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.

Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity.

We have previously used mosaic flies to screen for tumour suppressors or negative regulators of cell proliferation. The cellular composition of these flies resembles that of cancer patients who are chimaeric individuals carrying a small number of mutated somatic cells. One of the genes we identified is the large tumour suppressor gene, lats (also known as wts), which encodes a putative serine/threonine kinase. Somatic cells mutant for lats undergo extensive proliferation and form large tumours in many tissues in mosaic adults. Homozygous mutants for various lats alleles display a range of developmental defects including embryonic lethality. Although many tumour suppressors have been identified in Drosophila melanogaster, it is not clear whether these fly genes are directly relevant to tumorigenesis in mammals. Here, we have isolated mammalian homologues of Drosophila lats. Human LATS1 suppresses tumour growth and rescues all developmental defects, including embryonic lethality in flies. In mammalian cells, LATS1 is phosphorylated in a cell-cycle-dependent manner and complexes with CDC2 in early mitosis. LATS1-associated CDC2 has no mitotic cyclin partner and no kinase activity for histone H1. Furthermore, lats mutant cells in Drosophila abnormally accumulate cyclin A. These biochemical observations indicate that LATS is a novel negative regulator of CDC2/cyclin A, a finding supported by genetic data in Drosophila demonstrating that lats specifically interacts with cdc2 and cyclin A.

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.

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.

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.

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.

Progression of the culprit lesion in unstable coronary artery disease with warfarin and aspirin versus aspirin alone: preliminary study.

OBJECTIVES: This study assessed whether combination therapy with aspirin and warfarin for 10 weeks reduces the risk of progression or reocclusion of the unstable coronary artery lesion. BACKGROUND: Reocclusion of the culprit coronary artery occurs in up to one third of patients during the 3 months after myocardial infarction (MI) or unstable angina and is associated with increased morbidity and mortality. METHODS: Fifty-seven patients presenting with unstable angina or MI who had an identifiable culprit lesion at coronary angiography were randomized in double-blind manner to receive warfarin (target international normalized ratio [INR] 2.0 to 2.5) or placebo in addition to aspirin (150 mg daily). Changes in the culprit lesion were assessed by quantitative angiography in 50 patients after 10 weeks of therapy or after a clinical event. Progression of the culprit lesion was defined as a decrease in minimal lumen diameter > 0.4 mm or a new total occlusion. Regression was defined as an increase in minimal lumen diameter > 0.4 mm. RESULTS: In subjects randomized to receive warfarin, the culprit lesion was less likely to progress (1 [4%] vs. 8 [33%]) and more likely to regress (5[19%] vs. 2[9%]) than in subjects receiving placebo (p = 0.02). Recurrent MI or a new occlusion at angiography occurred in 2 (7%) of 29 patients receiving warfarin versus 11 (39%) of 28 patients receiving placebo (p = 0.005). CONCLUSIONS: In patients with an acute coronary syndrome, combined therapy with aspirin and warfarin with a target INR of 2.0 to 2.5 for 10 weeks reduces the risk of progression or reocclusion of the culprit coronary lesion.

Association between activity at onset of symptoms and outcome of acute myocardial infarction.

OBJECTIVES: This study sought to compare the clinical features and outcome of a first myocardial infarction with onset of symptoms during or within 30 min of exercise, at rest and in bed. BACKGROUND: It is not known whether activity at onset influences outcome of acute myocardial infarction. METHODS: Information collected using a standard questionnaire was used to relate activity at the onset of symptoms to in-hospital outcome in 2,468 consecutive patients admitted to a coronary care unit with a first myocardial infarction between 1975 and 1993. RESULTS: Patients with exercise-related onset were more likely to be younger and male. Those with onset in bed were more likely to be older and have a history of stable or unstable angina. Compared with patients whose symptoms began at rest, those with exercise-related onset had a lower in-hospital mortality rate after adjusting for age, gender and year of admission (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.40 to 0.89), and patients with onset in bed had a higher mortality rate (OR 1.38, 95% CI 1.03 to 1.85). The incidence of cardiac failure requiring diuretic therapy was also lower for exercise-related onset (OR 0.83, 95% CI 0.67 to 1.04) and higher when onset was in bed (OR 1.36, 95% CI 1.11 to 1.66). CONCLUSIONS: There is an association between activity at onset and outcome of acute myocardial infarction. Differences in pathophysiology or in the population at risk could explain this observation.

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.

Assessment of diastolic filling indexes obtained by radionuclide ventriculography.

This study assesses how differences in residual volume and heart rate influence the measurement and interpretation of commonly used indexes of left ventricular filling obtained by radionuclide ventriculography. Thirty patients with hypertrophic cardiomyopathy (HC) and 26 normal subjects were studied. The time to peak filling rate (168 +/- 42 vs 139 +/- 35 ms; p = 0.006) and time to 30% filling (154 +/- 32 vs 131 +/- 29 ms; p = 0.009 were prolonged in patients with HC compared to normal subjects, suggesting impaired early diastolic filling. However the peak filling rate, measured in end-diastolic counts/s, was greater in patients with HC (3.31 +/- 0.89 vs 3.06 +/- 0.51, p = 0.19). This measurement was influenced by the relative residual volume (HC r = 0.41, p less than 0.001; normal r = 0.29, difference not significant), which was smaller in patients with HC (22.4 +/- 8.0 vs 35.5 +/- 5.6%; p less than 0.0001). The peak filling rate measured in stroke volume counts did not vary with the relative residual volume (HC r = 0.10, difference not significant; normal r = 0.21, difference not significant) and was less than normal in patients with HC (4.27 +/- 0.69 vs 4.72 +/- 1.0; p = 0.58). There was a strong association between the first third filling fraction and the heart rate (HC r = 0.66, p less than 0.001; normal r = 0.71, p less than 0.001), reflecting its dependence on the duration of the first third of diastole.(ABSTRACT TRUNCATED AT 250 WORDS)

Time course of "warm-up" in stable angina.

Warm-up exercise can significantly reduce the severity of myocardial ischemia on exercise after a 10-minute rest, but this benefit is significantly less after a 30-minute rest. Further study is needed to clarify the mechanisms responsible for warm-up. The results of this study are consistent with a change in myocardial metabolism similar to ischemic preconditioning or a delayed increase in myocardial perfusion to the ischemic territory, which has returned toward baseline after 30 minutes.

Influence of heart rate on stroke volume variability in atrial fibrillation in patients with normal and impaired left ventricular function.

Both resting tachycardia and irregular ventricular rhythm may contribute to impaired cardiac performance in atrial fibrillation (AF). This study assesses the relation between resting heart rate and beat-to-beat changes in left ventricular (LV) ejection and filling in patients with normal and impaired LV systolic function. Beat-to-beat variation in LV outflow and inflow velocity-time integral was measured using pulsed Doppler ultrasound in 39 patients with chronic AF and normal (n=22) or impaired (n=17) LV systolic function. Aortic velocity-time integral variability increased with mean heart rate (p=0.003) even though RR interval variability decreased (p <0.001). Aortic velocity-time integral was more sensitive to the duration of both the preceding (p <0.001) and prepreceding (p <0.001) RR intervals at higher heart rates. These relations were similar for patients with normal and impaired LV systolic function. The sensitivity of the filling velocity-time integral to RR interval variability also increased with heart rate (p <0.001). However, at higher heart rates the filling velocity-time integral (p=0.009) and filling time (p=0.005) were less sensitive to change in RR intervals in patients with impaired LV function. We conclude that beat-to-beat stroke volume variability in AF increases with heart rate. Stroke volume variability was not influenced by LV systolic function.

Serial angiography in cocaine-induced myocardial infarction.

A young man suffered an acute inferior myocardial infarction following clinical use of cocaine as topical anesthesia. Coronary angiography showed occlusion of both the posterior descending and posterolateral arteries which was resistant to intracoronary administration of nitroglycerin and verapamil, a finding consistent with thrombotic occlusion. A subsequent angiogram 3 months later showed no residual lesions.

B7.1 costimulation increases T-cell proliferation and cytotoxicity via selective expansion of specific variable alpha and beta genes of the T-cell receptor.

BACKGROUND: Optimal T-cell activation requires not only ligation of the T-cell receptor (TcR) but also delivery of costimulatory signals by various accessory molecules. The interaction of the costimulatory molecule B7.1 (CD80) with its receptor CD28 provides a strong positive signal to T cells. METHODS: The B7.1 gene was transduced into cultured human ovarian, breast, and pancreatic tumor cells by using a retroviral vector. Autologous as well as allogeneic naive T-cells were stimulated with either wild-type or B7.1-transduced tumor cells in a mixed lymphocyte tumor cell culture (MLTC). In addition to cytolytic activity, T-cell proliferation, T-cell subset composition, and the frequencies of TcR variable (V) alpha and beta genes were compared in T cells from both types of MLTC. RESULTS: Introduction of the B7.1 gene into tumor cells was successful in all tumors to a varying degree. Those tumors expressing high levels of B7.1 induced significantly higher levels of T-cell proliferation than wild-type tumor cells. T-cell subset composition did not markedly differ between T cells stimulated with wild-type tumor cells or B7.1-expressing tumor cells. However, T cells stimulated with B7.1-expressing tumor cells showed a significantly increased cytolytic potential. The increased cytotoxic T lymphocyte activity was associated with a higher frequency of specific TcR V alpha and V beta genes. In addition, B7.1 costimulation promoted oligoclonality among the responding T cells. CONCLUSIONS: These data suggest that costimulation through B7.1 promotes T-cell proliferation and cytotoxic activity through clonal expansions of T cells bearing antigen-specific TcR V alpha and V beta genes and through promotion of oligoclonality. The data also suggest that promoting B7.1-mediated costimulation is an important aspect of immune therapies.

The effect of exercise on gait patterns in older women: a randomized controlled trial.

BACKGROUND: This study was undertaken to determine (a) whether a program of regular exercise can improve gait patterns in older women, and (b) whether any such improvement in gait is mediated by increased lower limb muscle strength. METHOD: A 22-week randomized controlled trial of exercise was conducted as part of the Randwick Falls and Fractures Study in Sydney, Australia. Subjects were 160 women aged 60-83 years (Mean age 71.1, SD = 5.2) who were randomly recruited from the community. Exercise and control subjects were tested prior to and at the end of the trial. At initial testing, exercisers and controls performed similarly in the strength and gait parameters. They were well matched in terms of age and a number of health and life-style characteristics. RESULTS: At the end of the trial, the exercise subjects showed improved strength in five lower limb muscle groups, increased walking speed, cadence, stride length, and shorter stride times as indicated by both reduced swing and stance duration. There were no significant improvements in any of the strength or gait parameters in the controls. Within the exercise group, increased cadence was associated with improved ankle dorsiflexion strength, and increased stride length was associated with improved hip extension strength. Exercise subjects with initial slow walking speed showed greater changes in velocity, stride length, cadence, and stance duration than those with initial fast walking speed. CONCLUSION: These findings show that exercise can increase gait velocity and related parameters in older persons, and that part of this increase may be mediated by improved lower limb muscle strength.

Coronary artery flow ten weeks after myocardial infarction or unstable angina: effects of combined warfarin and aspirin therapy.

Forty-three patients presenting with unstable angina or myocardial infarction were randomised double blind to warfarin [target international normalised ratio (INR), 2.0 to 2.5] and aspirin (150 mg) daily or placebo plus aspirin (150 mg) daily. Coronary flow was assessed with the thrombolysis in myocardial infarction (TIMI) flow grade and corrected TIMI frame count (CTFC). Coronary artery flow was reduced (higher CTFC) at baseline in culprit arteries (mean +/-SD, 37.1+/-15.4 frames) compared to nonculprit arteries (22.5+/-6.7 frames, P<0.0001). In patients with a patent artery at follow-up, coronary flow was unchanged after ten weeks of warfarin and aspirin (-2.0+/-19.9 frames) or aspirin alone (3.8+/-10.4 frames, P = 0.20). Patients randomised to aspirin alone were more likely to progress to total occlusion [aspirin, 7 of 19 (37%) vs. warfarin and aspirin, 1 of 24 (4%); P = 0.01). Higher baseline culprit artery CTFC was also associated with an increased risk of late occlusion [+10 frames; odds ratio (OR), 1.65; 95% CI, 1.01 to 2.33]. Coronary flow remained impaired ten weeks after presentation with myocardial infarction or unstable angina. Combination warfarin and aspirin therapy did not improve flow in vessels that remained patent but did reduce the risk of progression to occlusion.

Effects of self-esteem and status on size of signature.

142 second year university students from both Memorial University of Newfoundland (n = 81) and Laurentian University (n = 61) wrote their own signatures as they imagined the following people would do: (a) faculty member (high status) with high self-esteem, (b) faculty member (high status) with low self-esteem, (c) student (low status) with high self-esteem, and (d) student (low status) with low self-esteem. The areas of the signatures were calculated in square centimeters, and there was a significant positive relationship between size of signature and the conditions of high and low self-esteem for both "faculty" and "student" role-playing conditions. There was however no significant relationship between size of signature and status. The results held for both groups of subjects.