A practical evidence-based approach to management of type 2 diabetes in children and young people (CYP): UK consensus.

BACKGROUND: Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and globally is rising yet experience in managing this condition is limited. There are no consensus guidelines in the UK for the assessment and management of paediatric type 2 diabetes. METHODS: Multidisciplinary professionals from The Association of Children's Diabetes Clinicians (ACDC) and the National Type 2 Diabetes Working Group reviewed the evidence base and made recommendations using the Grading Of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. RESULTS AND DISCUSSION: Young people with type 2 diabetes should be managed within a paediatric diabetes team with close working with adult diabetes specialists, primary care and other paediatric specialties. Diagnosis of diabetes type can be challenging with many overlapping features. Diabetes antibodies may be needed to aid diagnosis. Co-morbidities and complications are frequently present at diagnosis and should be managed holistically. Lifestyle change and metformin are the mainstay of early treatment, with some needing additional basal insulin. GLP1 agonists should be used as second-line agents once early ketosis and symptoms are controlled. Glycaemic control improves microvascular but not cardiovascular risk. Reduction in excess adiposity, smoking prevention, increased physical activity and reduction of hypertension and dyslipidaemia are essential to reduce major adverse cardiovascular events. CONCLUSIONS: This evidence-based guideline aims to provide a practical approach in managing this condition in the UK.

Fostering diffusion of scientific contents of National Society Cardiovascular Journals:the new ESC search engine.

European Society of Cardiology (ESC) National Society Cardiovascular Journals (NSCJs) are high-quality biomedical journals focused on cardiovascular diseases. The Editors' Network of the ESC devises editorial initiatives aimed at improving the scientific quality and diffusion of NSCJ. In this article we will discuss on the importance of the Internet, electronic editions and open access strategies on scientific publishing. Finally, we will propose a new editorial initiative based on a novel electronic tool on the ESC web-page that may further help to increase the dissemination of contents and visibility of NSCJs.

A practical approach to continuous glucose monitoring (rtCGM) and FreeStyle Libre systems (isCGM) in children and young people with Type 1 diabetes.

Real-time continuous glucose monitoring (rtCGM) and FreeStyle Libre glucose monitoring systems (isCGM) are new evolving technologies used in the management of Type 1 diabetes. They offer potential to improve diabetes control and reduce hypoglycaemia. rtCGM can be linked to insulin pump providing hybrid closed loop therapy. Families of children and young people are keen to have the benefit from these technologies. These are relatively expensive so it is important that health care professionals, families of children and young people (CYP) with diabetes are adequately trained in the use of these devices. Health care professionals need to be able to make patient selection based on individual needs and preferences to achieve maximum benefit. Association of Children's Diabetes Clinicians (ACDC) developed a comprehensive guideline in 2017 to help identify which patients may be most likely to benefit and how these technologies may be practically implemented. Since then new technologies have been introduced and the use of GCM has expanded in routine clinical practice. This article, aims to provide a practical approach and help identify which patients may be most likely to benefit and how the technology may be implemented in order to maximise the clinical benefits.

Incidence and prognosis of angina pectoris in South Asians and Whites: 18 years of follow-up over seven phases in the Whitehall-II prospective cohort study.

BACKGROUND: Whether the higher coronary mortality in South Asians compared with White populations is due to a higher incidence of disease is not known. This study assessed cumulative incidence of chest pain in South Asians and Whites, and prognosis of chest pain. METHODS: Over seven phases of 18-year follow-up of the Whitehall-II study (9,775 civil servants: 9,195 White, 580 South Asian), chest pain was assessed using the Rose questionnaire. Coronary death/non-fatal myocardial infarction was examined comparing those with chest pain to those with no chest pain at baseline. RESULTS: South Asians had higher cumulative frequencies of typical angina by Phase 7 (17.0 versus 11.3%, P < 0.001) and exertional chest pain (15.4 versus 8.5%, P < 0.001) compared with Whites. Typical angina and exertional chest pain at baseline were associated with a worse prognosis compared with those with no chest pain in both groups (typical angina, South Asians: HR, 4.67 and 95% CI, 2.12-0.30; Whites: HR, 3.56 95% CI, 2.59-4.88). Baseline non-exertional chest pain did not confer a worse prognosis. Across all types of pain, prognosis was worse in South Asians. CONCLUSION: South Asians had higher cumulative incidence of angina than Whites. In both, typical angina and exertional chest pain were associated with worse prognosis compared with those with no chest pain.

Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study.

BACKGROUND: The long-term excess risk of death associated with diabetes following acute myocardial infarction is unknown. We determined the excess risk of death associated with diabetes among patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) after adjustment for comorbidity, risk factors and cardiovascular treatments. METHODS: Nationwide population-based cohort (STEMI n=281 259 and NSTEMI n=422 661) using data from the UK acute myocardial infarction registry, MINAP, between 1 January 2003 and 30 June 2013. Age, sex, calendar year and country-specific mortality rates for the populace of England and Wales (n=56.9 million) were matched to cases of STEMI and NSTEMI. Flexible parametric survival models were used to calculate excess mortality rate ratios (EMRR) after multivariable adjustment. This study is registered at ClinicalTrials.gov (NCT02591576). RESULTS: Over 1.94 million person-years follow-up including 120 568 (17.1%) patients with diabetes, there were 187 875 (26.7%) deaths. Overall, unadjusted (all cause) mortality was higher among patients with than without diabetes (35.8% vs 25.3%). After adjustment for age, sex and year of acute myocardial infarction, diabetes was associated with a 72% and 67% excess risk of death following STEMI (EMRR 1.72, 95% CI 1.66 to 1.79) and NSTEMI (1.67, 1.63 to 1.71). Diabetes remained significantly associated with substantial excess mortality despite cumulative adjustment for comorbidity (EMRR 1.52, 95% CI 1.46 to 1.58 vs 1.45, 1.42 to 1.49), risk factors (1.50, 1.44 to 1.57 vs 1.33, 1.30 to 1.36) and cardiovascular treatments (1.56, 1.49 to 1.63 vs 1.39, 1.36 to 1.43). CONCLUSIONS: At index acute myocardial infarction, diabetes was common and associated with significant long-term excess mortality, over and above the effects of comorbidities, risk factors and cardiovascular treatments.

Rapid-access chest pain clinics and the traditional cardiology out-patient clinic.

BACKGROUND: The National Service Framework for coronary heart disease recommends rapid-access chest pain clinics (RACPCs) for cardiological assessment of new-onset chest pain within 2 weeks of referral. AIM: To measure the extent to which an RACPC successfully substituted for an out-patient cardiology clinic (OPCC) at a general hospital, in assessing new-onset chest pain referrals. METHODS: Prospective measurement of attendance and waiting times for consecutive patients at the RACPC and OPCC, and multivariate analysis of factors associated with referral for angiography. RESULTS: From September 2002 to August 2004, 1382 patients with chest pain attended the RACPC, and 228 patients, the OPCC. All RACPC patients were seen within 24 h of referral, except those referred on Friday afternoons, or the day before national holidays. The mean +/- SD waiting time for OPCC appointments was 97 +/- 43 days. Of 208 OPCC patients, 30 (14%) fulfilled the RACPC referral criterion of recent onset chest pain (<4 weeks duration) vs. 926/1382 (67%) RACPC patients. Thus the RACPC substituted for the OPCC in 926/956 (97%) new chest pain referrals. Patients from the OPCC were 3.82 (95%CI 1.85-7.90) more likely to be referred for a coronary angiogram. compared to those attending the RACPC. DISCUSSION: The RACPC has provided efficient and effective substitution for the OPCC in the assessment of new chest pain referrals according to pre-defined referral criteria. Broadening the referral criterion of the RACPC to patients with chest pain of >4 weeks duration would result in more referrals.

Prolonged dual antiplatelet therapy in stable coronary disease: comparative observational study of benefits and harms in unselected versus trial populations.

OBJECTIVE:  To estimate the potential magnitude in unselected patients of the benefits and harms of prolonged dual antiplatelet therapy after acute myocardial infarction seen in selected patients with high risk characteristics in trials. DESIGN:  Observational population based cohort study. SETTING:  PEGASUS-TIMI-54 trial population and CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records). PARTICIPANTS:  7238 patients who survived a year or more after acute myocardial infarction. INTERVENTIONS:  Prolonged dual antiplatelet therapy after acute myocardial infarction. MAIN OUTCOME MEASURES:  Recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease. Fatal, severe, or intracranial bleeding. RESULTS:  1676/7238 (23.1%) patients met trial inclusion and exclusion criteria ("target" population). Compared with the placebo arm in the trial population, in the target population the median age was 12 years higher, there were more women (48.6% v 24.3%), and there was a substantially higher cumulative three year risk of both the primary (benefit) trial endpoint of recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease (18.8% (95% confidence interval 16.3% to 21.8%) v 9.04%) and the primary (harm) endpoint of fatal, severe, or intracranial bleeding (3.0% (2.0% to 4.4%) v 1.26% (TIMI major bleeding)). Application of intention to treat relative risks from the trial (ticagrelor 60 mg daily arm) to CALIBER's target population showed an estimated 101 (95% confidence interval 87 to 117) ischaemic events prevented per 10 000 treated per year and an estimated 75 (50 to 110) excess fatal, severe, or intracranial bleeds caused per 10 000 patients treated per year. Generalisation from CALIBER's target subgroup to all 7238 real world patients who were stable at least one year after acute myocardial infarction showed similar three year risks of ischaemic events (17.2%, 16.0% to 18.5%), with an estimated 92 (86 to 99) events prevented per 10 000 patients treated per year, and similar three year risks of bleeding events (2.3%, 1.8% to 2.9%), with an estimated 58 (45 to 73) events caused per 10 000 patients treated per year. CONCLUSIONS:  This novel use of primary-secondary care linked electronic health records allows characterisation of "healthy trial participant" effects and confirms the potential absolute benefits and harms of dual antiplatelet therapy in representative patients a year or more after acute myocardial infarction.

Geographic variation in the treatment of non-ST-segment myocardial infarction in the English National Health Service: a cohort study.

OBJECTIVES: To investigate geographic variation in guideline-indicated treatments for non-ST-elevation myocardial infarction (NSTEMI) in the English National Health Service (NHS). DESIGN: Cohort study using registry data from the Myocardial Ischaemia National Audit Project. SETTING: All Clinical Commissioning Groups (CCGs) (n=211) in the English NHS. PARTICIPANTS: 357 228 patients with NSTEMI between 1 January 2003 and 30 June 2013. MAIN OUTCOME MEASURE: Proportion of eligible NSTEMI who received all eligible guideline-indicated treatments (optimal care) according to the date of guideline publication. RESULTS: The proportion of NSTEMI who received optimal care was low (48 257/357 228; 13.5%) and varied between CCGs (median 12.8%, IQR 0.7-18.1%). The greatest geographic variation was for aldosterone antagonists (16.7%, 0.0-40.0%) and least for use of an ECG (96.7%, 92.5-98.7%). The highest rates of care were for acute aspirin (median 92.8%, IQR 88.6-97.1%), and aspirin (90.1%, 85.1-93.3%) and statins (86.4%, 82.3-91.2%) at hospital discharge. The lowest rates were for smoking cessation advice (median 11.6%, IQR 8.7-16.6%), dietary advice (32.4%, 23.9-41.7%) and the prescription of P2Y12 inhibitors (39.7%, 32.4-46.9%). After adjustment for case mix, nearly all (99.6%) of the variation was due to between-hospital differences (median 64.7%, IQR 57.4-70.0%; between-hospital variance: 1.92, 95% CI 1.51 to 2.44; interclass correlation 0.996, 95% CI 0.976 to 0.999). CONCLUSIONS: Across the English NHS, the optimal use of guideline-indicated treatments for NSTEMI was low. Variation in the use of specific treatments for NSTEMI was mostly explained by between-hospital differences in care. Performance-based commissioning may increase the use of NSTEMI treatments and, therefore, reduce premature cardiovascular deaths. TRIAL REGISTRATION NUMBER: NCT02436187.

Patient and hospital determinants of primary percutaneous coronary intervention in England, 2003-2013.

OBJECTIVE: Primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is insufficiently implemented in many countries. We investigated patient and hospital characteristics associated with PPCI utilisation. METHODS: Whole country registry data (MINAP, Myocardial Ischaemia National Audit Project) comprising PPCI-capable National Health Service trusts in England (84 hospital trusts; 92 350 hospitalisations; 90 489 patients), 2003-2013. Multilevel Poisson regression modelled the relationship between incidence rate ratios (IRR) of PPCI and patient and trust-level factors. RESULTS: Overall, standardised rates of PPCI increased from 0.01% to 86.3% (2003-2013). While, on average, there was a yearly increase in PPCI utilisation of 30% (adjusted IRR 1.30, 95% CI 1.23 to 1.36), it varied substantially between trusts. PPCI rates were lower for patients with previous myocardial infarction (0.95, 0.93 to 0.98), heart failure (0.86, 0.81 to 0.92), angina (0.96, 0.94 to 0.98), diabetes (0.97, 0.95 to 0.99), chronic renal failure (0.89, 0.85 to 0.90), cerebrovascular disease (0.96, 0.93 to 0.99), age >80 years (0.87, 0.85 to 0.90), and travel distances >30 km (0.95, 0.93 to 0.98). PPCI rates were higher for patients with previous percutaneous coronary intervention (1.09, 1.05 to 1.12) and among trusts with >5 interventional cardiologists (1.30, 1.25 to 1.34), more visiting interventional cardiologists (1-5: 1.31, 1.26 to 1.36; ≥6: 1.42, 1.35 to 1.49), and a 24 h, 7-days-a-week PPCI service (2.69, 2.58 to 2.81). Half of the unexplained variation in PPCI rates was due to between-trust differences. CONCLUSIONS: Following an 8 year implementation phase, PPCI utilisation rates stabilised at 85%. However, older and sicker patients were less likely to receive PPCI and there remained between-trust variation in PPCI rates not attributable to differences in staffing levels. Compliance with clinical pathways for STEMI is needed to ensure more equitable quality of care.

Silent myocardial ischemia: role of subclinical neuropathy in patients with and without diabetes.

OBJECTIVES: Silent myocardial ischemia is common in patients with diabetes. This study was designed to assess the role of subclinical autonomic impairment in diabetic patients with silent ischemia. BACKGROUND: Studies have suggested that silent ischemia is more common in diabetic patients with microvascular complications, but this has not been a consistent finding. METHODS: Twenty-two diabetic and 30 nondiabetic patients with proved coronary artery disease and a history of angina and ischemia on treadmill stress testing underwent clinical tests of autonomic function and measurement of 24-h heart rate variability. Diabetic patients with a history of microvascular complications were excluded. RESULTS: Although all 52 patients manifested ischemia during treadmill testing, only 36 patients experienced angina (angina group), whereas 16 did not (silent ischemia group). Diabetic and nondiabetic patients were similar in age (59 +/- 1 vs. 61 +/- 2 years, p = 0.56) and extent of coronary artery disease. However, clinical tests showed reduced parasympathetic function in the diabetic patients (Valsalva ratio 1.38 +/- 0.07 vs. 1.60 +/- 0.06; p = 0.007). Patients in the silent ischemia group were more often diabetic (33% vs. 63%, p = 0.05) and had prolonged time to ischemia on treadmill testing (200 +/- 20 vs. 271 +/- 20 s, p = 0.03). In addition, autonomic function was impaired in the silent group (supine/standing heart rate ratio 1.15 +/- 0.02 vs. 1.05 +/- 0.02, p = 0.002). Subgroup analysis showed that abnormalities of autonomic function were confined to the diabetic patients in the silent group. CONCLUSIONS: Despite the absence of overt microvascular complications, diabetic patients with silent exertional ischemia have evidence of significant autonomic impairment compared with findings in symptomatic patients. This difference is not seen in nondiabetic patients and indicates that subclinical neuropathy is an important cause of silent ischemia in patients with diabetes.

Mechanisms of cold intolerance in patients with angina.

OBJECTIVES: Patients with angina often report that symptoms are worse in cold weather. This study was designed to determine differences between cold-tolerant and cold-intolerant patients in the hemodynamic and ischemic response to exercise at cold temperatures and to assess the role of catecholamines and baroreceptor function. BACKGROUND: Studies have suggested that the heart rate response may differ at cold temperatures, but the mechanism and role of this variation have not been examined. METHODS: Seven cold-intolerant and seven cold-tolerant patients with angina underwent exercise treadmill testing at 6 and 25 degrees C with measurement of catecholamines. Baroreceptor function was assessed by the decrease in systolic blood pressure after patients stood up from the supine position. RESULTS: Norepinephrine levels increased by 139% in the cold environment, but there were no differences between cold-intolerant and cold-tolerant patients. Consequently, blood pressure was higher in the cold environment in all patients, but the heart rate response was similar. However, cold-intolerant patients had a steeper heart rate response in the cold and developed ischemia (mean [+/- SEM] 201 +/- 58 vs. 242 +/- 50 s, p = 0.05) and angina (348 +/- 87 vs. 449 +/- 60 s, p = 0.04) earlier in the cold environment, a difference not seen in the cold-tolerant patients. Baroreceptor function was impaired in cold-intolerant patients (decrease in systolic blood pressure after patients stood up from the supine position 19 +/- 7 vs. 0 +/- 4 mm Hg, p = 0.04). CONCLUSIONS: Exposure to cold causes an increase in blood pressure with an associated increase in myocardial oxygen demand in all patients. In cold-tolerant patients, this increase may be offset by a reduction in heart rate if baroreceptor function is normal. If baroreceptor function is abnormal, heart rate may not decrease in response to a cold-induced increase in blood pressure. This mechanism may account for some of the variability in tolerance to cold exposure that affects patients with exertional angina.

Anisoylated plasminogen streptokinase activator complex in acute myocardial infarction: a placebo-controlled arteriographic coronary recanalization study.

Anisoylated plasminogen streptokinase activator complex (APSAC) is a new thrombolytic agent that is of interest because of its ease of administration as an intravenous bolus injection. This report describes the first double-blind, placebo-controlled evaluation of intravenous APSAC for coronary recanalization in acute myocardial infarction. Unequivocal documentation of recanalization was provided by coronary arteriography before and after the drug intervention. Forty patients with acute myocardial infarction underwent coronary arteriography 3.1 +/- 1.2 hours after the onset of symptoms. This demonstrated occlusion of the infarct-related coronary artery in 29 patients who were then randomized to treatment with intravenous APSAC, 30 mg (n = 16), and placebo (n = 13) 3.3 +/- 1.3 hours after the onset of symptoms. Repeat arteriography 90 minutes later demonstrated recanalization of the infarct-related coronary artery in nine patients who had received APSAC compared with only one patient who had received placebo (56 versus 8%, p less than 0.05). The 95% confidence limits for this 48% difference between the groups are 20 to 76%. Arteriography at 3 days showed persistent patency of all recanalized coronary arteries except one (APSAC group) and also showed late recanalization in another four patients, three of whom had received APSAC. In the patients who had a patent infarct-related coronary artery at the initial arteriographic study, patency was maintained throughout the study period regardless of whether the patient was randomized to APSAC (n = 4) or placebo (n = 7). Complications related to APSAC therapy were excessive bruising at the catheterization site in seven patients and minor sensitivity reactions in three.(ABSTRACT TRUNCATED AT 250 WORDS)

Reexamination of the role of endogenous opiates in silent myocardial ischemia.

OBJECTIVES: This study was designed to examine the role of beta-endorphin and met-enkephalin in the pathophysiology of silent myocardial ischemia, with emphasis on their role in the physiologic response to stress. BACKGROUND: Silent myocardial ischemia is more common in patients whose perception of pain is reduced. Whether endogenous opiates can contribute to this process remains uncertain largely because of the conflicting findings of previous studies. METHODS: Forty-three patients with coronary artery disease and ischemia on treadmill stress testing underwent electrical pain tests and exercise treadmill tests during naloxone and placebo infusion in a randomized, double-blind crossover study. Thirty-one patients developed angina during both treadmill tests (group A), and 12 had silent ischemia (group B). Plasma beta-endorphin, metenkephalin, epinephrine, norepinephrine and cortisol were measured before and after exercise in a subgroup of 17 patients. RESULTS: Naloxone reduced electrical pain tolerance (1.40 +/- 0.10 [mean +/- SEM] vs. 1.72 +/- 0.19 mA, p = 0.04) but did not affect the time to angina in group A (260 +/- 20 vs. 248 +/- 20 s, p = 0.72) or induce angina in group B patients. Beta-endorphin and met-enkephalin levels during placebo infusion were not significantly different in groups A and B at baseline and after exercise, although beta-endorphin levels were significantly increased during naloxone infusion, confirming effective opiate receptor blockade. Norepinephrine and cortisol increased with exercise, but catecholamines and cortisol were similar in both groups and were unaffected by naloxone. CONCLUSIONS: Beta-endorphin and met-enkephalin were similar in patients with painful and silent ischemia, and naloxone infusion did not influence anginal symptoms despite effective opiate receptor blockade and a reduction in somatic pain tolerance. These findings suggest that endogenous opiates do not play an important role in modulating symptoms in myocardial ischemia. The increase in beta-endorphin with exercise that coincided with an increase in plasma cortisol is most likely due to its release from the anterior pituitary gland as part of the physiologic stress response.

Prolonged anginal perceptual threshold in diabetes: effects on exercise capacity and myocardial ischemia.

Anginal perceptual threshold (the time from onset of 0.1 mV of ST segment depression to onset of angina during treadmill exercise) is prolonged in diabetic patients with coronary artery disease. In the present study, the functional significance of this perceptual abnormality was evaluated by analysis of its effect on exercise capacity and the severity of myocardial ischemia. Treadmill exercise in 32 diabetic patients and 36 nondiabetic control patients showed a close linear correlation between the time to onset of electrical ischemia (ST segment depression) and exercise capacity in both groups (r = 0.8 and 0.9, respectively; p less than 0.001). However, the slope of the relation was flatter in the diabetic group because prolongation of the anginal perceptual threshold permitted continued exercise as ischemia intensified. The anginal perceptual threshold itself showed a close linear correlation with exercise capacity in the diabetic group (r = 0.8, p less than 0.001), although in the nondiabetic group these variables were unrelated. The permissive effect of a prolonged anginal perceptual threshold on exercise capacity is undesirable as reflected by its correlation with ischemia at peak exercise (r = 0.6, p less than 0.001): the longer the threshold, the greater the exercise capacity and the more severe the ischemia. Indeed, the inverse relation between the severity of ischemia at peak exercise and exercise capacity in the nondiabetic group (r = 0.4, p less than 0.02) was completely lost in the diabetic group. Thus, in diabetic patients with coronary artery disease, anginal perceptual threshold is a major determinant of exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Exertional myocardial ischemia in diabetes: a quantitative analysis of anginal perceptual threshold and the influence of autonomic function.

Patients with diabetes are prone to silent myocardial infarction and silent exertional ischemia. Although the mechanism is not clear, it may reflect a specific impairment of the sensory innervation of the heart. To test this hypothesis, anginal perceptual threshold was measured in 32 diabetic patients and 36 nondiabetic control patients, all of whom had typical exertional angina. Anginal perceptual threshold was defined as the time from onset of 0.1 mV ST depression to the onset of chest pain during treadmill stress electrocardiography. Although ST depression occurred earlier in the diabetic than in the nondiabetic group (111 +/- 82 versus 216 +/- 162 s, p less than 0.005), the anginal perceptual threshold in the diabetic group was delayed by a mean of 86 s (149 +/- 76 versus 63 +/- 59 s, p less than 0.001), with 95% confidence intervals of 53 to 119 s. Autonomic function tests were abnormal in the diabetic group, and in both groups regression analyses (using a third order polynomial) showed marked prolongations of anginal perceptual threshold as the heart rate responses to the Valsalva maneuver decreased to below the normal range (r = 0.5, p less than 0.001). There was a similar though less pronounced relation between anginal perceptual threshold and the heart rate responses to deep breathing (r = 0.3, p less than 0.02). These data suggest that prolongation of the anginal perceptual threshold may be caused by autonomic neuropathy involving the sensory innervation of the heart. To test sensory function, median nerve conduction studies were performed in 19 patients (10 diabetic and 9 nondiabetic).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of aspirin on C-reactive protein as a marker of risk in unstable angina.

OBJECTIVES: This study was designed to assess the interaction between aspirin and C-reactive protein (CRP) release in unstable angina. BACKGROUND: C-reactive protein release in acute coronary syndromes may be a response to myocardial necrosis or may reflect the inflammatory process that drives atherogenesis. Aspirin has the potential to influence CRP release, either by its anti-inflammatory activity or by reducing myocardial necrosis. The clinical significance of this potential interaction has not previously been tested. METHODS: We conducted a prospective cohort study of 304 consecutive patients admitted with non-ST-elevation acute coronary syndromes. Serial blood samples were obtained for CRP and troponin I assay. End points were cardiac death and nonfatal myocardial infarction during follow-up for 12 months. RESULTS: A total of 174 patients (57%) were taking aspirin before admission. Patients taking aspirin had lower troponin I concentrations throughout the sampling period, only 45 (26.0%) having concentrations >0.1 mg/l compared with 48 (37.8%) patients not taking aspirin (p = 0.03). Maximum CRP concentrations were also lower in patients taking aspirin (8.16 mg/l [3.24 to 24.5]) than in patients not taking aspirin (11.3 mg/l [4.15 to 26.1]), although the difference was not significant. However, there was significant interaction (p = 0.04) between prior aspirin therapy and the predictive value of CRP concentrations for death and myocardial infarction at 12 months. Thus, odds ratios (95% confidence intervals) for events associated with an increase of 1 standard deviation in maximum CRP concentration were 2.64 (1.22-5.72) in patients not pretreated with aspirin compared with 0.98 (0.60-1.62) in patients pretreated with aspirin. CONCLUSIONS: The association between CRP and cardiac events in patients with unstable angina is influenced by pretreatment with aspirin. Modification of the acute-phase inflammatory responses to myocardial injury is the major mechanism of this interaction.

Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors.

OBJECTIVES: To examine circadian changes in the sympathovagal balance, the activity of the renin-angiotensin system and hemostatic variables in patients with stable coronary artery disease, and the effects of beta-adrenoceptor blockade and angiotensin-converting enzyme inhibition. BACKGROUND: Sympathovagal balance and key components of the fibrinolytic system show circadian variability. The effects of beta-adrenergic blocking agents and angiotensin-converting enzyme inhibitors on these autonomic and hemostatic rhythms are not well defined. METHODS: Twenty patients with coronary artery disease underwent 24-h Holter monitoring for heart rate variability and blood sampling (6 hourly for 24 hours) after three consecutive treatment phases, (firstly with placebo, then bisoprolol, and finally quinapril). The effects on sympathovagal balance, hemostatic variables and the renin-angiotensin system activity were measured. RESULTS: The fibrinolytic capacity showed marked circadian variation at the end of the placebo phase (p = 0.002), plasminogen activator inhibitor-1 (PAI-1) activity peaking at 06.00 AM when tissue plasminogen activator (tPA) activity was at its nadir. Sympathovagal balance showed a sharp increase at approximately the same time but plasma renin activity did not rise until later in the day. Inspection of the 24-h profiles suggested that bisoprolol reduced sympathovagal balance and the morning peak of PAI-1 activity and antigen, with a small increase in tPA activity, although these changes were not significant. Quinapril produced a substantial rise in renin (p = 0.01) but did not significantly affect either PAI-1 or tPA. Sympathovagal balance was unaffected by quinapril. CONCLUSIONS: In patients with stable coronary artery disease, angiotensin-converting enzyme inhibition with quinapril does not affect either sympathovagal balance or the endogenous fibrinolytic system. Our data suggest that the sympathoadrenal system may modify fibrinolytic activity, judged by the response to beta-adrenoreceptor blockade with bisoprolol.

Clinical characteristics determining the mode of presentation in patients with acute coronary syndromes.

OBJECTIVES: The purpose of this study was to examine clinical characteristics of patients with acute coronary syndromes to identify factors that influence the mode of presentation. BACKGROUND: In acute coronary syndromes, presentation with myocardial infarction or unstable angina has major prognostic implications, yet clinical factors affecting the mode of presentation are not well defined. METHODS: A prospective cohort study was made of 1,111 patients with acute coronary syndromes. Baseline demographic, clinical and biochemical data were compared in groups with myocardial infarction (n = 633) and unstable angina (n = 478). RESULTS: The risk of myocardial infarction relative to unstable angina was increased by age >70 years (odds ratio [OR] 2.21; 95% confidence interval [CI] 1.33 to 3.66), male gender (OR 1.56; CI 1.13 to 2.16) and cigarette smoking (OR 1.49; CI 1.09 to 2.03). A rise in admission creatinine from the 10th to the 90th centile of the distribution also increased the odds of myocardial infarction (OR 1.30; CI 1.05 to 1.94). Conversely, the risk of myocardial infarction relative to unstable angina was reduced by previous treatment with aspirin (OR 0.37; CI 0.27 to 0.52), hypertension (OR 0.64; CI 0.47 to 0.86) and previous acute coronary syndromes (OR 0.36; CI 0.26 to 0.51) and revascularization procedures (OR 0.36; CI 0.21 to 0.62). CONCLUSIONS: The clinical presentation of acute coronary syndromes may be influenced by various factors that have the potential to influence the coagulability of the blood, the collateralization of the coronary circulation and myocardial mass. Myocardial infarction is favored by cigarette smoking, advanced age and renal impairment, while unstable angina is favored by treatment with aspirin, hypertension, previous revascularization and previous coronary syndromes.

Angiotensin-converting enzyme inhibition is associated with reduced troponin release in non-ST-elevation acute coronary syndromes.

OBJECTIVES: This study was done to determine the effects of angiotensin-converting enzyme (ACE) inhibition and other clinical factors on troponin release in non-ST-elevation acute coronary syndrome (ACS). BACKGROUND: Troponin is now widely used as a marker of risk in ACS, but determinants of its release have not been defined. METHODS: This was a prospective cohort study of 301 consecutive patients admitted with non-ST-elevation ACS. Baseline clinical data were recorded, ACE gene polymorphism was determined and serial blood samples were obtained for troponin-I assay. RESULTS: Significant troponin-I release (>0.1 microg/l) was detected in 93 (31%) patients. Pretreatment with ACE inhibitors, recorded in 53 patients (17.6%), independently reduced the odds of troponin-I release (odds ratio 0.25; 95% confidence intervals 0.10 to 0.64) and was associated with lower maximum troponin-I concentrations (median [interquartile range]) compared with patients not pretreated with ACE inhibitors (0.44 microg/l [0.19 to 2.65 microg/l] vs. 4.18 microg/l [0.91 to 12.41 microg/l], p = 0.01). Pretreatment with aspirin, recorded in 173 patients (57.5%), did not significantly reduce the odds of troponin-I release after adjustment but was associated with lower maximum troponin-I concentrations compared with patients not pretreated with aspirin (2.31 microg/l [0.72 to 8.02 microg/l] vs. 5.85 microg/l [1.19 to 12.79 microg/l], p = 0.05). The ACE genotyping (n = 268) showed 81 patients (30%) DD homozygous and 77 (29%) II homozygous. There was no association between ACE genotype and troponin release. CONCLUSIONS: We conclude that ACE inhibition reduces troponin release in non-ST-elevation ACS. This is likely to be mediated by the beneficial effects of treatment on vascular reactivity and the coagulation system.