Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 2007;357:470–6.
In: Carapetis JR, ed. Rheumatic heart disease in developing countries. N Engl J Med 2007;357:439–41.
Patients with peripheral vascular disease have about three times the risk of myocardial infarction, stroke or death from cardiovascular causes as those without the disease. Antiplatelet treatment has been shown to reduce the incidence of major adverse cardiovascular events in these patients, but might the combination of oral antiplatelet agents and warfarin help to decrease this risk even further?
The Warfarin Antiplatelet Vascular Evaluation (WAVE) Trial was a randomised open‐label clinical trial involving 80 centres world wide and 2161 patients. Eligibility included patients aged 35–85 years with peripheral vascular disease, defined as atherosclerosis of the arteries of the lower extremities, carotid or subclavian arteries. There was an active run‐in phase of 2–4 weeks during which patients received both oral antiplatelet agents (including aspirin, clopidogrel or ticlopidine) and anticoagulants (including warfarin and acenocoumarol). Once a stable international normalisation ratio of 2–3 was achieved, patients were randomly assigned to either combined treatment with antiplatelet and antithrombotic agents (n=1080) or antiplatelet treatment alone (n=1081). Dual antiplatelet treatment was not allowed unless the patient had an acute coronary syndrome or coronary stent during the follow‐up period.
Myocardial infarction, stroke or death from cardiovascular causes occurred in 132/1080 patients in the combined treatment arm (12.2%) and in 144/1081 patients in the antiplatelet arm (13.3%, relative risk (RR)= 0.92, 95% CI 0.73 to 1.16, p=0.48). Myocardial infarction, stroke, severe ischaemia of the peripheral or coronary arteries requiring intervention, or death from cardiovascular causes, occurred in 172 patients receiving combination treatment (15.9%) compared with 188 patients receiving antiplatelet treatment alone (17.4%, RR=0.91, 95% CI 0.74 to 1.12, p=0.37). Life‐threatening bleeding occurred in 43 patients receiving combination treatment (4%) compared with 13 patients receiving antiplatelet treatment alone (1.2%, RR=3.41, 95% CI 1.84 to 6.35, p<0.001).
Antiplatelet agents are known to reduce the incidence of major adverse cardiovascular events in patients with peripheral arterial disease and therefore the hypothesis of a benefit with the addition of an anticoagulant to an antiplatelet agent was reasonable. However, the excess bleeding that occurred in patients receiving combination treatment effectively “neutralised” any benefit of that regimen; the rates of serious bleeding and haemorrhagic stroke were higher in this study than in a similar study in patients with known coronary artery disease. This may be because this group of patients tended to be older and have more systemic atherosclerosis (including cerebrovascular disease) and other comorbidities.
On the basis of these data oral anticoagulation combined with antiplatelet treatment is not indicated in patients with peripheral arterial disease as no significant benefit was seen and it was associated with substantial risk. According to these data, giving 1000 patients combined treatment as opposed to a single antiplatelet agent for 3 years would lead to 24 fewer cardiovascular events at the expense of 28 more episodes of life‐threatening bleeding. Further studies to evaluate alternatives to vitamin K antagonists will be beneficial.
The Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007;357:217–27.
In: Mohler ER, ed. Atherothrombosis – wave goodbye to combined anticoagulation and antiplatelet therapy? N Engl J Med 2007;357:293–6.
How effective are implantable cardioverter‐defibrillator (ICD) devices in patients with hypertrophic cardiomyopathy?
Maron et al studied 506 unrelated patients with hypertrophic cardiomyopathy who were judged to be at high risk for sudden death and had been implanted with an ICD. Measured risk factors for sudden death included a family history of sudden death, massive left ventricular hypertrophy, non‐sustained ventricular tachycardia on Holter monitoring and unexplained prior syncope.
The patients studied were predominantly young (mean age 42 years) at the time of implantation, and the majority (87%) had no or only mildly limiting symptoms. One hundred and three patients (20%) had an episode of ventricular tachycardia or fibrillation appropriately terminated; however, the time to the first appropriate discharge was up to 10 years, with a 27% probability 5 years or more after implantation. Intervention (discharge) rates were 10.6% a year for secondary prevention after cardiac arrest, and 3.6% a year for primary prevention.
For primary prevention, 18/51 patients with appropriate ICD interventions (35%) had undergone implantation for only a single risk factor—but the likelihood of an appropriate discharge was similar in patients with either 1, 2, 3 or more risk markers. (3.83, 2.65 and 4.82 per 100 person‐years, respectively; p=0.77). The authors noted only one sudden death due to an arrhythmia—when an ICD malfunctioned.
In this group of patients at high risk, ICD interventions were common and effective in restoring normal rhythm. There is currently little disagreement over the use of ICD devices for secondary prevention in hypertrophic cardiomyopathy, but it was noticeable that in this trial a significant number of discharges were in primary prevention patients who had undergone implantation for a single risk factor only. Should we therefore insert ICD devices in all patients with hypertrophic cardiomyopathy who have just a single risk factor for sudden death? In an accompanying editorial, Rick A Nishimura and Steve R Ommen from the Mayo Clinic College of Medicine suggest that the decision whether or not to implant an ICD in this group of patients should still “include a thorough and earnest discussion of the accuracy of current risk‐assessment tools, the risks and benefits of ICD therapy, and the individual patient's viewpoints on procedures, devices and death”.
Maron BJ, Spirito P, Shen WK, et al Implantable cardioverter‐defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405–12.
There has been marked enthusiasm recently for the idea that resident cardiac stem cells may be able to regenerate mammalian myocardium. However, it is thought that such regeneration would not be sufficient to repair the extensive myocardial injury that is typical of human disease processes. Hsieh et al report evidence that stem cells contribute to the replacement of adult mammalian cardiomyocytes after injury but do not contribute significantly to cardiomyocyte renewal during normal aging.
Double transgenic mice were generated to document the fate of adult cardiomyocytes. These cells were marked with green fluorescent protein (GFP), a fluorescent tag allowing identification during normal aging or experimental injury. At baseline 82.7% of cardiomyocytes expressed GFP. During normal aging (up to 1 year) this number remained unchanged, indicating that stem cells did not refresh uninjured cardiomyocytes significantly during this time. In contrast, after injury induced by myocardial infarction or pressure overload, the percentage of GFP‐positive cardiomyocytes fell from 82.8% in cardiac tissues of sham‐treated mice to 67.5% in areas bordering a myocardial infarction, 76.6% in areas away from a myocardial infarction and 75.7% in hearts submitted to pressure overload. This suggests that stem cells had refreshed the cardiomyocytes.
Further studies in this complex area will be necessary to provide additional insight into the potential clinical roles for stem cell treatments.
Hsieh PC, Segers VFM, Davis ME, et al. Evidence from a genetic fate‐mapping study that stem cells refresh mammalian cardiomyocytes after injury. Nat Med 2007;13:970–4.
Although lifestyle and environmental factors have a role in the development of coronary artery disease, the disease tends to cluster in families, suggesting that there might be a genetic predisposition. Yet despite extensive analysis strong evidence for a molecular genetic association has not yet been identified. Recent technological advances, including the development of high‐density genotyping arrays, have allowed whole‐genome assessment of those variants associated with common diseases for the first time.
Chromosomal loci that were strongly associated with coronary artery disease were identified from subjects in the Wellcome Trust Case Control Consortium (WTCCC) Study of 1926 case subjects with coronary artery disease and 2938 controls. Case subjects had a history of either myocardial infarction or coronary revascularisation before the age of 66 years and a strong family history of cardiac disease. Results were compared with the German Myocardial Infarction Family Study involving 875 case subjects and 1644 controls. Case subjects had had a myocardial infarction age <60 years and had at least one first‐degree relative with premature coronary artery disease. Data on single nucleotide polymorphisms that were significantly associated with coronary artery disease in either study (p<0.001) were combined with the aim of identifying loci with a high probability of a true association.
The same locus, chromosome 9p21.3 had the strongest association in both the WTCCC and German study (p=1.80×10−14 and p=3.4×10−6, respectively). In total, the WTCCC Study identified nine loci that were strongly associated with coronary artery disease (p<1.2×10−5) and two of these were also identified in the German study (chromosome 6q25.1 and chromosome 2q36.3). Combined analyses identified four additional loci (chromosome 1p13.3, 1q41, 10q11.21 and 15q22.33) associated with significant coronary disease (p<1.3×10−6) and a high probability (>80%) of a true association.
With the increasing burden of coronary artery disease on healthcare resources it is of paramount importance to fully understand the causes of coronary artery disease and identify people at risk. By identifying genetic factors, more precise and accurate estimates of risk can be calculated. It may also lead to the identification of individual risk, allowing therapeutic strategies to be tailored to the individual with a personalised approach to care.
Samani NJ, Erdmann J, Hall AS. Genomewide association analysis of coronary artery disease. N Engl J Med 2007;357:443–53.
Rosenzweig A. Scanning the genome for coronary risk. N Engl J Med 2007;357:497–9.
American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Lancet; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax
Dr Alistair Lindsay, Dr Katie Qureshi