Early cardiovascular structural and functional abnormalities as a guide to future morbid events.

AIMS: Our aim was to evaluate the predictive value of a battery of 10 non-invasive tests of cardiovascular structural and functional health on the future risk of cardiovascular morbid events. METHODS AND RESULTS: A total of 1900 asymptomatic adults concerned about their risk for cardiovascular disease underwent non-invasive assessment with 10 tests of vascular and cardiac structure and function. A disease score (DS) was calculated for each individual based on these 10 tests. Follow-up (mean 9.2 years) for cardiovascular morbidity and mortality was available for 1442 individuals (mean age 53.2 years, 48.2% women). Those in the lowest DS tertile (0-2) experienced 0.16 cardiovascular events per 100 patient-years (PY), those in the middle tertile (3-5) experienced 0.86 events per 100 PY, and those in the highest tertile (6+) experienced 1.3 events per 100 PY (p < .001). Sensitivity analysis, assuming a neutral effect of DS on projected events in subjects not followed, did not alter statistical significance. Risk assessment using the Framingham risk score (FRS) also predicted morbid events but the two methods differed in identifying individuals at high risk. The net reclassification index was improved by 0.11 (p = 0.01) when DS was added to FRS. CONCLUSIONS: Assessing the biological disease process in the arteries and heart of asymptomatic adults provides a guide to the risk of a future cardiovascular morbid event. Larger and longer studies are needed to determine whether risk factor algorithms, the severity of the biological process or some combination is the optimal method for identifying individuals in need of intervention to delay morbid events.

Perceived stress and smoking-related behaviors and symptomatology in male and female smokers.

INTRODUCTION: Stress has been found to be a significant risk factor for cigarette smoking. Stress affects males and females differently, as does the use of smoking for stress reduction. Few studies have examined gender differences with the interrelation of perceived stress and smoking behaviors and nicotine related symptomatology. Our study investigates this association, as well as the influence of sociodemographic variables. METHODS: This is a retrospective analysis of 62 smokers (41 males, 21 females) enrolled in a smoking cessation study. At the screening visit sociodemographic information, smoking behaviors and survey measures were completed. These included the Perceived Stress Scale (PSS), Minnesota Nicotine Withdrawal Scale (MNWS), and others. Analyses were conducted using multiple linear regression models. RESULTS: PSS score was found to have a negative association with number of cigarettes smoked in males (slope -0.29±0.08; p=0.0009) and females (slope -0.20±0.18; p=0.26) with no difference in effect between genders (p=0.64). Linear regression of MNWS on PSS revealed a positive association for both males (slope 0.41±0.068; p<0.0001) and females (slope 0.73±0.14; p<0.0001). There was a significant difference in effect between genders (p=0.04). CONCLUSIONS: A strong positive association was observed between perceived stress and nicotine withdrawal symptomatology in smokers of both sexes, with a larger effect seen in women. These findings emphasize the importance of stress reduction in smokers, which may lead to fewer withdrawal symptoms and more effective smoking cessation.

Multiple risk factor intervention trial revisited: a new perspective based on nonfatal and fatal composite endpoints, coronary and cardiovascular, during the trial.

BACKGROUND: The Multiple Risk Factor Intervention Trial evaluated a multifactor intervention on coronary heart disease (CHD) in 12 866 men. A priori defined endpoints (CHD death, CHD death or nonfatal myocardial infarction, cardiovascular disease [CVD] death, and all-cause death) did not differ significantly between the special intervention (SI) and usual care (UC) groups over an average follow-up period of 7 years. Event rates were lower than anticipated, reducing power. Other nonfatal CVD outcomes were prespecified but not considered in composite outcomes comparing SI with UC. METHODS AND RESULTS: Post-trial CVD mortality risks associated with nonfatal CVD events occurring during the trial were determined with Cox regression. Nonfatal outcomes associated with >2-fold risk of CVD death over the subsequent 20 years were combined with during-trial deaths to create 2 new composite outcomes. SI/UC hazard ratios and 95% confidence intervals were estimated for each composite outcome. Of 10 during-trial nonfatal events, 6 were associated (P<0.001) with >2-fold risk of CVD death. A CHD composite outcome (CHD death, myocardial infarction [clinical or serial ECG change], CHF, or coronary artery surgery) was experienced by 520 SI and 602 UC men (SI/UC hazard ratio = 0.86; 95% confidence interval, 0.76-0.97; P=0.01). A CVD composite outcome (CHD [as above], other CVD deaths, stroke, or renal impairment) was experienced by 581 SI and 652 UC men (hazard ratio = 0.89; 95% confidence interval, 0.79-0.99; P=0.04). CONCLUSIONS: In post hoc analyses, composite fatal/nonfatal CHD and CVD rates over 7 years were significantly lower for SI than for UC. These findings reinforce recommendations for improved dietary/lifestyle practices, with pharmacological therapy as needed, to prevent and control major CVD risk factors.

Vascular and cardiac functional and structural screening to identify risk of future morbid events: preliminary observations.

Risk factors have served to identify patients in need of antihypertensive and lipid-lowering therapy. Because of their limited sensitivity and specificity, we developed a screening program using noninvasive testing and a scoring system aimed at detecting functional and structural cardiovascular abnormalities in asymptomatic individuals. Ten cardiovascular tests were performed in 1 hour by a single technologist. Tests were scored as normal (0), borderline abnormal (1), or abnormal (2). Total disease score (DS) could range from 0 (all tests normal) to 20 (all tests abnormal). Scores of 0-2 were classified as normal, 3-5 as early disease, and 6+ as advanced disease. Morbid events during follow-up of 6 months to 8 years were determined from mailed questionnaires. Framingham risk scores (FRS) were calculated using published algorithms. Thirty-five morbid events (1 of 169 in the "normal" group, 8 of 214 in the "early disease" group, and 26 of 230 in the "advanced disease" group) occurred during the follow-up period among the 613 individuals who completed the questionnaire. Risk for morbid events was highly significantly different between the Kaplan-Meier curves based on disease detection (log rank 21.75, P ≤ .0001). FRS were significantly different but less discriminating, with five morbid events in the 227 subjects with FRS <10, eight in 162 with FRS 10-13, and 22 of 227 with FRS >13 (log rank 9.80, P = .0074). The area under receiver operating characteristic curve for DS (0.74) surpassed that of FRS (0.66) and was not improved when both were included in the model. Neither blood pressure levels nor low-density lipoprotein cholesterol levels provided adequate discrimination. Identifying early disease in asymptomatic individuals provides a better guide to the need for preventive therapy than traditional risk factor assessment.

Relation of heart rate parameters during exercise test to sudden death and all-cause mortality in asymptomatic men.

Heart rate (HR) profile during exercise predicts all-cause mortality. However, less is known about its relation to sudden (vs nonsudden) death in asymptomatic people. The relation of exercise HR parameters (HR at rest, target HR achievement, HR increase, and HR recovery) with sudden death, coronary heart disease (CHD) death, myocardial infarction, and all-cause mortality was assessed in 12,555 men who participated in MRFIT. Subjects were 35 to 57 years old without clinical CHD, but with higher than average Framingham risk. Trial follow-up was 7 years, and extended follow-up after the trial for all-cause mortality was 25 years. After adjusting for cardiac risk factors, having to stop exercise before achieving 85% of age-specific maximal HR was associated with increased risk of sudden death (hazard ratio 1.8, 95% confidence interval [CI] 1.3 to 2.5, p = 0.001), CHD death (hazard ratio 1.4, 95% CI 1.2 to 1.5, p <0.001), and all-cause mortality (hazard ratio 1.3, 95% CI 1.2 to 1.4, p <0.001). Increased HR at rest (p = 0.001), attenuated HR increase (p = 0.02), delayed HR recovery (p = 0.04), and exercise duration (p <0.0001) were independent predictors of all-cause death in the overall study population and also in the subgroup that achieved target HR. In conclusion, middle-aged men without clinical CHD who stopped exercise before reaching 85% of maximal HR had a higher risk of sudden death. Other exercise HR parameters and exercise duration predicted all-cause mortality.

Asymptomatic myocardial ischaemia in HIV-infected adults.

BACKGROUND: Asymptomatic ischaemic heart disease (IHD) in HIV-infected patients has not been studied. METHODS: Resting, 12-lead electrocardiograms (ECG) were evaluated for asymptomatic IHD (Q-wave and/or ST segment depression) at baseline from HIV-infected participants with no known IHD enrolling in the SMART study. The ECG recordings were standardized and centrally analysed. Factors associated with asymptomatic IHD were identified by logistic regression, sequentially adjusted for demographics, clinical history, metabolic risk factors and type and duration of antiretroviral therapy (ART). RESULTS: Of 4831 participants with an evaluable, baseline ECG and no prior IHD, mean age was 44 years (SD, 9.3); 28.4% were female; 6.6% had diabetes; 16.5% were receiving antihypertensive therapy; and 95.4% were ART experienced. ECG evidence of IHD was detected in 526 (10.9%) [Q-wave in 283 (5.9%), ST segment depression in 264 (5.5%)]; 16.7% in those 60 years or older. Variables independently associated with these abnormalities were older age [age > or= 60 versus < 40 years: odds ratio (OR), 2.2; 95% confidence interval (CI), 1.5-3.2; P < 0.001], current antihypertensive therapy (OR, 1.5; 95% CI, 1.1-1.9; P = 0.003) and recruitment in Europe (OR, 1.4; 95% CI, 1.1-1.7; P = 0.004) or Asia (OR, 1.6; 95% CI, 1.0-2.6; P = 0.05), both compared with North America. Diabetes was borderline significant (OR, 1.4; 95% CI, 1.0-2.0; P = 0.06). CONCLUSIONS: ECG evidence of asymptomatic IHD was common in this large cohort of HIV-infected adults and more common than a history of symptomatic IHD. Traditional factors were the predominant determinants of risk. No clear association between ART type or duration and asymptomatic IHD was noted.

Lipoprotein particles, insulin, adiponectin, C-reactive protein and risk of coronary heart disease among men with metabolic syndrome.

We tested the hypotheses whether nuclear magnetic resonance (NMR) determined lipoprotein particles, insulin and adiponectin, and C-reactive protein (CRP) and white blood cell (WBC) count as markers of inflammation predicted risk of coronary heart disease (CHD) death among 428 men age 35-57 years with metabolic syndrome (MetSyn) in a matched case control study within the multiple risk factor intervention trial. Blood samples collected at entry into the study and stored at -60 degrees C were obtained from central storage for blood analyte analysis. Two hundred and fourteen men with MetSyn who died of CHD were matched with 214 men with MetSyn who did not die of CHD during 18 years of follow-up. Cases were matched to controls on age, study group, number of factors present in the MetSyn, and presence or absence of a nonfatal CVD event during the trial. Mortality follow-up was determined using the National Death Index. Higher levels of high density lipoprotein particles (HDL-P), especially medium-sized HDL-P [hazard ratio (95% confidence interval) 0.45 (0.25-0.83, P<0.01), quartile 1 as compared to quartile 4], were associated with lower risk of CHD death. Low density lipoprotein (LDL) particles were not associated with increased risk of CHD. Elevated LDL cholesterol (LDL-C), smoking and WBC count were, but levels of adiponectin, insulin and CRP were not significantly related to CHD death. In multivariate models adjusting for smoking and LDL-C, medium HDL-P and WBC count remained independent predictors of CHD death. Number of HDL particles, especially medium-sized HDL particles and WBC count were independent predictors of CHD death among men with MetSyn.

Arterial elasticity as part of a comprehensive assessment of cardiovascular risk and drug treatment.

Early cardiovascular disease can be identified in asymptomatic individuals by noninvasive evaluation of functional and structural abnormalities of the vasculature and heart. These abnomalities are usually a consequence of endothelial dysfunction. A panel of 10 tests, including small and large artery elasticity, has been used as the basis for a screening system that provides a score of 0 to 20 as a guide to the severity of disease. Using that Rasmussen score allows for stratification of patients into low, intermediate, or high risk for progression to cardiovascular morbid events. This comprehensive screening can be performed efficiently in a single room with a single technician. The sensitivity and specificity of this screening system in predicting future cardiovascular events, its superiority to traditional risk factor assessment, and its potential to track the response to therapeutic interventions must be validated in long-term follow-up studies.

Results of the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) trial by geographical region.

OBJECTIVE: To examine regional differences in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) trial. DESIGN: Double-blind, randomized, international clinical trial. SETTING: Six hundred and sixty-one clinical centers in 15 countries. PATIENTS: Hypertensive volunteers (n = 16,602) with > or =1 additional cardiovascular risk factor, grouped into four regions: USA (n = 8144), Canada (n = 3405), Western Europe (Spain, UK, Italy, Sweden, Germany; n = 2048) or 'other' (Bulgaria, Israel, Mexico, Czech Republic, Hungary, Poland, Slovakia, Brazil; n = 2879); subgroupings included country and state/province within the USA and Canada. INTERVENTIONS: Randomized to COER-verapamil or the investigator's choice of either atenolol or hydrochlorothiazide, titrated and additional drugs added as required. MAIN OUTCOME MEASURES: Baseline characteristics; blood pressure control, medication adherence and lost-to-follow-up at 2 years; and composite primary endpoint (stroke, myocardial infarction, cardiovascular death) by regional groupings. RESULTS: Regional differences were found at baseline for age, gender, blood pressure, percentage receiving antihypertensive drug therapy, initial choice of atenolol or hydrochlorothiazide, and risk factor profile. Blood pressure control rates increased markedly during follow-up in all regions, but varied significantly by region. Blood pressure control, medication adherence and lost-to-follow-up rates were poorest in the USA. After adjustment for baseline differences, the primary-event rate for each region was significantly lower than for the USA. Although baseline factors, blood pressure control and event rates varied by region, treatment differences did not. CONCLUSION: Despite differences in baseline and follow-up measures across geographical regions, the absence of treatment differences by region suggests that the overall findings of CONVINCE are robust.

Elevated prostate-specific antigen levels up to 25 years prior to death from prostate cancer.

OBJECTIVES: We tested the hypothesis that prostate-specific antigen (PSA) levels would be higher among prostate cancer deaths as compared with controls over time in the 25-year follow-up of the Multiple Risk Factor Intervention Trial of participants ages 35-57 at entry. METHODS: The initial stored serum samples were collected in 1973-1975 and the mean length of follow-up to prostate cancer death was 17 years. RESULTS: There were 63 prostate cancer deaths and 63 controls matched by age, clinical site, and length of follow-up. The mean PSA level for prostate cancer decedents was 2.84 ng/ml as compared with 1.10 ng/ml for controls (P = 0.002 for difference). There were nine men who died from prostate cancer and no controls with PSA levels > 4 ng/ml. Risk of prostate cancer death increased with increasing PSA levels, with increased risk observed even at moderate levels of PSA. Many of those with high PSA levels in 1973-1975 died from prostate cancer many years after the elevated PSA. CONCLUSIONS: PSA levels measured from blood obtained before the introduction of widespread PSA testing were a strong predictor of prostate cancer death over 25 years of follow-up. Studies of prostate cancer etiology and chemoprevention need to focus on middle-aged or younger men with longer follow-up.

Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial.

CONTEXT: Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk, but the benefit compared with other drug classes is controversial. OBJECTIVE: To determine whether initial therapy with controlled-onset extended-release (COER) verapamil is equivalent to a physician's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results. INTERVENTION: Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, beta-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed. MAIN OUTCOME MEASURES: First occurrence of stroke, myocardial infarction, or cardiovascular disease-related death. RESULTS: Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P =.77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease-related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease-related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54 [95% CI, 1.16-2.04]; P =.003). More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53). CONCLUSIONS: The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment.

Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial.

-Blood pressure (BP) control rates around the world are suboptimal. Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of hypertensive Americans aged 18 to 74 years have a BP of <140/90 mm Hg. We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study, an international clinical trial that compares outcomes in hypertensive patients randomized to initial treatment with either controlled-onset extended-release verapamil or the investigator's choice of atenolol or hydrochlorothiazide. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16 602 subjects (average+/-SD age 65.6+/-7.4 years; 56% women, 84% white/7% black/7% Hispanic). The average BP at enrollment was 148/85 mm Hg for patients taking BP medications (n=13 879) and 161/94 mm Hg for previously untreated patients (n=2723). After medication titration, with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg, 84.8% of the subjects attained the goal BP. During 2 years of treatment, BP control was maintained in 67% to 69% of the subjects (69% to 71% for systolic BP of <140 mm Hg and 90% for diastolic BP of <90 mm Hg). These data suggest that the control of systolic BP is more difficult than the control of diastolic BP. The US national goal of having 50% of hypertensives with a BP of <140/90 mm Hg may be achievable if a forced titration strategy is used. Interested investigators, free care and medications, and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population.