Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Reliability of vertebral fracture assessment using multidetector CT lateral scout views: the Framingham Osteoporosis Study.

UNLABELLED: Two radiologists evaluated images of the spine from computed tomography (CT) scans on two occasions to diagnose vertebral fracture in 100 individuals. Agreement was fair to good for mild fractures, and agreement was good to excellent for more severe fractures. CT scout views are useful to assess vertebral fracture. INTRODUCTION: We investigated inter-reader agreement between two radiologists and intra-reader agreement between duplicate readings for each radiologist, in assessment of vertebral fracture using a semi-quantitative method from lateral scout views obtained by CT. METHODS: Participants included 50 women and 50 men (age 50-87 years, mean 70 years) in the Framingham Study. T4-L4 vertebrae were assessed independently by two radiologists on two occasions using a semi-quantitative scale as normal, mild, moderate, or severe fracture. RESULTS: Vertebra-specific prevalence of grade ≥ 1 (mild) fracture ranged from 3% to 5%. We found fair (κ = 56-59%) inter-reader agreement for grade ≥ 1 vertebral fractures and good (κ = 68-72%) inter-reader agreement for grade ≥ 2 fractures. Intra-reader agreement for grade ≥ 1 vertebral fracture was fair (κ = 55%) for one reader and excellent for another reader (κ = 77%), whereas intra-reader agreement for grade ≥ 2 vertebral fracture was excellent for both readers (κ = 76% and 98%). Thoracic vertebrae were more difficult to evaluate than the lumbar region, and agreement was lowest (inter-reader κ = 43%) for fracture at the upper (T4-T9) thoracic levels and highest (inter-reader κ = 76-78%) for the lumbar spine (L1-L4). CONCLUSIONS: Based on a semi-quantitative method to classify vertebral fractures using CT scout views, agreement within and between readers was fair to good, with the greatest source of variation occurring for fractures of mild severity and for the upper thoracic region. Agreement was good to excellent for fractures of at least moderate severity. Lateral CT scout views can be useful in clinical research settings to assess vertebral fracture.

Association between single-slice measurements of visceral and abdominal subcutaneous adipose tissue with volumetric measurements: the Framingham Heart Study.

OBJECTIVE: Volumetric visceral abdominal adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) as measured by computed tomography (CT) are associated with metabolic risk factors. We sought to identify the correlations of VAT and SAT between area-based measures at different anatomic locations with volumetric measurements to identify the optimal anatomic site, and to relate measurements at this site with metabolic risk factors. METHODS: We measured SAT and VAT volumes across the total imaging volume, whereas we measured SAT and VAT area at seven predefined anatomic landmarks in 200 participants from the Framingham Heart Study (mean age 54 years, 50% women) who underwent abdominal multi-detector CT. Correlation coefficients were used to assess the association between area measurements and volumes as well as metabolic risk factors stratified by gender. RESULTS: Area-based measurements of SAT and VAT obtained at all anatomic landmarks were strongly associated with SAT and VAT volumes (all r>0.93, P<0.0001 and r>0.87, P<0.0001, for women and men; respectively). Consistently, area-based measurements of SAT and VAT obtained at L(3/4) were most strongly associated with volumetric measured VAT and SAT independent of age (both r=0.99 in men, r=0.96 for SAT and r=0.99 for VAT in women, all P-value <0.0001) and were similarly correlated with risk factors compared with SAT and VAT volumes (all P<0.05 for fasting plasma glucose, triglycerides, high-density lipoprotein, systolic blood pressure). CONCLUSION: Among area-based measurements of SAT and VAT, those obtained at the level of L(3/4) were strongly associated with SAT and VAT volumes and cardio-metabolic risk factors in both men and women.

Novel measurements of periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue.

BACKGROUND: Perivascular adipose tissue may be associated with the amount of local atherosclerosis. We developed a novel and reproducible method to standardize volumetric quantification of periaortic adipose tissue by computed tomography (CT) and determined the association with anthropometric measures of obesity, and abdominal adipose tissue. METHODS: Measurements of adipose tissue were performed in a random subset of participants from the Framingham Heart Study (n=100) who underwent multidetector CT of the thorax (ECG triggering, 2.5 mm slice thickness) and the abdomen (helical CT acquisition, 2.5 mm slice thickness). Abdominal periaortic adipose tissue (AAT) was defined by a 5 mm cylindrical region of interest around the aortic wall; thoracic periaortic adipose tissue (TAT) was defined by anatomic landmarks. TAT and AAT were defined as any voxel between -195 and -45 HU and volumes were measured using dedicated semiautomatic software. Measurement reproducibility and association with anthropometric measures of obesity, and abdominal adipose tissue were determined. RESULTS: The intra- and inter-observer reproducibility for both AAT and TAT was excellent (ICC: 0.97 and 0.97; 0.99 and 0.98, respectively). Similarly, the relative intra- and inter-observer difference was small for both AAT (-1.85+/-1.28% and 7.85+/-6.08%; respectively) and TAT (3.56+/-0.83% and -4.56+/-0.85%, respectively). Both AAT and TAT were highly correlated with visceral abdominal fat (r=0.65 and 0.77, P<0.0001 for both) and moderately correlated with subcutaneous abdominal fat (r=0.39 and 0.42, P<0.0001 and P=0.009), waist circumference (r=0.49 and 0.57, P<0.0001 for both) and body mass index (r=0.47 and 0.58, P<0.0001 for both). CONCLUSION: Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible. Further investigation is warranted regarding associations of periaortic adipose tissue with other body fat deposits, cardiovascular risk factors and clinical outcomes.

Endogenous circulating testosterone and sex hormone-binding globulin levels and measures of myocardial structure and function: the Framingham Heart Study.

BACKGROUND: The relation between endogenous testosterone concentrations and myocardial mass and function remains incompletely understood. OBJECTIVES: To determine the cross-sectional association between endogenous hormone levels with cardiac magnetic resonance measures of myocardial mass, structure, and function in community-dwelling men across a wide age range. METHODS: A total of 720 men from the Framingham Heart Study Offspring Cohort (age range 37-82, mean = 59.6 years) who underwent cardiac magnetic resonance imaging and had hormone levels measured. Total testosterone (measured using liquid chromatography-tandem mass spectrometry), sex hormone-binding globulin (measured using an immunofluorometric assay), and calculated free testosterone levels were assessed in male participants of the Framingham Heart Study Offspring Cohort at examination 7. Cardiac magnetic resonance imaging was performed between examinations 7 and 8 (2002-2006). RESULTS: Age-adjusted linear regression models showed statistically significant association between total testosterone levels and left ventricular mass (p = 0.009), left ventricular mass index (p = 0.006), cardiac output (p = 0.001), and main pulmonary artery diameter (p = 0.008); the association between total testosterone and these cardiac magnetic resonance measures was weak and was not significant after adjustment for established risk factors-age, body mass index, diabetes, and hypertension. Furthermore, calculated free testosterone level was not significantly associated with any measure of myocardial mass or function. Sex hormone-binding globulin level was significantly associated with left ventricular mass (p = 0.002), left ventricular mass index (p = 0.004), cardiac output (p = 0.003), left ventricular ejection fraction (p = 0.039), and main pulmonary artery diameter (p = 0.042) in age-adjusted models; these associations were also rendered non-significant after adjusting for cardiovascular risk factors. CONCLUSIONS: Neither testosterone nor sex hormone-binding globulin levels in men are associated significantly with myocardial mass and function independent of established cardiovascular risk factors.

Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study.

INTRODUCTION: Although plasminogen activator inhibitor (PAI-1) plays a key regulatory role in fibrinolysis, it has not been clearly shown to independently predict cardiovascular disease (CVD) among individuals without prior CVD. We investigated, in the Framingham Heart Study offspring cohort, whether PAI-1 predicted CVD risk among individuals without prior CVD. METHODS: Plasma PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured in 3203 subjects without prior CVD between 1991 and 1995; average follow-up of 10 years. PAI-1 was remeasured 4 years after baseline, to determine the effect of serial change on risk. RESULTS: PAI-1 levels (mean ± SD) were 29.1 ng/ml (19.2) versus 22.1 (16.5) for those and without incident CVD; p<0.001, and TPA levels were 12.0 ng/ml (5.7) versus 9.0 (4.7); p<0.001. PAI-1 and TPA antigen levels had a strong unadjusted linear relation with incident CVD (p<0.001). After adjustment for conventional risk factors, the hazard ratios (HRs) for higher quartiles of PAI-1, compared with the lowest, were 1.9, 1.9, 2.6 (linear trend p=0.006), and 1.6, 1.6, 2.9 (p<0.001) for TPA antigen. The adjusted HRs for increasing quartiles of serial change in PAI-1 at 4 years, compared with the lowest, were 0.9, 0.8, 1.3 (p=0.050). C statistic assessment showed that adding PAI-1 or TPA to conventional risk factors resulted in small increases in discrimination and modest reclassification of risk, which was statistically significant for TPA (net reclassification 6.8%, p=0.037) but not PAI-1 (4.8%, p=0.113). CONCLUSION: PAI-1 and TPA antigen levels are predictive of CVD events after accounting for established risk factors. A serial increase in PAI-1 is associated with a further increase in risk. These findings support the importance of fibrinolytic potential in CVD.

Activation of lipolysis and cyclic AMP accumulation in rabbit adipocytes by isoproterenol in the presence of forskolin or pertussis toxin.

Adipocytes from rabbits are relatively insensitive to catecholamines or forskolin. However, the combination of catecholamines plus forskolin increased cyclic AMP accumulation and lipolysis much more than either agent alone. Pertussis toxin treatment also restored sensitivity to catecholamines. No defect in activation by catecholamines of adenylate cyclase was seen in isolated membranes incubated in the presence of GTP. Rabbit adipocytes appear to have an excess of the inhibitory guanine nucleotide binding protein (Ni). However, in plasma membranes this protein appeared to be relatively inactive as there was an activation of adenylate cyclase activity by catecholamines in the presence of GTP. These data suggest that in intact rabbit adipocytes catecholamines and forskolin are ineffective as stimulators of adenylate cyclase due to an excess of inhibitory guanine nucleotide binding proteins.

Heritability of heart rate variability: the Framingham Heart Study.

BACKGROUND: There is evolving evidence that heart rate (HR) is genetically determined. Heart rate variability (HRV) measured by power spectral analysis provides quantitative phenotypic markers of autonomic nervous system activity. Reported determinants of HR and HRV only partially explain their variability in the population. The purpose of this study was to assess the heritability of HR and HRV and estimate the contribution of genetic factors to their variance. METHODS AND RESULTS: Subjects who underwent ambulatory recordings at a routine examination were eligible; subjects with congestive heart failure, coronary artery disease, diabetes mellitus, and those taking cardioactive medications were excluded. We analyzed high-frequency power, low-frequency power, very low-frequency power, total power, low-frequency/high-frequency ratio, and the standard deviation of normal R-R intervals from 2-hour continuous ECG recordings. Heritability analysis was done by studying correlations between siblings (n=682, in 291 sibships, 517 pairs) and between spouse pairs (n=206 pairs) after adjusting for important covariates. Results from separate models were combined to estimate the components of variance attributable to measured covariates, additive genetic effects (heritability), and household effects. After adjusting for covariates, the correlations were consistently higher among siblings (0.21 to 0.26) compared with spouses (0.01 to 0.19). The measured covariates in general accounted for 13% to 40% of the total phenotypic variance, whereas genetic factors accounted for 13% to 23% of the variation among HR and HRV measures. CONCLUSIONS: Heritable factors may explain a substantial proportion of the variance in HR and HRV. These results highlight the contribution of genetic versus environmental factors to autonomic nervous system activity.

Blood pressure response during treadmill testing as a risk factor for new-onset hypertension. The Framingham heart study.

BACKGROUND: Although systolic blood pressure (SBP) response to exercise has been shown to predict subsequent hypertension in small samples of men, this association has not been studied in a large population-based sample of middle-aged men and women. The purpose of this study was to examine, in normotensive subjects, the relations of SBP and diastolic blood pressure (DBP) during the exercise and recovery periods of a graded treadmill test to the risk of developing new-onset hypertension. METHODS AND RESULTS: BP data from exercise testing in 1026 men and 1284 women (mean age, 42+/-10 years; range, 20 to 69 years) from the Framingham Offspring Study who were normotensive at baseline were related to the incidence of hypertension 8 years later. New-onset hypertension, defined as an SBP >/=140 mm Hg or DBP >/=90 mm Hg or the initiation of antihypertensive drug treatment, occurred in 228 men (22%) and 207 women (16%). Exaggerated SBP (Ex-SBP 2) and DBP (Ex-DBP 2) response and delayed recovery of SBP (R-SBP 3) and DBP (R-DBP 3) were defined as an age-adjusted BP greater than the 95th percentile during the second stage of exercise and third minute of recovery, respectively. After multivariable adjustment, Ex-DBP 2 was highly predictive of incident hypertension in both men (OR, 4.16; 95% CI, 2.15, 8.05) and women (OR, 2.17; CI, 1.19, 3.96). R-SBP 3 was predictive of hypertension in men in a multivariable model that included exercise duration and peak exercise BP (OR, 1.92; CI, 1.00, 3.69). Baseline resting SBP (chi2, 23.4 in men and 34.7 in women) and DBP (chi2, 11.3 in men and 13.1 in women) had stronger associations with new-onset hypertension than exercise DBP (chi2, 16.4 in men and 6.1 in women) and recovery SBP (chi2, 6.5 in men and 2.1 in women) responses. CONCLUSIONS: An exaggerated DBP response to exercise was predictive of risk for new-onset hypertension in normotensive men and women. An elevated recovery SBP was predictive of hypertension in men. These findings may reflect subtle pathophysiological features in the preclinical stage of hypertension.

Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality.

BACKGROUND: The impact of abdominal arterial calcific deposits on the prediction of cardiovascular disease (CVD) over a long follow-up interval deserves greater scrutiny. METHODS AND RESULTS: Lateral lumbar radiographs were studied as a predictor of incident coronary heart disease (CHD), CVD, and CVD mortality in 1049 men and 1466 women (mean age, 61 years) who were followed from 1967 to 1989. Anterior and posterior wall calcific deposits in the aorta at the level of the first through fourth lumbar vertebrae were graded according to increasing severity using a previously validated rating scale for abdominal aortic calcium (AAC) that ranges from 0 to 24 points. There were 454 cases of CHD, 709 cases of CVD, and 365 CVD deaths. Proportional hazards logistic regression was used to test for associations between AAC and later events after adjustment for age, cigarette use, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy, body mass index, cholesterol, and HDL cholesterol. In comparisons with the lowest AAC tertile, the multivariate age-adjusted relative risks (RR) for CVD were increased in tertile 2 (men: RR, 1.33; 95% confidence interval [CI], 1.02 to 1.74; women: RR, 1.25; 95% CI, 0.95 to 1.65) and tertile 3 (men: RR, 1.68; 95% CI, 1.25 to 2.27; women: RR, 1.78; 95% CI, 1.33 to 2.38). Similar results were obtained with CHD and CVD mortality. CONCLUSIONS: AAC deposits, detected by lateral lumbar radiograms, are a marker of subclinical atherosclerotic disease and an independent predictor of subsequent vascular morbidity and mortality.

Genetic and environmental contributions to platelet aggregation: the Framingham heart study.

BACKGROUND: Platelet aggregation plays an important role in arterial thrombosis in coronary heart disease, stroke, and peripheral arterial disease. However, the contribution of genetic versus environmental influences on interindividual variation in platelet aggregability is poorly characterized. METHODS AND RESULTS: We studied the heritability of platelet aggregation responses in 2413 participants in the Framingham Heart Study. The threshold concentrations of epinephrine and ADP required to produce biphasic platelet aggregation and collagen lag time were determined. Mixed-model linear regression was used to calculate correlation coefficients within sibships and within spouse pairs. Variance and covariance component methods were used to estimate the proportion of platelet aggregation attributable to measured covariates versus additive genetic effects. After accounting for environmental covariates, the adjusted sibling correlations for epinephrine, ADP, and collagen lag time were 0.24, 0.22, and 0.31, respectively (P=0.0001 for each). In contrast, adjusted correlations for spouse-pairs were -0.01, 0.05, and -0.02, respectively (all P>0.30). The estimated heritabilities were 0.48, 0.44, and 0.62, respectively. Measured covariates accounted for only 4% to 7% of the overall variance in platelet aggregation, and heritable factors accounted for 20% to 30%. The platelet glycoprotein IIIa Pl(A2) polymorphism and the fibrinogen Hind III beta-148 polymorphism contributed <1% to the overall variance. CONCLUSIONS: In our large, population-based sample, heritable factors play a major role in determining platelet aggregation, and measured covariates play a lesser role. Future studies are warranted to identify the key genetic variants that regulate platelet function and to lay the groundwork for rational pharmacogenetic approaches.

Platelet glycoprotein IIIa Pl(a) polymorphism, fibrinogen, and platelet aggregability: The Framingham Heart Study.

BACKGROUND: Recent data suggest that the Pl(A2) allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the Pl(A2) allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that Pl(A2)-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with Pl(A) genotype in modulating platelet aggregability. Methods and Results-- Glycoprotein IIIa Pl(A) genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the Pl(A1/A1) genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the Pl(A2)-positive genotype (P>0.90). CONCLUSION: Higher fibrinogen levels were associated with increased platelet aggregability. However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding Pl(A) genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.

Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction.

BACKGROUND: Recent advances in high-throughput genomics technology have expanded our ability to catalogue allelic variants in large sets of candidate genes related to premature coronary artery disease. METHODS AND RESULTS: A total of 398 families were identified in 15 participating medical centers; they fulfilled the criteria of myocardial infarction, revascularization, or a significant coronary artery lesion diagnosed before 45 years in men or 50 years in women. A total of 62 vascular biology genes and 72 single-nucleotide polymorphisms were assessed. Previously undescribed variants in 3 related members of the thrombospondin protein family were prominent among a small set of single-nucleotide polymorphisms that showed a statistical association with premature coronary artery disease. A missense variant of thrombospondin 4 (A387P) showed the strongest association, with an adjusted odds ratio for myocardial infarction of 1.89 (P=0.002 adjusted for covariates) for individuals carrying the P allele. A variant in the 3' untranslated region of thrombospondin-2 (change of thymidine to guanine) seemed to have a protective effect against myocardial in individuals homozygous for the variant (adjusted odds ratio of 0.31; P=0.0018). A missense variant in thrombospondin-1 (N700S) was associated with an adjusted odds ratio for coronary artery disease of 11.90 (P=0.041) in homozygous individuals, who also had the lowest level of thrombospondin-1 by plasma assay (P=0.0019). CONCLUSIONS: This large-scale genetic study has identified the potential of multiple novel variants in the thrombospondin gene family to be associated with familial premature myocardial infarction. Notwithstanding multiple caveats, thrombospondins specifically and high-throughput genomic technology in general deserve further study in familial ischemic heart disease.

Current issues concerning thrombolytic therapy for acute myocardial infarction.

Data are now available from three large-scale randomized trials that directly compare the risks and benefits of thrombolytic agents in acute myocardial infarction. In the interpretation of results from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial and its International Extension, the Third International Study of Infarct Survival (ISIS-3), and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, there are areas of both agreement and controversy. It is generally agreed that the agents most commonly used in the United States--tissue-type plasminogen activator (t-PA), streptokinase and anisoylated plasminogen streptokinase activator complex (APSAC)--all reduce mortality when given to patients with acute evolving myocardial infarction. Further, it is clear that thrombolytic therapy given to such patients presenting up to 12 h after onset of symptoms reduces the mortality rate by approximately 20%, that aspirin therapy for patients presenting up to 24 h reduces the mortality rate by approximately 23% and that the benefits of thrombolytic therapy and aspirin are additive. Finally, and of most importance, the earlier administration as well as the more widespread use of thrombolytic therapy and aspirin would save many more lives. The totality of evidence clearly indicates that streptokinase produces significantly fewer strokes and cerebral hemorrhages than either t-PA or APSAC. Whether or not accelerated t-PA has a small advantage for mortality is less conclusive.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombotic therapy for acute myocardial infarction.

Antithrombotic therapy is clearly beneficial in the treatment of acute myocardial infarction, but the optimal regimen is controversial. Treatment with aspirin leads to substantial and significant reductions in rates of mortality, reinfarction and stroke in patients with acute myocardial infarction, and the benefits are additive with those of thrombolytic therapy. It is unclear whether heparin confers additional net benefits over aspirin alone. In patients receiving aspirin and thrombolytic therapy, there is no mortality benefit from adding delayed subcutaneous heparin, no consistent patency benefit from adding immediate intravenous heparin and no reduction in mortality from adding immediate intravenous heparin, at least for patients treated with streptokinase. However, heparin is consistently associated with increased rates of intracranial and other serious bleeding events when used with both aspirin and thrombolytic therapy. Existing data support the need for further large-scale trials of current and newer antithrombotic regimens in acute myocardial infarction to assess the balance of benefits and risks of these regimens compared with that for aspirin alone. In patients not receiving thrombolytic therapy, randomized trial data are currently insufficient to adequately compare the benefits and risks of adding heparin to aspirin alone. The First American Study of Infarct Survival (ASIS-1) will directly compare the balance of risks and benefits of aspirin alone, aspirin plus intravenous heparin and aspirin plus intravenous hirudin in patients with acute myocardial infarction not receiving thrombolytic therapy.

Association of unstable angina guideline care with improved survival.

BACKGROUND: An unstable angina guideline was published in 1994 by the Agency for Health Care Policy and Research, Bethesda, Md. However, the relationship between guideline-concordant care and patient outcomes is unknown. OBJECTIVE: To determine whether guideline-concordant care is associated with improved outcomes. METHODS: The study sample consisted of 275 consecutive nonreferral patients hospitalized with primary unstable angina. One-year survival and survival free of myocardial infarction were compared between patients who received care concordant with 8 selected guideline recommendations and patients who received discordant care. RESULTS: Care concordant with the 8 key guideline recommendations was associated with improved 1-year survival (95% vs 81%; log-rank P<.001) and survival free of myocardial infarction (91% vs 74%; P<.001), compared with guideline-discordant care. Patients in high-risk subgroups had the largest survival benefit associated with guideline-concordant care (aged -65 years, 91% vs 74% [P=.005]; heart failure at presentation, 91% vs 68% [P=.10]). Aspirin therapy was the single recommendation most strongly associated with improved 1-year survival (94% vs 78%; P=.002). CONCLUSIONS: Care as outlined in the unstable angina clinical practice guideline is associated with improved 1-year outcomes. Subgroups of patients at highest risk and recommendations firmly based on randomized clinical trial data were most strongly associated with better outcomes. These findings support the use of an evidence-based approach to guideline development and assessment of quality of care in patients with primary unstable angina.

Cross-classification of JNC VI blood pressure stages and risk groups in the Framingham Heart Study.

BACKGROUND: The recently published Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) includes a classification of blood pressure stages and a new risk stratification component. Patients with high-normal blood pressure or hypertension are stratified into risk group A (no associated cardiovascular disease risk factors, no target organ damage or cardiovascular disease); group B (> or =1 associated cardiovascular disease risk factor excluding diabetes, no target organ damage or cardiovascular disease); or group C (diabetes or target organ damage or cardiovascular disease). OBJECTIVE: To examine the prevalence of risk groups and blood pressure stages in a community-based sample. METHODS: We evaluated 4962 subjects from the Framingham Heart Study and Framingham Offspring Study examined between 1990 and 1995. We cross-classified men and women separately according to their JNC VI blood pressure stages and risk groups. RESULTS: In the whole sample, 43.7% had optimal or normal blood pressure and 13.4% had high-normal blood pressure; 12.9% had stage 1 hypertension and 30.0% had stage 2 or greater hypertension or were receiving medication. As blood pressure stage increased, the proportion of subjects in group A decreased, whereas the proportion in group C increased. Among those with high-normal blood pressure or hypertension, only 2.4% (all women) were in risk group A, 59.3% were in group B, and 38.2% were in group C. In the high-normal or hypertensive group, 39.4% qualified for lifestyle modification as the initial intervention according to JNC VI recommendations, whereas 60.6% were eligible for initial drug therapy or were already receiving drug therapy. Nearly one third of high-normal subjects were in risk group C, in which early drug therapy may be needed. Among those in stage 1, only 4.0% were in group A, in which prolonged lifestyle modification is recommended. CONCLUSIONS: These results provide a foundation for estimating the number of individuals with hypertension who fall into different risk groups that require different treatment approaches. With nearly 50 million individuals with hypertension in the United States, there are important implications for clinicians and policymakers if JNC VI recommendations are widely adopted in clinical practice.

Elderly patients receive less aggressive medical and invasive management of unstable angina: potential impact of practice guidelines.

BACKGROUND: The Agency for Health Care Policy and Research (AHCPR) released a practice guideline on the diagnosis and management of unstable angina in 1994. OBJECTIVE: To examine practice variation across the age spectrum in the management of patients hospitalized with unstable angina 2 years before release of the AHCPR guideline. DESIGN: Retrospective cohort. SETTING: Urban academic hospital. PATIENTS: All nonreferral patients diagnosed as having unstable angina who were hospitalized directly from the emergency department to the intensive care or telemetry unit between October 1, 1991, and September 30, 1992. MEASUREMENTS: Percentage of eligible patients receiving medical treatment concordant with 8 important AHCPR guideline recommendations. RESULTS: Half of the 280 patients were older than 66 years; women were older than men on average (70 vs 64 years; P<.001). After excluding those with contraindications to therapy, patients in the oldest quartile (age, 75.20-93.37 years) were less likely than younger patients to receive aspirin (P<.009), beta-blockers (P<.04), and referral for cardiac catheterization (P<.001). Overall guideline concordance weighted for the number of eligible patients declined with increasing age (87.4%, 87.4%, 84.0%, and 74.9% for age quartiles 1 to 4, respectively; chi2, P<.001). Increasing age, the presence of congestive heart failure at presentation, a history of congestive heart failure, previous myocardial infarction, increasing comorbidity, and elevated creatinine concentration were associated with care that was less concordant with AHCPR guideline recommendations; only age and congestive heart failure at presentation remained significant in the multivariate analysis (odds ratios, 1.28 per decade [95% confidence interval, 1.02-1.61] and 3.16 [95% confidence interval, 1.57-6.36], respectively). CONCLUSIONS: Older patients were less likely to receive standard therapies for unstable angina before release of the 1994 AHCPR guideline. Patients presenting with congestive heart failure also received care that was more discordant with guideline recommendations. The AHCPR guideline allows identification of patients who receive nonstandard care and, if applied to those patients with the greatest likelihood to benefit, could lead to improved health care delivery.

Applicability of cholesterol-lowering primary prevention trials to a general population: the framingham heart study.

BACKGROUND: Four large trials have shown cholesterol-reduction therapy to be effective for primary prevention of coronary heart disease (CHD). METHODS: To determine the generalizability of these trials to a community-based sample, we compared the total cholesterol and high-density lipoprotein cholesterol (HDL-C) distributions of patients in the 4 trials with those of Framingham Heart Study subjects. Lipid profiles that have not been studied were identified. Twelve-year rates of incident CHD were compared between subjects who met eligibility criteria and those who did not. RESULTS: The Framingham sample included 2498 men and 2870 women aged 30 to 74 years. Among Framingham men, 23.4% to 42.0% met eligibility criteria for each of the 4 trials based on their lipid levels; 60.2% met eligibility criteria for at least 1 trial. For the 1 trial that included women, 20.2% of Framingham women met eligibility criteria. In general, subjects with desirable total cholesterol levels and lower HDL-C levels and subjects with average total cholesterol levels and average to higher HDL-C levels have not been included in these trials. Among subjects who developed incident CHD during follow-up, 25.1% of men and 66.2% of women would not have been eligible for any trial. Most ineligible subjects who developed CHD had isolated hypertriglyceridemia (>2.25 mmol/L [>200 mg/dL]). CONCLUSIONS: In our sample, 40% of men and 80% of women had lipid profiles that have not been studied in large trials to date. We observed a large number of CHD events in "ineligible" subjects in whom hypertriglyceridemia was common. Further studies are needed to define the role of lipid-lowering therapy vs other strategies for primary prevention in the general population.

Differential impact of systolic and diastolic blood pressure level on JNC-VI staging. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

The sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classifies blood pressure into stages on the basis of both systolic (SBP) and diastolic (DBP) blood pressure levels. When a disparity exists between SBP and DBP stages, patients are classified into the higher stage ("up-staged"). We evaluated the effect of disparate levels of SBP and DBP on blood pressure staging and eligibility for therapy. We examined 4962 Framingham Heart Study subjects between 1990 and 1995 and determined blood pressure stages on the basis of SBP alone, DBP alone, or both. After the exclusion of subjects on antihypertensive therapy (n=1306), 3656 subjects (mean age 58+/-13 years; 55% women) were eligible. In this sample, 64.6% of subjects had congruent stages of SBP and DBP, 31.6% were up-staged on the basis of SBP, and 3.8% on the basis of DBP; thus, SBP alone correctly classified JNC-VI stage in approximately 96% (64.6%+31.6%) of the subjects. Among subjects >60 years of age, SBP alone correctly classified 99% of subjects; in those