Karol M. Pencina

Carotid-Wall Intima-Media Thickness and Cardiovascular Events

BACKGROUND Intima-media thickness of the walls of the common carotid artery and internal carotid artery may add to the Framingham risk score for predicting cardiovascular events. METHODS We measured the mean intima-media thickness of the common carotid artery and the maximum intima-media thickness of the internal carotid artery in 2965 members of the Framingham Offspring Study cohort. Cardiovascular-disease outcomes were evaluated for an average follow-up of 7.2 years. Multivariable Cox proportional-hazards models were generated for intima-media thickness and risk factors. We evaluated the reclassification of cardiovascular disease on the basis of the 8-year Framingham risk score category (low, intermediate, or high) after adding intima-media thickness values. RESULTS A total of 296 participants had a cardiovascular event. The risk factors of the Framingham risk score predicted these events, with a C statistic of 0.748 (95% confidence interval [CI], 0.719 to 0.776). The adjusted hazard ratio for cardiovascular disease with a 1-SD increase in the mean intima-media thickness of the common carotid artery was 1.13 (95% CI, 1.02 to 1.24), with a nonsignificant change in the C statistic of 0.003 (95% CI, 0.000 to 0.007); the corresponding hazard ratio for the maximum intima-media thickness of the internal carotid artery was 1.21 (95% CI, 1.13 to 1.29), with a modest increase in the C statistic of 0.009 (95% CI, 0.003 to 0.016). The net reclassification index increased significantly after addition of intima-media thickness of the internal carotid artery (7.6%, P<0.001) but not intima-media thickness of the common carotid artery (0.0%, P=0.99). With the presence of plaque, defined as intima-media thickness of the internal carotid artery of more than 1.5 mm, the net reclassification index was 7.3% (P=0.01), with an increase in the C statistic of 0.014 (95% CI, 0.003 to 0.025). CONCLUSIONS The maximum internal and mean common carotid-artery intima-media thicknesses both predict cardiovascular outcomes, but only the maximum intima-media thickness of (and presence of plaque in) the internal carotid artery significantly (albeit modestly) improves the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort. (Funded by the National Heart, Lung, and Blood Institute.).

Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial.

IMPORTANCE Testosterone use in older men is increasing, but its long-term effects on progression of atherosclerosis are unknown. OBJECTIVE To determine the effect of testosterone administration on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels. DESIGN, SETTING, AND PARTICIPANTS Testosterones Effects on Atherosclerosis Progression in Aging Men (TEAAM) was a placebo-controlled, double-blind, parallel-group randomized trial involving 308 men 60 years or older with low or low-normal testosterone levels (100-400 ng/dL; free testosterone <50 pg/mL), recruited at 3 US centers. Recruitment took place between September 2004 and February 2009; the last participant completed the study in May 2012. INTERVENTIONS One hundred fifty-six participants were randomized to receive 7.5 g of 1% testosterone and 152 were randomized to receive placebo gel packets daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL. MAIN OUTCOMES AND MEASURES Coprimary outcomes included common carotid artery intima-media thickness and coronary artery calcium; secondary outcomes included sexual function and health-related quality of life. RESULTS Baseline characteristics were similar between groups: patients were a mean age of 67.6 years; 42% had hypertension; 15%, diabetes; 15%, cardiovascular disease; and 27%, obesity. The rate of change in intima-media thickness was 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group (mean difference adjusted for age and trial site, 0.0002 mm/year; 95% CI, -0.003 to 0.003, P = .89). The rate of change in the coronary artery calcium score was 41.4 Agatston units/year in the placebo group and 31.4 Agatston units/year in the testosterone group (adjusted mean difference, -10.8 Agatston units/year; 95% CI, -45.7 to 24.2; P = .54). Changes in intima-media thickness or calcium scores were not associated with change in testosterone levels among individuals assigned to receive testosterone. Sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life did not differ significantly between groups. Hematocrit and prostate-specific antigen levels increased more in testosterone group. CONCLUSIONS AND RELEVANCE Among older men with low or low-normal testosterone levels, testosterone administration for 3 years vs placebo did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium nor did it improve overall sexual function or health-related quality of life. Because this trial was only powered to evaluate atherosclerosis progression, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00287586.

Associations of Carotid Artery Intima-Media Thickness (IMT) With Risk Factors and Prevalent Cardiovascular Disease Comparison of Mean Common Carotid Artery IMT With Maximum Internal Carotid Artery IMT

Objective. The goal of this study was to compare internal carotid artery (ICA) intima‐media thickness (IMT) with common carotid artery (CCA) IMT as global markers of cardiovascular disease (CVD). Methods. Cross‐sectional measurements of the mean CCA IMT and maximum ICA IMT were made on ultrasound images acquired from the Framingham Offspring cohort (n = 3316; mean age, 58 years; 52.7% women). Linear regression models were used to study the associations of the Framingham risk factors with CCA and ICA IMT. Multivariate logistic regression models and receiver operating characteristic (ROC) curve analysis were used to compare the associations of prevalent CVD with CCA and ICA IMT and determine sensitivity and specificity. Results. The association between age and the mean CCA IMT corresponded to an increase of 0.007 mm/y; the increase was 0.037 mm/y for the ICA IMT. Framingham risk factors accounted for 28.6% and 27.5% of the variability in the CCA and ICA IMT, respectively. Age and gender contributed 23.5% to the variability of the CCA IMT and 22.5% to that of the ICA IMT, with the next most important factor being systolic blood pressure (1.9%) for the CCA IMT and smoking (1.6%) for the ICA IMT. The CCA IMT and ICA IMT were statistically significant predictors of prevalent CVD, with the ICA IMT having a larger area under the ROC curve (0.756 versus 0.695). Conclusions. Associations of risk factors with CCA and ICA IMT are slightly different, and both are independently associated with prevalent CVD. Their value for predicting incident cardiovascular events needs to be compared in outcome studies.

Association of Lifestyle Factors with Abdominal Subcutaneous and Visceral Adiposity: The Framingham Heart Study

OBJECTIVE— The purpose of this study was to assess the relationship between lifestyle factors and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based setting. RESEARCH DESIGN AND METHODS— Cross-sectional associations between lifestyle factors (dietary quality, physical activity, smoking, and alcohol consumption) and SAT and VAT volumes were examined in 2,926 Framingham Heart Study participants (48.6% women, aged 50 ± 10 years). RESULTS— Diets consistent with the 2005 Dietary Guidelines Adherence Index and greater physical activity were inversely associated with SAT and VAT (P < 0.0001–0.002). In men, former smoking was associated with higher SAT (2,743 ± 56 cm3) compared with current smokers (2,629 ± 88 cm3) or those who never smoked (2,538 ± 44 cm3; P = 0.02). Both former and current smoking was associated with higher VAT (P = 0.03 [women]; P = 0.005 [men]). Women with high amounts of alcohol intake (>7 drinks/week) had lower SAT (2,869 ± 106 cm3) than those who consumed less alcohol (3,184 ± 44 cm3, P = 0.006); significant differences in VAT were not observed (P = 0.18). In men, high amounts of alcohol intake (>14 drinks/week) were associated with higher VAT (2,272 ± 59 cm3) compared with intake of ≤14 drinks/week (2,139 ± 25 cm3, P = 0.04), whereas SAT did not differ (P = 0.91). An increasing number of healthy lifestyle factors were associated with lower SAT and VAT volumes (all P < 0.003). CONCLUSIONS— Adherence to recommended dietary guidelines and physical activity are associated with lower SAT and VAT volumes. However, both smoking and high alcohol intake are differentially associated with VAT volumes. Further research to uncover the putative mechanisms is warranted.

Hepatic steatosis and cardiovascular disease outcomes: An analysis of the Framingham Heart Study

BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and is associated with development of metabolic disease including atherosclerotic cardiovascular disease (CVD). Our aim is to examine the association of hepatic steatosis with prevalent clinical and subclinical CVD outcomes in a large community-based sample, the Framingham Heart Study. METHODS Hepatic steatosis was measured in 3529 participants using multidetector computed tomography scanning. Multivariable logistic regression was used to determine whether hepatic steatosis is associated with prevalent CVD adjusted for covariates. We also tested whether associations were independent of other metabolic diseases/traits. The primary clinical outcome was composite prevalent clinical CVD defined by prior non-fatal myocardial infarction, stroke, transient ischemic attack, heart failure, or peripheral arterial disease. Subclinical cardiovascular outcomes were coronary artery calcium (CAC) and abdominal artery calcium (AAC). RESULTS 3014 participants were included (50.5% women). There was a non-significant association of hepatic steatosis with clinical CVD (OR 1.14 [p=0.07]). Hepatic steatosis was associated with both CAC and AAC (OR 1.20 [p<0.001] and OR 1.16 [p<0.001], respectively). Associations persisted for CAC even when controlling for other risk factors/metabolic diseases, but for AAC, the associations became non-significant after adjustment for visceral adipose tissue. The association between hepatic steatosis and AAC was stronger in men than in women (p sex interaction=0.022). CONCLUSION There was a significant association of hepatic steatosis with subclinical CVD outcomes independent of many metabolic diseases/traits with a trend towards association between hepatic steatosis and clinical CVD outcomes. The association with AAC was stronger in men than in women.

Relations of Matrix Remodeling Biomarkers to Blood Pressure Progression and Incidence of Hypertension in the Community

Background— Biomarkers of extracellular matrix remodeling are associated with prevalent hypertension in cross-sectional studies, but their relations to longitudinal changes in blood pressure (BP) and hypertension incidence are unknown. Methods and Results— We evaluated 595 nonhypertensive Framingham Offspring Study participants (mean age 55 years; 360 women) without prior heart failure or myocardial infarction who underwent routine measurements of plasma tissue inhibitor of metalloproteinase-1 (TIMP-1), metalloproteinase-9 (MMP-9), and procollagen III N-terminal peptide. We related plasma TIMP-1, procollagen III N-terminal peptide, and MMP-9 to the incidence of hypertension and progression of BP by ≥1 category (defined on the basis of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure). On follow-up (4 years), 81 participants (51 women) developed hypertension, and 198 (114 women) progressed to a higher BP category. In multivariable models, a 1-SD increment of log-TIMP-1 was associated with a 50% higher incidence of hypertension (95% CI 1.08 to 2.08) and a 21% (95% CI 1.00 to 1.47) higher risk of BP progression. Individuals in the top TIMP-1 tertile had a 2.15-fold increased risk of hypertension (95% CI 0.99 to 4.68) and 1.68-fold (95% CI 1.05 to 2.70) increased risk of BP progression relative to the lowest tertile. Individuals with detectable MMP-9 had a 1.97-fold higher risk of BP progression (95% CI 1.06 to 3.64) than those with undetectable levels. Plasma procollagen III N-terminal peptide was not associated with hypertension incidence or BP progression. Conclusions— In the present community-based sample, higher TIMP-1 and MMP-9 concentrations were associated with BP progression on follow-up. Additional studies are warranted to confirm our findings.

Risk Estimation for Recurrent Clostridium difficile Infection Based on Clinical Factors

BACKGROUND The incidence of Clostridium difficile infection (CDI) has risen dramatically during the last decade. Although patients respond well to medical therapy such as vancomycin, 20%-30% of patients treated suffer a recurrence of CDI. METHODS We developed a simple/practical scoring rule (logistic regression model) for recurrent CDI using data from 2 large phase 3 clinical trials. Seventy-seven baseline CDI factors were classified: demographics, comorbidity, medications, vital signs, laboratory tests, severity, and symptoms. Predictors with the highest discrimination in each class (using receiver operating characteristics curve) were selected. For the final model, stepwise selection was performed. Discrimination, calibration, and internal validation were used to assess the model. RESULTS The final model with a simple scoring rule was developed. It includes 4 independent risk factors that are readily available when the patient makes initial contact: age (<75 vs ≥75 years), number of unformed bowel movements during previous 24 hours (<10 vs ≥10), serum creatinine leves (<1.2 mg/dL vs ≥1.2 mg/dL) and prior episode of CDI (yes vs no). In addition, the model includes choice of treatment (vancomycin or fidaxomicin). CONCLUSIONS The prediction model for recurrence may be useful for treatment decision. CLINICAL TRIALS REGISTRATION NCT00314951 and NCT00468728.

Trends in Diabetes Incidence: The Framingham Heart Study

OBJECTIVE Obesity and type 2 diabetes continue to increase in prevalence in the U.S. Whether diabetes incidence continues to increase in recent times is less well documented. We examined trends in diabetes incidence over the previous four decades. RESEARCH DESIGN AND METHODS Framingham Heart Study participants ages 40–55 years and free of diabetes at baseline (n = 4,795; mean age 45.3 years; 51.6% women) were followed for the development of diabetes in the 1970s, 1980s, 1990s, and 2000s. Diabetes was defined as either fasting glucose ≥126 mg/dL or use of antidiabetes medication. Poisson regression was used to calculate sex-specific diabetes incidence rates for a 47-year-old individual in each decade. Rates were also calculated among obese, overweight, and normal weight individuals. RESULTS The annualized rates of diabetes per 1,000 individuals were 2.6, 3.8, 4.7, and 3.0 (women) and 3.4, 4.5, 7.4, and 7.3 (men) in the 1970s, 1980s, 1990s, and 2000s, respectively. Compared with the 1970s, the age- and sex-adjusted relative risks of diabetes were 1.37 (95% CI 0.87–2.16; P = 0.17), 1.99 (95% CI 1.30–3.03; P = 0.001), and 1.81 (95% CI 1.16–2.82; P = 0.01) in the 1980s, 1990s, and 2000s, respectively. Compared with the 1990s, the relative risk of diabetes in the 2000s was 0.85 (95% CI 0.61–1.20; P = 0.36). CONCLUSIONS In our community-based sample, the risk of new-onset diabetes continued to be higher in the 2000s compared with the 1970s. In the past decade, diabetes incidence remained steady despite the ongoing trend of rising adiposity.

Effects of Testosterone Supplementation for 3-Years on Muscle Performance and Physical Function in Older Men.

Context: Findings of studies of testosterone’s effects on muscle strength and physical function in older men have been inconsistent; its effects on muscle power and fatigability have not been studied. Objective: To determine the effects of testosterone administration for 3 years in older men on muscle strength, power, fatigability, and physical function. Design, Setting, and Participants: This was a double-blind, placebo-controlled, randomized trial of healthy men ≥60 years old with total testosterone levels of 100 to 400 ng/dL or free testosterone levels <50 pg/mL. Interventions: Random assignment to 7.5 g of 1% testosterone or placebo gel daily for 3 years. Outcome Measures: Loaded and unloaded stair-climbing power, muscle strength, power, and fatigability in leg press and chest press exercises, and lean mass at baseline, 6, 18, and 36 months. Results: The groups were similar at baseline. Testosterone administration for 3 years was associated with significantly greater performance in unloaded and loaded stair-climbing power than placebo (mean estimated between-group difference, 10.7 W [95% confidence interval (CI), −4.0 to 25.5], P = 0.026; and 22.4 W [95% CI, 4.6 to 40.3], P = 0.027), respectively. Changes in chest-press strength (estimated mean difference, 16.3 N; 95% CI, 5.5 to 27.1; P < 0.001) and power (mean difference 22.5 W; 95% CI, 7.5 to 37.5; P < 0.001), and leg-press power were significantly greater in men randomized to testosterone than in those randomized to placebo. Lean body mass significantly increased more in the testosterone group. Conclusion: Compared with placebo, testosterone replacement in older men for 3 years was associated with modest but significantly greater improvements in stair-climbing power, muscle mass, and power. Clinical meaningfulness of these treatment effects and their impact on disability in older adults with functional limitations remains to be studied.

Prevalence, Clinical Correlates, and Prognosis of Discrete Upper Septal Thickening on Echocardiography: The Framingham Heart Study

The upper interventricular septum may be prominent in elderly individuals, a finding referred to as discrete upper septal thickening (DUST). We examined the prevalence, clinical and echocardiographic correlates, and prognostic significance of DUST in a community‐based sample. We evaluated Framingham Study participants who underwent routine echocardiography. In 3562 Framingham Study participants (mean age 58 years, 57% women), DUST was observed in 52 participants. The clinical correlates of DUST were increasing age (odds ratio [OR] per 10 year increment 2.59, 95% confidence intervals [CI] 1.64–4.08) and systolic blood pressure (OR per SD increment 1.55, 95% CI 1.15–2.09). DUST was positively associated with left ventricular (LV) fractional shortening and mitral annular calcification but inversely with LV diastolic dimensions (P < 0.02 for all). On follow‐up (mean 15 years), 732 individuals died (33 with DUST) and 560 experienced a cardiovascular disease (CVD) event (18 with DUST). Adjusting for cardiovascular risk factors, DUST was not associated with CVD or mortality risk (P > 0.30 for both). The follow‐up component of our study suggests that DUST is not independently associated with adverse prognosis.