Managing cardiovascular risk factors: trial evidence in women.

Cardiovascular disease remains by far the leading cause of death for women worldwide. Despite a large body of research identifying effective interventions to reduce cardiovascular risk, translation into practice has been slow. This review pinpoints areas in particular need of improvement and summarizes gender-specific analyses in recent randomized trials assessing the impact of risk factor modulation on cardiovascular events.

Markers for detection of supplementation in narcotic programs--deuterium-labeled methadone.

Specific deuterium labeling of methadone and use of gas chromatography-mass spectroscopy technique permits rapid and quanitative determination of the ratio of the labeled to unlabeled drug in body fluids. A trideuertiomethadone (methadone-d3) was shown to have exactly the same analgesic activity and toxicity in mice as methadone. The rates of absorption, distribution, and excretion of methadone-d3 and methadone were identical in rats. These observations suggest that methadone-d3 may be used as an in vivo marker for monitoring methadone intake of patients, and thus may improve the effectiveness of methadone treatment programs.

Determination of the distribution of fatty acids and diethylstilbestrol between serum albumin and alpha-fetoprotein by concanavalin A affinity chromatography.

The distribution of fatty acids and diethylstilbestrol between serum albumin and alpha-fetoprotein was measured in vitro by a new method based on the separation of the two proteins by virtue of the binding specificity of concanavalin A for the carbohydrate moiety of alpha-fetoprotein. Human and bovine proteins were investigated. It was found that palmitate and oleate were distributed almost equally between albumin and alpha-fetoprotein, while docosahexaenoate and diethylstilbestrol bound preferentially to alpha-fetoprotein even at an albumin: alpha-fetoprotein ratio of 10:1. The results confirm the binding specificity of alpha-fetoprotein for polyunsaturated fatty acids and also show that alpha-fetoprotein binds diethylstilbestrol much more strongly than albumin does. This suggests that alpha-fetoprotein may play a role in the fetal uptake of diethylstilbestrol.

Peripheral arterial disease in randomized trial of estrogen with progestin in women with coronary heart disease: the Heart and Estrogen/Progestin Replacement Study.

BACKGROUND: Postmenopausal estrogen use has been associated with reduced carotid atherosclerosis in observational studies, but this relationship has not been confirmed in a clinical trial. The impact of estrogen on atherosclerotic disease in other peripheral arteries is unknown. METHODS AND RESULTS: Postmenopausal women with coronary heart disease (CHD) and an intact uterus (n=2763) were randomly assigned to conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) daily or to placebo in a secondary CHD prevention trial. This analysis focuses on incident peripheral arterial procedures and deaths in the 2 treatment groups; peripheral vascular disease was a predefined secondary outcome. During a mean of 4.1 years of follow-up, 311 peripheral arterial events were reported in 213 women, an annual incidence of 2.9%. The number of women who had peripheral arterial events was 99 among those assigned to active estrogen/progestin and 114 among those assigned to placebo, a nonsignificant difference (relative hazard 0. 87, 95% CI 0.66 to 1.14). In the placebo group, hypertension and diabetes mellitus were independently associated with higher rates of peripheral arterial events, and plasma HDL cholesterol and body mass index were associated with lower rates of peripheral arterial events. In the estrogen/progestin group, current smoking and diabetes were independent predictors of peripheral arterial events. Incident peripheral arterial disease was not a significant predictor of coronary, cardiovascular, or total mortality. CONCLUSIONS: Treatment with oral conjugated estrogen plus medroxyprogesterone acetate was not associated with a significant reduction in incident peripheral arterial events in postmenopausal women with preexisting CHD.

Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-progestin Replacement Study (HERS).

BACKGROUND: Observational studies have shown that postmenopausal hormone therapy may increase, decrease, or have no effect on the risk of stroke. To date, no clinical trial has examined this question. To investigate the relation between estrogen plus progestin therapy and risk of stroke among postmenopausal women, we analyzed data collected from the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease prevention trial. METHODS AND RESULTS: Postmenopausal women (n=2763) were randomly assigned to take conjugated estrogen plus progestin or placebo. Primary outcomes for these analyses were stroke incidence and stroke death during a mean follow-up of 4.1 years. The number of women with strokes was compared with the number of women without strokes. A total of 149 women (5%) had 1 or more strokes, 85% of which were ischemic, resulting in 26 deaths. Hormone therapy was not significantly associated with risk of nonfatal stroke (relative hazard [RH] 1.18; 95% CI 0.83 to 1.66), fatal stroke (RH 1.61; 95% CI 0.73 to 3.55), or transient ischemic attack (RH 0.90; 95% CI 0.57 to 1.42). Independent predictors of stroke events included increasing age, hypertension, diabetes, current cigarette smoking, and atrial fibrillation. Black women were at increased risk compared with white women, and unexpectedly, body mass index was inversely associated with stroke risk. CONCLUSIONS: Hormone therapy with conjugated equine estrogen and progestin had no significant effect on the risk for stroke among postmenopausal women with coronary disease.

Heparin-induced prolongation of partial thromboplastin time after thrombolysis: relation to coronary artery patency. HART Investigators.

Having previously shown in the Heparin Aspirin Reperfusion Trial that the empiric use of early intravenous heparin after recombinant tissue-type plasminogen activator (rt-PA) is an important component in the overall treatment strategy, we examine in this report the specific relation between the degree of prolongation of activated partial thromboplastin time and coronary artery patency. To evaluate the hypothesis that arterial patency after administration of rt-PA for acute myocardial infarction is sustained by effective anticoagulation, activated partial thromboplastin time of heparin recipients was determined 8 and 12 h after the start of thrombolysis. Mean activated partial thromboplastin time was higher among patients with an open infarct-related artery than in those with a closed artery (81 +/- 4 vs. 54 +/- 9 s, p less than 0.02). Only 45% of patients with values less than 45 s at both 8 and 12 h had Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 in the infarct-related artery at 18 h. In contrast, 88% of patients with activated partial thromboplastin time greater than 45 s and 95% of those with values greater than 60 s had an open infarct-related artery at 18 h (p = 0.003 and 0.0006, respectively). Among patients with an initially patent infarct-related artery who underwent repeat angiography at 7 days, activated partial thromboplastin time was similar in those with a persistently patent artery and those with late reocclusion. Excessive anticoagulation did not appear to increase hemorrhagic risk except that access site-related hemorrhage was more common in patients with activated partial thromboplastin time greater than 100 s at 8 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Pre-tracheal lymph node metastasis in squamous cell carcinoma of the thoracic esophagus.

AIMS: To clarify the incidence of pre-tracheal lymph node metastasis in squamous cell carcinoma of the esophagus, and their impact on survival. METHODS: A cohort of 101 patients with squamous cell carcinoma of the thoracic esophagus who underwent esophagectomy together with 2-field lymphadenectomy including the pre-tracheal region was analysed, retrospectively. The p-TNM staging included stage I in 9, stage IIa in 33, stage IIb in 4, stage III in 43, and stage IV in 12 cases. RESULTS: Nodal metastases were identified in 56 patients (55.4%). Subcarinal lymph node and pre-tracheal lymph-node metastases were found in 24 patients (23.8%) and 15 patients (14.9%), respectively. The 5-year cumulative survival rates were 26.5 and 2.5% in nodal negative and nodal positive patients, respectively. Patients with pre-tracheal nodal metastasis all died within 2 years. Cox proportional hazards model in patients with nodal involvement revealed T-factor (p=0.0017), pre-tracheal nodal involvement (p=0.0055) and distant metastasis (p=0.0024) as independent prognostic factors. CONCLUSIONS: Our findings suggest that pre-tracheal lymph node metastasis indicates a dismal prognosis. Its occurrence is not unusual, especially in tumour of upper or middle thoracic esophagus. The subcarinal node cannot be regarded as a sentinel node of the pre-tracheal nodal station. Complete lymphadenectomy excluding the pre-tracheal lymph nodes in treating esophageal cancers is only a myth.

Spin membrane immunoassay: simplicity and specificity.

The many disadvantages of radioimmunoassay (RIA) have stimulated attempts to develop non-radioactive assays. These include spin immunoassay (SIA), which is simple, specific, and requires no separation procedures but is much less sensitive than RIA. The membrane immunoassay (MIA) described here is more sensitive than the SIA. Serum is prepared as for RIA. The MIA employs liposomes sensitized with epsilon-dinitrophenylated aminocaproyl phosphatidylethanolamine. It records liposome lysis induced by specific anti-Dnp antibodies, and complement which is monitored by the release of trapped spin labels (N-(2,2,6,6-tetramethylpiperidinyl-1-oxyl)-choline chloride). The sensitized liposomes are stable and give reproducible results for up to 4 weeks. The system's sensitivity is limited by the antibody's affinity (Ka approximately 10(8) M-1) rather than the sensitivity of the electron spin resonance spectrometer (approximately 1 X 10(-7) M). The inhibition of liposome lysis is hapten specific: (epsilon-Dnp-aminocaproic acid,epsilon-Dnp-lysine) greater than alpha-Dnp-glycine; o-nitroaniline and epsilon-dansyl-lysine are ineffective. Inhibition is quantitative without augmentation.

Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins.

PURPOSE: Most patients fail to achieve and maintain low-density lipoprotein (LDL) cholesterol goals established by the National Cholesterol Education Program (NCEP). The Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS) was a randomized study comparing the efficacy and safety of five statins and their ability reduce LDL cholesterol to the NCEP target level. SUBJECTS AND METHODS: Of 7542 patients screened, 3916 hypercholesterolemic patients were randomly assigned to treatment with a statin, beginning with the lowest recommended dose (atorvastatin, pravastatin, and simvastatin, 10 mg; fluvastatin and lovastatin, 20 mg). If the NCEP target was not achieved, the dose was titrated up to the recommended maximum (atorvastatin, fluvastatin, and lovastatin, 80 mg; pravastatin and simvastatin, 40 mg). The total duration of treatment was 54 weeks. RESULTS: Atorvastatin achieved the greatest mean reduction in LDL cholesterol: 36% +/- 11% at 6 weeks (initial dose) and 42% +/- 13% at 54 weeks. More patients receiving atorvastatin at its initial dose (53%, 997 of 1888) achieved their NCEP target levels than patients receiving simvastatin (38%, 174 of 462), lovastatin (28%, 134 of 472), pravastatin (15%, 71 of 461), or fluvastatin (15%, 69 of 474) at the initial dose. Atorvastatin-treated patients were more likely to maintain their target levels from week 6 to week 54. The percent reduction in LDL cholesterol achieved at the initial dose correlated strongly with the proportion of patients who maintained their goals at 54 weeks (r = -0.84). CONCLUSION: For patients treated with statins, providing a greater margin between the NCEP target level and the achieved LDL cholesterol level enhances the likelihood of maintaining NCEP goal levels.

Late potentials and their relation to ventricular function in human immunodeficiency virus infection.

Signal-averaged electrocardiograms were performed in 225 patients with serologic evidence of human immunodeficiency virus infection as part of a prospective longitudinal study of patients with HIV-associated heart disease and 12 seronegative control subjects. The duration of signal-averaged QRS vector, root-mean-square voltage of the terminal 40 ms of the vector magnitude and the duration of the low-amplitude (less than 40 microV) signal were determined during serial visits at 4-month intervals. One or more of these variables was abnormal on initial visit in 59 of patients (26%); QRS duration was greater than 114 ms in 9 patients (4%), root-mean-square voltage less than 20 microV in 55 patients (24%) and low-amplitude signal duration greater than 39 ms in 43 (19%). In contrast, none of the seronegative control subjects had any abnormal variables (p less than 0.03). During follow-up (mean 10 +/- 8 months), 26 patients with initially normal studies developed abnormal variables and 24 with abnormal signal-averaged electrocardiograms reverted to normal. Left ventricular contractility was assessed by echocardiography using the rate-corrected velocity of fiber shortening-end-diastolic wall stress relation. Late potentials were not related to contractile abnormalities. Clinical arrhythmias were rare and did not appear more frequent among patients with late potentials. Thus, late potentials were both common and evanescent in patients infected with human immunodeficiency virus.

Effects of hormone replacement therapy on the circadian pattern of atherothrombotic risk factors.

Onset of acute atherothrombotic events (acute myocardial infarction, unstable angina, ischemic stroke) exhibit a circadian pattern that parallels the diurnal pattern of endogenous fibrinolytic activity. Hormone replacement therapy in postmenopausal women has been shown to enhance fibrinolytic capacity by lowering plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator inhibitor (tPA) antigen values. We evaluated the impact of 4 weeks of estrogen alone (Premarin 0.625 mg/day) and 2 weeks of estrogen plus progesterone (Provera 2.5 mg/day) on PAI-1 and tPA in 17 postmenopausal women at multiple time points to assess hormone impact on the diurnal pattern of fibrinolytic potential. At baseline, both PAI-1 and tPA exhibited circadian variability. Estrogen alone selectively lowered 8 A.M. PAI-1 (35.8 +/- 7.1 ng/ml at baseline, 19.8 +/- 3.7 ng/ml on estrogen; p = 0.0002 vs baseline). There was no significant change in the noon or 4 P.M. values, and the diurnal pattern was attenuated. The 8 A.M. PAI-1 remained low at 17.1 +/- 3.6 ng/ml (p = 0.0001 vs baseline) with total loss of the circadian rhythm. Estrogen supplementation reduced tPA antigen at all time points, and the diurnal pattern, although blunted, persisted. Addition of progesterone to estrogen did not reverse effects of the estrogen alone phase of either PAI-1 or tPA values. This hormone-associated reduction of PAI-1 was observed despite increased triglycerides, a known inducer of PAI-1 levels. These observations suggest that hormone replacement therapy may protect postmenopausal women from excess early morning acute ischemic events.

Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels.

Apolipoprotein B has been shown to be a better predictor of coronary heart disease than low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol may also be a better parameter for coronary heart disease risk assessment and as a target for therapy. Data from the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS) were used to assess the correlation between lipid and apolipoprotein B levels before and after lipid-lowering therapy and to examine the effects of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on lipids and apolipoprotein B. The 54-week study randomized 3,916 hypercholesterolemic patients to atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin, initiated at recommended starting doses with titrations as needed at weeks 6, 12, and 18 to achieve National Cholesterol Education Program LDL targets. Compared with LDL cholesterol, non-HDL cholesterol correlated better with apolipoprotein B levels at baseline (r = 0.914, p <0.0001) and at week 54 (r = 0.938, p <0.0001), and the correlation was strong across all baseline triglyceride strata. At starting doses, atorvastatin (10 mg) lowered non-HDL cholesterol by 33.3% compared with 26.6% with simvastatin (10 mg), 24.1% with lovastatin (20 mg), 17.2% with fluvastatin (20 mg), and 17.0% with pravastatin (10 mg). Atorvastatin also provided greater reductions in non-HDL cholesterol after dose titration, and a greater percentage of patients taking atorvastatin achieved non-HDL cholesterol targets. Baseline triglyceride did not affect non-HDL cholesterol reductions with any of the 5 hydroxymethylglutaryl coenzyme A reductase inhibitors. Fewer patients achieved non-HDL cholesterol targets than LDL cholesterol targets, particularly among high-risk patients, implying that if non-HDL cholesterol was used as a target for treatment, more patients would need to be treated more aggressively than National Cholesterol Education Program guidelines require.

Importance of myocardial infarct artery patency on the prevalence of ventricular arrhythmia and late potentials after thrombolysis in acute myocardial infarction.

Sustained infarct artery patency is an important determinant of survival in patients with acute myocardial infarction. We studied 61 patients with acute myocardial infarction who received intravenous recombinant tissue-type plasminogen activator, aspirin or heparin within 6 hours of symptom onset, to determine if infarct artery patency after intravenous thrombolytic therapy influences myocardial electrical stability as measured by the prevalence of spontaneous ventricular ectopy or late potential activity. Infarct artery patency was determined by angiographic evaluation 2.5 +/- 3 days after infarction. Forty-eight patients (79%) had a patent infarct-related artery and 13 (21%) patients had an occluded vessel. The mean number of ventricular premature complexes (VPCs)/hour (p less than 0.01) and the prevalence of late potentials (54 vs 19%; p less than 0.03) were significantly higher in patients with an occluded versus patent-infarct related vessel. Although VPC frequency and late potentials were not influenced by the time to thrombolytic treatment, patients with a patent infarct-related artery had a lower prevalence of late potentials regardless of whether treatment was initiated less than or equal to 2 hours (25% patent vs 50% occluded; p = not significant) or 2 to 6 hours (16% patent vs 55% occluded; p greater than 0.03) after symptom onset. Thus, successful thrombolysis decreases the frequency of ventricular ectopic activity and late potentials in the early postinfarction phase. The reduction in both markers of electrical instability may help explain why the prognosis after successful thrombolysis is improved after acute myocardial infarction.

Cardiac myocytes and dendritic cells harbor human immunodeficiency virus in infected patients with and without cardiac dysfunction: detection by multiplex, nested, polymerase chain reaction in individually microdissected cells from right ventricular endomyocardial biopsy tissue.

Two hundred fifteen patients infected with human immunodeficiency virus (HIV) participated in a prospective longitudinal study of HIV-related heart disease. Evaluation included signal-averaged electrocardiography and echocardiography. Fifteen patients underwent endomyocardial biopsy, 5 had cardiovascular symptoms and 10 did not. Cardiac myocytes or dendritic cells were prepared by individual cell microdissection to sort them from other cell types such as interstitial cells or circulating blood elements. HIV proviral sequences were amplified in samples of 15 to 20 cells of each type by multiplex, nested, polymerase chain reaction and hybridized to 32P-labeled probes specific for regions within the gag and pol genes of HIV-1. The results showed the presence of HIV sequences in myocytes of 2 of 5 patients with cardiac symptoms and in 6 of 10 without. Thus, symptomatic HIV cardiomyopathy did not appear to be a direct consequence of the virus on myocardial cells. In dendritic cells, HIV sequences were detected in 5 of 5 patients with cardiac symptoms and in 8 of 10 with apparently normal ventricular function. Furthermore, dendritic cells were somewhat more numerous in the myocardium of symptomatic than asymptomatic patients. Our studies are the first to directly detect the HIV genome in purified cardiac myocytes from patients with and without cardiac dysfunction. Our findings do not support a direct role of the virus in myocardial dysfunction. However, the results do suggest that the interstitial dendritic cells may be involved in some manner in the development of cardiac dysfunction observed in HIV-infected patients.

Prevention of events with angiotensin-converting enzyme inhibition (the PEACE study design). Prevention of Events with Angiotensin-Converting Enzyme Inhibition.

The Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) trial is an 8,100 patient, randomized, double-blind, placebo-controlled trial designed to determine the usefulness of angiotensin-converting enzyme (ACE) inhibitors in treating coronary patients with preserved left ventricular ejection fraction. The hypothesis being tested in this trial is that patients with coronary disease and ejection fraction > or =40% who are treated with ACE inhibitors will experience a reduction in the incidence of cardiovascular death, nonfatal myocardial infarction, or a revascularization procedure compared with patients treated with conventional therapy. The design of the PEACE trial is described herein.

Experiences in thoracoscopic sympathectomy for axillary hyperhidrosis and osmidrosis: focusing on the extent of sympathectomy.

HYPOTHESIS: A more selective sympathectomy can improve the outcome of axillary hyperhidrosis and osmidrosis and minimize the potential sequelae. DESIGN: Retrospective cohort. SETTING: Tertiary care center. PATIENTS: Between July 1, 1996, and May 30, 2000, 171 patients with axillary hyperhidrosis and osmidrosis were studied. INTERVENTIONS: T3-4 sympathectomies were performed in 40 patients (group 1), T4 sympathectomies were performed in 56 patients (group 2), and T4-5 sympathectomies were performed in 75 patients (group 3). MAIN OUTCOME MEASURES: The surgical outcomes were evaluated by direct patient interview in the outpatient clinic or by telephone or mail questionnaires. The results were categorized as excellent (significant or complete disappearance of symptoms), good (>/=50% improvement), or poor (<50% improvement). RESULTS: There were no surgical mortalities in this study. Twenty-eight group 1 patients (70%), 16 group 2 patients (29%), and 22 group 3 patients (29%) developed compensatory perspiration (P<.001). Six group 1 patients (15%), 1 group 2 patient (2%), and 1 group 3 patient (1%) developed dry hands (P =.02). In the group 1 patients, the surgical outcomes were excellent in 21 (52%), good in 6 (15%), and poor in 13 (32%). In the group 2 patients, the surgical outcomes were excellent in 29 (52%), good in 10 (18%), and poor in 17 (30%). In the group 3 patients, the surgical outcomes were excellent in 53 (71%), good in 11 (15%), and poor in 11(15%) (P =.04). (Percentages may not sum to 100 because of rounding.) CONCLUSION: T4-5 sympathectomies provide higher patient satisfaction rates in treating axillary hyperhidrosis and osmidrosis, with fewer sequelae.

Outpatient thoracoscopic limited sympathectomy for hyperhidrosis palmaris.

Thoracoscopic sympathectomy is considered the most effective treatment for hyperhidrosis palmaris. We have treated 1,043 cases of this disease by this method. We have developed an outpatient technique of thoracoscopic sympathectomy using electrocautery. This procedure has been used in 47 patients with hyperhidrosis palmaris. The early results have been favorable. We describe this fast, safe, economic, and effective method for the treatment of hyperhidrosis palmaris.

Coronary flow reactions to arachidonic acid are inhibited by docosahexaenoic acid.

Arachidonic acid (AA) administered to isolated perfused rat hearts produced coronary vasoconstriction followed by vasodilatation due to biotransformation of AA into vasoactive metabolites. The formation of these metabolites may be blocked with ibuprofen or fenclorac. Slow infusions of docosahexaenoic acid (DHx) resulted in an inhibition of the coronary responses to AA. These results indicate that DHx behaves as a modulator of coronary responses elicited by AA metabolites.

Cardiovascular diseases in women.

Cardiovascular disease is the leading cause of death in women. Approaches to diagnosis and management of cardiovascular disease in women often differ from those in men. In some instances, these differences are justified by clinical trial and epidemiologic data.

Concordant expression of the telomerase-associated genes in non-small cell lung cancer.

AIMS: h-TERT is the keystone gene in controlling telomerase expression under the modulation of many associated genes. Our study was designed to observe the concordant expression of the telomerase associated genes in NSCLC (non-small cell lung cancer). METHODS: Between January 1999 and December 1999, 78 NSCLC patients were studied. The telomerase activity was measured by TRAP (telomeric repeat amplification protocol) assay, and the associated genes (h-TERT, h-TERC, TP1, c-Myc, TRF1, and TRF2) were detected using RT-PCR method. RESULTS: Positive telomerase activity was identified in 47 (60.3%) patients. Expression of the h-TERT, h-TERC, TP1, c-Myc, TRF1 and TRF2 genes were observed in 66.6, 92.3, 100.0, 91.0, 74.4 and 83.3% of the tumor tissues, respectively. Higher expression of the telomerase activity was found in advanced T-status (p=0.0265), and late TNM stages (p=0.0497) patients. In addition to the tumor tissue itself (p<0.0001), higher telomerase expression rates were observed in positive h-TERT (p<0.0001), and positive TRF1 (p=0.003) tumor tissues compared to their normal counterparts. Furthermore, h-TERT expression was closely related to the TRF1 (p=0.003), TRF2 (p=0.024), and c-Myc (p=0.042) expression. CONCLUSIONS: Our data demonstrate that expression of the telomerase activity can be observed in the majority of NSCLC tumor tissues, and is also closely related to the T-status and TNM stage of the tumor. h-TERT expression and subsequent telomerase activation leads to telomere repair under modulation by the TRF1, TRF2 and c-Myc genes.