Excessive daytime sleepiness, morning tiredness and major adverse cardiovascular events in patients with chronic coronary syndrome.

BACKGROUND: Sleep-related breathing disorders (SRBDs), particularly obstructive sleep apnoea, are associated with increased cardiovascular (CV) risk. However, it is not known whether individual questions used for SRBD screening are associated with major adverse CV events (MACE) and death specifically in patients with chronic coronary syndrome (CCS). METHODS: Symptoms associated with SRBD were assessed by a baseline questionnaire in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. The patients reported the frequency (never/rarely, sometimes, often and always) of: 1) loud snoring; 2) more than one awakening/night; 3) morning tiredness (MT); 4) excessive daytime sleepiness (EDS); or 5) gasping, choking or apnoea when asleep. In adjusted Cox regression models, associations between the frequency of SRBD symptoms and CV outcomes were assessed with never/rarely as reference. RESULTS: During a median follow-up time of 3.7 years, 1,588 MACE events (541 CV deaths, 749 nonfatal myocardial infarctions [MI] and 298 nonfatal strokes) occurred. EDS was associated (hazard ratio [HR], 95% confidence interval [CI]) with increased risk of MACE (sometimes 1.14 [1.01-1.29], often 1.19 [1.01-1.40] and always 1.43 [1.15-1.78]), MI (always 1.61 [1.17-2.20]) and all-cause death (often 1.26 [1.05-1.52] and always 1.71 [1.35-2.15]). MT was associated with higher risk of MACE (often 1.23 [1.04-1.45] and always 1.46 [1.18-1.81]), MI (always 1.61 [1.22-2.14]) and all-cause death (always 1.54 [1.20-1.98]). The other SRBD-related questions were not consistently associated with worse outcomes. CONCLUSIONS: In patients with CCS, gradually higher levels of EDS and MT were independently associated with increased risk of MACE, including mortality.

Psychosocial stress and major cardiovascular events in patients with stable coronary heart disease.

OBJECTIVES: Assess the risk of ischaemic events associated with psychosocial stress in patients with stable coronary heart disease (CHD). METHODS: Psychosocial stress was assessed by a questionnaire in 14 577 patients (median age 65.0, IQR 59, 71; 81.6% males) with stable CHD on optimal secondary preventive therapy in the prospective randomized STABILITY clinical trial. Adjusted Cox regression models were used to assess associations between individual stressors, baseline cardiovascular risk factors and outcomes. RESULTS: After 3.7 years of follow-up, depressive symptoms, loss of interest and financial stress were associated with increased risk (hazard ratio, 95% confidence interval) of CV death (1.21, 1.09-1.34; 1.15, 1.05-1.27; and 1.19, 1.08-1.30, respectively) and the primary composite end-point of CV death, nonfatal MI or nonfatal stroke (1.21, 1.13-1.30; 1.19, 1.11-1.27; and 1.17, 1.10-1.24, respectively). Living alone was related to higher risk of CV death (1.68, 1.38-2.05) and the primary composite end-point (1.28, 1.11-1.48), whereas being married as compared with being widowed, was associated with lower risk of CV death (0.64, 0.49-0.82) and the primary composite end-point (0.81, 0.67-0.97). CONCLUSIONS: Psychosocial stress, such as depressive symptoms, loss of interest, living alone and financial stress, were associated with increased CV mortality in patients with stable CHD despite optimal medical secondary prevention treatment. Secondary prevention of CHD should therefore focus also on psychosocial issues both in clinical management and in future clinical trials.

Studying the peripheral sympathetic nervous system and neuroblastoma in zebrafish.

The zebrafish serves as an excellent model to study vertebrate development and disease. Optically clear embryos, combined with tissue-specific fluorescent reporters, permit direct visualization and measurement of peripheral nervous system formation in real time. Additionally, the model is amenable to rapid cellular, molecular, and genetic approaches to determine how developmental mechanisms contribute to disease states, such as cancer. In this chapter, we describe the development of the peripheral sympathetic nervous system (PSNS) in general, and our current understanding of genetic pathways important in zebrafish PSNS development specifically. We also illustrate how zebrafish genetics is used to identify new mechanisms controlling PSNS development and methods for interrogating the potential role of PSNS developmental pathways in neuroblastoma pathogenesis in vivo using the zebrafish MYCN-driven neuroblastoma model.

Maternal contact differentially modulates central and peripheral oxytocin in rat pups during a brief regime of mother-pup interaction that induces a filial huddling preference.

Central oxytocin mediates the acquisition of a filial preference for maternal odour in rat pups, manifested by their huddling preferences. The present study was designed to examine whether maternal care modulates oxytocin concentrations in rat pups and, if so, how different types of maternal contact are associated with the pups' oxytocin concentrations. Pairs of 14-day-old littermates were removed from their home cage for 1 h and then placed with a lactating foster mother for 2 h, or they remained isolated at room temperature. Enzyme immunoassays revealed that maternal care and maternal separation can differentially modulate pups' oxytocin concentrations. Both hypothalamic and serum oxytocin increased during the 1-h separation. Pups placed with a foster mother after the separation maintained the same concentrations in the hypothalamus and serum through the fostering period. By contrast, pups placed with no mother showed a further increase in hypothalamic oxytocin but serum oxytocin decreased. Behavioural analyses revealed that skin-to-skin contact with the mother, but not simple physical contact or maternal licking/grooming, was positively correlated with the pups' hypothalamic oxytocin concentrations. These neuroendocrine data match previous findings showing that skin-to-skin contact with mother facilitates the acquisition of the pups' huddling preference for a maternally-associated odour. Taken together, the present study suggests that maternal skin-to-skin contact stimulates pups' central oxytocin, at the same time as creating the conditions for inducing a preference for maternal odour and establishing a social affiliation in rat pups; the natural schedule of maternal separation and reunion may modulate pups' oxytocin concentrations, providing scaffolding for the acquisition of their filial huddling preference.

Extended periods of neural induction and propagation of embryonic stem cell-derived neural progenitors with EGF and FGF2 enhances Lmx1a expression and neurogenic potential.

Neural stem (NS) cells are multipotent cells defined by their capacity to proliferate and differentiate into all neuronal and glial phenotypes. NS cells can be obtained from specific regions of the adult brain, or generated from embryonic stem cells (ESCs). NS cells differentiate into neural progenitor (NP) cells and subsequently neural precursors, as transient steps towards terminal differentiation into specific mature neuronal or glial phenotypes. When cultured in EGF and FGF2, ESC-derived NS cells have been reported to be stable and multipotent. Conditions that enable differentiation of NS cells through the committed progenitor and precursor stages to specific neuronal subtypes have not been fully established. In this study we investigated, using Lmx1a reporter ESCs, whether the length of neural induction (NI) dictated the phenotypic potential of cultures of ESC-derived NS cells or NP cells. Following 4, 7 or 10 day periods of NI, ESCs in monolayer culture were harvested and cultured as neurospheres, prior to replating as monolayer cultures for several passages in EGF and FGF2. The NS/NP cultures were then directed towards mature neuronal fates over 16-17 days. 4 and 7-day NS cell cultures could not be differentiated towards dopaminergic, serotonergic or cholinergic fates as determined by the absence of tyrosine hydroxylase, 5-HT or choline acetyltransferase (ChAT) immunolabelling. In contrast NS/NP cultures derived after 10 days of NI were able to generate tyrosine hydroxylase and 5-HT positive neurons (24±6 and 13±1% of the ßIII-tubulin positive population, respectively, n=3). Our data suggest that extended periods of neural induction enhanced the potential of mouse ESC-derived NS/NP cells to generate specific subtypes of neurons. NS/NP cells derived after shorter periods of NI appeared to be lineage-restricted in relation to the neuronal subtypes observed after removal of EGF.

Oral progestin induces rapid, reversible suppression of ovarian activity in the cat.

The influence of oral progestin (altrenogest; ALT) on cat ovarian activity was studied using non-invasive fecal steroid monitoring. Queens were assigned to various ALT dosages: (1) 0mg/kg (control; n=5 cats); (2) 0.044 mg/kg (LOW; n=5); (3) 0.088 mg/kg (MID; n=6); or (4) 0.352 mg/kg (HIGH; n=6). Fecal estrogen and progestagen concentrations were quantified using enzyme immunoassays for 60 days before, 38 days during and 60 days after ALT treatment. Initiation of follicular activity was suppressed in all cats during progestin treatment, whereas controls continued to cycle normally. Females (n=6) with elevated fecal estrogens at treatment onset completed a normal follicular phase before returning to baseline and remained suppressed until treatment withdrawal. All cats receiving oral progestin re-initiated follicular activity after treatment, although MID cats experienced the most synchronized return (within 10-16 days). Mean baseline fecal estrogens and progestagens were higher (P<0.05) after treatment in HIGH, but not in LOW or MID cats compared to pre-treatment values. The results demonstrate that: (1) oral progestin rapidly suppresses initiation of follicular activity in the cat, but does not influence a follicular phase that exists before treatment initiation; and (2) queens return to normal follicular activity after progestin withdrawal. This study provides foundational information for research aimed at using progestin priming to improve ovarian response in felids scheduled for ovulation induction and assisted breeding.

Relationship of QRS duration at baseline and changes over 60 min after fibrinolysis to 30-day mortality with different locations of ST elevation myocardial infarction: results from the Hirulog and Early Reperfusion or Occlusion-2 trial.

OBJECTIVE: To discern if the prognostic meaning of QRS prolongation differs according to the location of ST elevation acute myocardial infarction DESIGN: Measuring QRS duration in patients with normal conduction or right bundle branch block SETTING: HERO-2 trial with prospective collection of electrocardiograms at randomisation and at 60 min after fibrinolytic therapy PATIENTS: 12 456 patients with normal conduction at both randomisation and 60-min time points and 510 with right bundle branch block (RBBB) at both time points MAIN OUTCOME MEASURE: 30-day mortality. RESULTS: On the baseline ECG, there was a positive association between QRS duration and 30-day mortality with anterior acute myocardial infarction (AMI) (p<0.0001 for those with normal conduction and = 0.007 for those with RBBB) but not with inferior AMI (p = 0.29 and p = 0.32, respectively). For anterior AMI, with or without RBBB, an increment of 20 ms increase in QRS duration predicted a significant 30-40% relative increase in 30-day mortality both before and after adjusting for clinical and ECG variables including baseline ST elevation and presence of Q waves. The association was not present for inferior AMI. Changes in QRS duration over 60 min after fibrinolytic therapy were uncommon and unrelated to mortality. CONCLUSION: Baseline QRS duration independently stratifies 30-day mortality in patients with anterior AMI, even when unaccompanied by RBBB, but does not stratify mortality risk in patients with inferior AMI.

BIM and other BCL-2 family proteins exhibit cross-species conservation of function between zebrafish and mammals.

Here we investigate the function of zebrafish Bcl-2 family proteins and demonstrate important conservation of function across zebrafish and mammalian systems. We have isolated a zebrafish ortholog of mammalian BIM and show that it is the most toxic of the zebrafish BH3-only genes examined, sharing this characteristic with the mammalian BIM gene. The zebrafish bad gene shows a complete lack of embryonic lethality, but like mammalian BAD, its pro-apoptotic activity is regulated through phosphorylation of critical serines. We also found that the pattern of mitochondrial dysfunction observed by zebrafish BH3 domain peptides in a mammalian cytochrome c release assay recapitulates the pattern of embryonic lethality induced by the respective mRNA injections in vivo. In contrast to zebrafish Bim, Bid exhibited only weak binding to zebrafish Bcl-2 and moderate-to-weak overall lethality in zebrafish embryos and isolated mitochondria. Given that zebrafish Bcl-2 binds strongly to mammalian BID and BIM peptides and proteins, the protein identified as the zebrafish Bid ortholog has different properties than mammalian BID. Overall, our results demonstrate the high degree of functional conservation between zebrafish and mammalian Bcl-2 family proteins, thus validating the zebrafish as a model system to further dissect the molecular mechanisms that regulate apoptosis in future forward genetic and chemical modifier screens.

B-type natriuretic peptide and left ventricular dysfunction on exercise echocardiography in patients with chronic aortic regurgitation.

OBJECTIVE: To determine whether plasma levels of B-type natriuretic peptide (BNP) predict left ventricular (LV) dysfunction on exercise echocardiography in patients with moderate to severe aortic regurgitation (AR). DESIGN: Case-control study. SETTING: Outpatient cardiology departments. PATIENTS: 39 asymptomatic or mildly symptomatic patients with chronic moderate to severe AR and a normal LV ejection fraction (>50%), and 10 normal controls. MAIN OUTCOME MEASURES: Plasma level of BNP and echocardiographic measures of LV function at rest and immediately after treadmill exercise. RESULTS: LV end systolic volume index (LVESVI) was significantly increased in AR patients with normal BNP (0.05 for all). However, there were modest but statistically significant associations between the plasma level of BNP and severity of AR indicated by a greater AR:LV outflow tract width ratio (r = 0.37, p = 0.02) and lower diastolic blood pressure (r = -0.44, p = 0.004). Increased BNP was also associated with a greater LVESVI (r = 0.33, p = 0.04) and lower LV longitudinal strain rate (r = -0.037, 0.02) on echocardiography after exercise. CONCLUSIONS: In moderate to severe AR compensatory LV remodelling can occur with no increase in plasma BNP. Increased BNP is associated with more severe regurgitation and changes consistent with early LV dysfunction on exercise echocardiography.

Variations in the use of emergency PCI for the treatment of re-infarction following intravenous fibrinolytic therapy: impact on outcomes in HERO-2.

BACKGROUND: Patients who suffer re-infarction during initial hospitalization for ST-elevation myocardial infarction (STEMI) have decreased survival compared to patients without re-infarction, so treatment of re-infarction may influence survival. METHODS AND RESULTS: To determine whether the utilization of reperfusion therapies varied within 12 h of re-infarction and was associated with 30-day mortality, we studied 552 patients with re-infarction of 17,073 patients with STEMI enrolled in HERO-2 in five regions (Russia, Eastern Europe, Western Countries, Asia, and Latin America). Patients presenting within 6 h of symptom-onset were randomized to receive either bivalirudin or unfractionated heparin intravenously just prior to streptokinase. Re-infarction occurred in 2.8 and 3.6% of bivalirudin and heparin treated patients, respectively (P = 0.004), but treatment assignment did not influence mortality after re-infarction. Patients with re-infarction had a higher 30-day mortality than those without re-infarction (24 vs. 10%; P < 0.001 by Cox model). Within 12 h of re-infarction, fibrinolytic therapy was administered to 12.0 and 8.2% underwent percutaneous coronary intervention (PCI); these two treatments were more frequently utilized in patients from Western countries (n = 112), compared to patients from other countries (n = 440) (34.8 and 16.1% compared to 6.1 and 6.1%, respectively, P < 0.001). Mortality was 15% in patients receiving reperfusion therapy for re-infarction and 27% for those with conservative management, hazard ratio (HR) 0.53 (95% CI 0.32-0.88), P = 0.01. In multiple Cox regression analysis which included adjustment for clinical variables and randomized treatment assignment, 30-day mortality after re-infarction varied by region (highest Latin America 29%, lowest Western countries 15%; P = 0.01). Other independent prognostic factors included age, time from randomization to re-infarction, and Killip class at randomization. The HR for PCI treatment of re-infarction was 0.18 [(95% CI 0.04-0.76), P = 0.02] in analyses which excluded deaths within 12 h. CONCLUSION: Treatment of re-infarction with reperfusion therapies was markedly under-utilized, especially in non-western countries. PCI for re-infarction, in particular, was associated with a lower 30-day mortality, which may reflect both patient selection and effects of treatment.

Detection of Coccidioides species in clinical specimens by real-time PCR.

Coccidioides spp. are dimorphic fungal pathogens endemic to the semiarid regions of North, Central, and South America. Currently, direct smear and culture are the most common means of identifying Coccidioides spp. While these methods offer relatively sensitive and specific means of detecting Coccidioides spp., growth in culture may take up to 3 weeks, potentially delaying the diagnosis and initiation of appropriate antifungal therapy. In addition, growth of the organism represents a significant safety risk to laboratory personnel. The need for a rapid and safe means of diagnosing coccidioidomycosis prompted us to develop a real-time PCR assay to detect Coccidioides spp. directly from clinical specimens. Primers and fluorescent resonance energy transfer (FRET) probes were designed to target the internal transcribed spacer 2 region of Coccidioides. The assay's limit of detection is below 50 targets per reaction. An analysis of 40 Coccidioides sp. clinical isolates grown in culture demonstrated 100% sensitivity of the assay. A cross-reactivity panel containing fungi, bacteria, mycobacteria, and viruses was tested and demonstrated 100% specificity for Coccidioides spp. An analysis of 266 respiratory specimens by LightCycler PCR demonstrated 100% sensitivity and 98.4% specificity for Coccidioides spp. compared with culture. Analysis of 66 fresh tissue specimens yielded 92.9% sensitivity and 98.1% specificity versus those of the culture method. The sensitivity of the assay testing 148 paraffin-embedded tissue samples is 73.4%. A rapid method for the detection of Coccidioides spp. directly from clinical material will greatly assist in the timely diagnosis and treatment of patients, while at the same time decreasing the risk of accidental exposure to laboratory personnel.

Lack of association between baseline plasma homocysteine concentrations and restenosis rates after a first elective percutaneous coronary intervention without stenting.

OBJECTIVE: To evaluate the association between baseline homocysteine concentrations and restenosis rates in patients electively undergoing their first percutaneous coronary intervention (PCI) without stenting. DESIGN: Prospective, single centre, observational study. SETTING AND PATIENTS: Patients electively undergoing their first PCI without stenting at a tertiary referral centre between 1990 and 1998. METHODS: Blood samples were collected from all patients at baseline and assayed to determine the patients' homocysteine concentrations. Patients whose PCI was successful underwent repeat angiography at a median of 6.4 (interquartile range 6-6.8) months. Their baseline and follow up angiograms were compared by quantitative coronary angiography to assess the incidence of restenosis. For the analysis, the patients were divided into two groups based on whether their baseline homocysteine concentrations were above or below the median value. These two groups were compared to determine whether there was any association between their baseline homocysteine concentrations and the incidence of restenosis at six months. RESULTS: 134 patients had a successful first PCI without stenting (involving 200 lesions). At six month angiography, restenosis was observed in 33 patients (49.3%) with baseline homocysteine concentrations above the median value and in 31 patients (46.3%) with concentrations below the median value (p = 0.74). There was no difference in the percentage of lesions developing restenosis (38 (39.6%) v 40 (38.5%), respectively, p = 0.87) or late lumen loss (0.40 mm v 0.31 mm, respectively, p = 0.24). On multivariable analysis, there was no association between homocysteine concentrations and late lumen loss (r = -0.11, p = 0.11) or the percentage diameter stenosis at follow up (r = -0.07, p = 0.32). CONCLUSION: Baseline homocysteine concentrations were not associated with six month restenosis rates in patients electively undergoing their first PCI without stenting.

Importance of amino-acid and electrolyte balance in experimental diets used to determine the apparent metabolisable energy (AME) value of wheat.

1. An experiment was done with male, Ross broiler chicks to study the effect of diet composition and electrolyte balance on the measurement of diet AME and performance parameters in diets containing high levels of wheat inclusion. 2. The control diet (G) was based on wheat (667 g/kg) with full-fat soya, soyabean meal, Extrupro and herring meal providing the protein supplements. The experimental treatments were based on 2 diets, one based on wheat (790 g/kg) with casein as the protein supplement and the other containing 667 g/kg wheat plus casein, cellulose and starch. Each of these was formulated to contain one of three concentrations of sodium and potassium bicarbonate giving final values for dietary electrolyte balance of approximately 90, 180 and 280 meq/kg diet. 3. DM intake was numerically lower with the lower level of wheat inclusion and LWG (P < 0.05) and gain:food (P < 0.001) were reduced. ME:GE was similar for the two levels of wheat/casein but higher (P < 0.001) than for the control diet. 4. The two higher electrolyte balances improved DM intake (P < 0.01), LWG and gain:food (P < 0.01) compared with the diets containing no added bicarbonate. ME:GE was unaffected by electrolyte inclusion. 5. Viscosity of ileal digesta supernatant fell (P < 0.01) with increasing bicarbonate inclusion but the value for the highest electrolyte level was still higher than for the control diet. 6. It is concluded that addition of both arginine and electrolyte is needed with a wheat/casein diet to improve performance to levels seen with a more commercial diet but that the determination of diet AME, with the type of fat addition used in this study, is unaffected by electrolyte balance. The interaction between electrolyte balance and in vivo viscosity requires further study.

Effects of variety, the 1B/1R translocation and xylanase supplementation on nutritive value of wheat for broilers.

1. Three consecutive studies were done with 12 wheat samples (4 per study), each of different variety (6 containing the 1B/1R rye translocation) to examine the effects of wheat variety, presence of 1B/1R and interactions with xylanase addition (Avizyme 1310). The wheat varieties covered a wide range of in vitro viscosity (6.3 to 19.8 cps). In each study 64 male, Ross broilers were individually caged and given the diets ad libitum from d 7 to 28. Bird performance, viscosity of ileal contents and diet metabolisability (AME) were measured. 2. The diets contained (g/kg): wheat 790, casein 134, dicalcium phosphate 21.4, potassium bicarbonate 10.8, sodium bicarbonate 7.5, soya oil 10, arginine 5, minerals etc. 21.3. 3. Within each study there were large differences in dry matter (DM) intake between varieties but the variety effect was significant (P<0.01) only in study 2. Liveweight gain (LWG) differences mirrored DM intake, being significant (P<0.01) in study 2. Mean gain:food was unaffected by variety in any study. 4. Calculated wheat AME (MJ/kg DM) ranged from 13.4 to 14.4 in study 2 (P<0.05), the values for studies 1 and 3 lying within this range. 5. Across all 3 studies, in vivo viscosity (proximal ileum) ranged from 5.0 to 37.6 in the absence of enzyme and from 3.9 to 12.1 with enzyme addition; in studies 1 and 2 variety differences were significant (P<0.05). 6. Enzyme addition had no effect on DM intake or LWG but gain:food tended to be improved (NS), metabolisability of energy (ME:GE) was increased (P<0.01) by 2.2% and calculated wheat AME by 4% while in vivo viscosity was reduced (P<0.001). 7. There were no significant differences in DM intake, LWG, gain:food, ME:GE or calculated wheat AME concentration associated with the presence of the 1B/1R translocation and no interactions between enzyme and 1B/1R. 8. There were poor relationships between either gain:food or wheat AME concentration and in vitro or in vivo viscosity. There was no significant relationship between AME concentration and either specific weight or thousand grain weight. 9. It was concluded that (a) variety differences tended to be small (b) there was no negative impact of the 1B/1R rye translocation with the diet formulation used (c) in vitro viscosity failed to predict satisfactorily any aspect of performance with the high wheat/low fat diet formulation used.

Long-term assessment of psychological well-being in a randomized placebo-controlled trial of cholesterol reduction with pravastatin. The LIPID Study Investigators.

BACKGROUND: There is controversial evidence that a low serum cholesterol level is associated with an increased risk of depression, suicide, and violence. The aim of this study was to identify or exclude any small or infrequent adverse effect of long-term reduction of serum cholesterol with pravastatin sodium on psychological well-being. METHODS: The study population consisted of 1130 respondents from a representative sample of 1222 patients with stable coronary artery disease participating in the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study. Subjects were randomized in a double-blind manner to treatment with pravastatin sodium, 40 mg/d (n = 559), or placebo (n = 571) for at least 4 years. Psychological well-being was assessed with a standard self-administered questionnaire at baseline and after 6 months, 1 year, 2 years, and 4 years. The questionnaire assessed anxiety and depression, anger, impulsiveness, alcohol consumption, and adverse life events. RESULTS: Serum cholesterol levels decreased by an average of 1.3 mmol/L (50 mg/dL) with pravastatin therapy and did not change with placebo. During follow-up there was no significant difference by treatment group in measures of anxiety and depression, anger expression, or impulsiveness (95% confidence interval excluded differences of >0.2 SD) and no difference in the proportion of subjects with excessive alcohol consumption or adverse life events (odds ratio, 1.0; 95% confidence interval, 0.8-1.2). There was no evidence of a treatment effect for persons whose baseline serum cholesterol level was in the lowest 10% (<4.6 mmol/L [178 mg/dL]) or whose scores for anxiety and depression, anger, or impulsiveness were in the highest 10% at baseline. There was no association between change in the serum cholesterol level and measures of anxiety and depression, anger, or impulsiveness during follow-up. CONCLUSION: Long-term reduction of serum cholesterol with pravastatin has no adverse effect on psychological well-being.

Statistical methods to improve the precision of the treadmill exercise test.

OBJECTIVES: The study systematically compared different measures of ST segment depression from the treadmill exercise test. BACKGROUND: The value of the treadmill exercise test for objectively measuring treatment effects is limited by random error in the measurement of ST depression and may be biased by regression to the mean or by the decision to terminate the test. METHODS: Treadmill exercise was performed in 21 subjects with ischemic heart disease 1 h after isosorbide dinitrate 10 mg or placebo in a double-blind randomized crossover study. A 12-lead electrocardiogram (ECG) was recorded every 30 s during and at peak exercise. The relative sample size needed to detect the nitrate effect was compared for different summary measures of ST depression. RESULTS: The ST depression measured from a single unmatched lead at longest equivalent sub-maximal exercise needed the lowest sample size to detect the nitrate effect in paired comparisons (p = 0.000006). Averaging over multiple leads or times did not improve detection of the nitrate effect. The rate of increase in ST depression (in mm/min) calculated by linear regression needed a similar sample size (x1.32, 95% CI 0.62 to 2.58). A larger sample size was needed for ST depression at peak exercise (x2.9, CI 1.3, 11.1) and exercise duration (x4.5, CI 1.5, 38). Time to 1-mm ST depression was the least efficient measurement (relative sample size x15.5, CI 1.6, >1,000). Comparison of matched leads resulted in >2-fold differences in estimates of the nitrate effect because of bias from regression to the mean. CONCLUSIONS: Maximal ST depression at longest equivalent sub-maximal exercise and the maximal rate of increase in ST depression had less bias and random variation than did other commonly used measures. The rate of increase in ST depression is preferred because it can be calculated in either paired or unpaired studies.

Randomised comparison of the effects of nicardipine and esmolol on coronary artery wall stress: implications for the risk of plaque rupture.

OBJECTIVE: To determine whether the beta blocker esmolol reduces coronary artery wall stress more than the short acting dihydropyridine calcium antagonist nicardipine. DESIGN: Randomised double blind placebo controlled trial. SETTING: Tertiary cardiology centre. PATIENTS: Patients with coronary artery disease. INTERVENTIONS: 20 patients were randomised double blind to an infusion of nicardipine (n = 10) or esmolol (n = 10) titrated to reduce systolic blood pressure by 20 mm Hg. MAIN OUTCOME MEASURES: Peak systolic wall circumferential stress. RESULTS: Esmolol reduced peak coronary stress by a mean of 0.17 x 10(6) dyn/cm(2) (95% confidence interval (CI) 0.14 to 0.21 x 10(6) dyn/cm(2)) compared with a reduction of 0.07 x 10(6) dyn/cm(2) (95% CI 0.05 to 0.10 x 10(6) dyn/cm(2)) after nicardipine. Peak systolic radius was reduced by 0.04 mm (95% CI 0.03 to 0.06 mm) after esmolol compared with an increase of 0.08 mm (95% CI 0.05 to 0.10 mm) after nicardipine. Heart rate increased by 11.5 beats/min (95% CI 6.9 to 16.2 beats/min) after nicardipine and decreased by 5.3 beats/min (95% CI 1.9 to 8.6 beats/min) after esmolol. CONCLUSIONS: Intravenous esmolol is more effective than nicardipine at reducing circumferential coronary artery wall stress.