Inhaled hypertonic saline is recommended as therapy for cystic fibrosis (CF) patients 6 years of age and older, but its efficacy has never been evaluated in CF patients <6 years of age.
To determine if hypertonic saline reduces the rate of protocol-defined pulmonary exacerbations in CF patients <6 years of age.
Design and Setting
A multicenter, randomized, double-blind placebo-controlled trial was conducted from April 2009 to October 2011 at 30 CF care centers in the United States and Canada.
Participants had an established diagnosis of CF and were 4 to 60 months of age. A total of 344 patients were assessed for eligibility; 321 participants were randomized; 29 (9%) withdrew prematurely.
The active group (n=158) received 7% hypertonic saline and the control group (n=163) received 0.9% isotonic saline nebulized twice daily for 48 weeks. Both groups received albuterol or levalbuterol prior to each study drug dose.
Main Outcome Measures
the rate of protocol-defined pulmonary exacerbations during the 48 week treatment period treated with oral, inhaled or intravenous antibiotics.
The mean pulmonary exacerbation rate (events/person-year) was 2.3 (95% CI, 2.0, 2.5) in the hypertonic saline group and 2.3 (95% CI, 2.1, 2.6) in the isotonic saline group; the rate ratio was 0.98 (95% CI, 0.84, 1.14)). Among participants with pulmonary exacerbations, the mean number of total antibiotic treatment days for a pulmonary exacerbation was 60 (95% CI 49, 70) in the hypertonic saline group and 52 (95% CI 43, 61) in the isotonic saline group. There was no significant difference in secondary endpoints including height, weight, respiratory rate, oxygen saturation, cough or respiratory symptom scores. Infant pulmonary function testing performed as an exploratory outcome in a subgroup (N=73, with acceptable measurements at 2 visits in 45) did not demonstrate significant differences between groups except for the mean change in forced expiratory volume in 0.5 seconds which was 38 ml greater (95% CI 1, 76) in the hypertonic saline group.
Adherence by returned study drug ampoules was at least 75% in each group. Adverse event profiles were also similar, with the most common adverse event of moderate or severe severity in each group being cough (39% of hypertonic saline group, 38% of isotonic saline group).
Among infants and children with cystic fibrosis less than 6 years old, the use of inhaled hypertonic saline compared with isotonic saline did not reduce the rate of pulmonary exacerbations over 48 weeks of treatment.
The risk of pulmonary exacerbation following Pseudomonas aeruginosa (Pa) acquisition in children with cystic fibrosis (CF) is unknown.
To determine if failure of antibiotic therapy to eradicate Pa and frequency of Pa recurrence are associated with increased exacerbation risk.
The cohort included 282 children with CF who participated in the EPIC trial ages 1–12 with newly acquired Pa, defined as either a first lifetime Pa positive respiratory culture or positive after two years of negative cultures (past isolation of Pa but >2 years prior to the trial). All received antibiotics to promote initial eradication followed by 15 months of intermittent maintenance antibiotics. Quarterly cultures were used to define initial eradication success and subsequent number of Pa recurrences. A standardized symptom-based definition of exacerbation was utilized. Cox proportional hazards models were used to estimate exacerbation risk.
Failure to initially eradicate Pa was associated with exacerbation risk (hazard ratio [HR]: 2.49, 95% confidence interval [CI] 1.26,4.93). In 245/282 with successful initial eradication during the trial, past isolation of Pa >2 years before the trial was the most significant predictor of exacerbation (HR 1.62, 95% CI 1.12,2.35). In 37/282 who failed initial eradication, persistent Pa during the maintenance phase (1 or more Pa recurrences after failure to initially eradicate) added even greater exacerbation risk (HR 4.13, 95% CI 1.28, 13.32).
Children with CF who fail to eradicate after initial antibiotic treatment are at higher risk of subsequent exacerbation, suggesting clinical benefit to successful early eradication of Pa infection.
New acquisition; early intervention; eradication; clinical outcome
Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.
arteries; cardiovascular diseases; elasticity; risk factors
Extent of atherosclerosis measured by amount of coronary artery calcium (CAC) in computed tomography (CT) has been traditionally assessed using thresholded scoring methods, such as the Agatston score (AS). These thresholded scores have value in clinical prediction, but important information might exist below the threshold, which would have important advantages for understanding genetic, environmental, and other risk factors in atherosclerosis. We developed a semi-automated threshold-free scoring method, the spatially weighted calcium score (SWCS) for CAC in the Multi-Ethnic Study of Atherosclerosis (MESA).
Chest CT scans were obtained from 6814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The SWCS and the AS were calculated for each of the scans. Cox proportional hazards models and linear regression models were used to evaluate the associations of the scores with CHD events and CHD risk factors. CHD risk factors were summarized using a linear predictor.
Among all participants and participants with AS > 0, the SWCS and AS both showed similar strongly significant associations with CHD events (hazard ratios, 1.23 and 1.19 per doubling of SWCS and AS; 95% CI, 1.16 to 1.30 and 1.14 to 1.26) and CHD risk factors (slopes, 0.178 and 0.164; 95% CI, 0.162 to 0.195 and 0.149 to 0.179). Even among participants with AS = 0, an increase in the SWCS was still significantly associated with established CHD risk factors (slope, 0.181; 95% CI, 0.138 to 0.224). The SWCS appeared to be predictive of CHD events even in participants with AS = 0, though those events were rare as expected.
The SWCS provides a valid, continuous measure of CAC suitable for quantifying the extent of atherosclerosis without a threshold, which will be useful for examining novel genetic and environmental risk factors for atherosclerosis.
Background and Purpose
Little is known about acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with short-term risk of stroke.
The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days prior to incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years prior to stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios and 95% confidence intervals (OR, 95% CI) were calculated using conditional logistic regression. Confirmatory analyses assessed hazard ratios (HR) of stroke from Cox regression models with hospitalization for infection as a time-varying exposure.
During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days prior to stroke, OR=3.4 (95% CI 1.8–6.5). The point estimates of risks were higher when examining shorter intervals: for 30 days, OR= 7.3 (95% CI 1.9–40.9), and 14 days, OR=8.0 (95% CI 1.7–77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted HR=2.4 (95% CI 1.6–3.4).
Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.
Epidemiology; Cerebral Infarction; Infectious Diseases
Right ventricular (RV) morphology is an important predictor of outcomes in heart and lung disease, however determinants of RV anatomy have not been well-studied. We examined the demographic factors associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease.
Methods and Results
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging (MRI) on 5098 participants. RV volumes and mass were available for 4204 participants. Normative equations for RV parameters were derived using an allometric approach. The study sample (N = 4123) was 61.5 ± 10.1 years old and 47.5% male. Older age was associated with lower RV mass (~5% lower mass per decade) with larger age-related decrements in men than in women (p for interaction < 0.05). Older age was also associated with higher RV ejection fraction (RVEF), an association which differed between races/ethnicities (p for interaction ≤ 0.01). Overall, men had greater RV mass (~8%) and larger RV volumes than women, but had lower RVEF (4% in absolute terms) (p < 0.001). African Americans had lower RV mass than Caucasians (p ≤ 0.002), whereas Hispanics had higher RV mass (p ≤ 0.02). Using the derived normative equations, 7.3% (95%CI, 6.5–8.1%) met criteria for RV hypertrophy and 5.9% (95%CI, 5.2–6.6%) had RV dysfunction.
In conclusion, age, sex, and race are associated with significant differences in RV mass, RV volumes and RVEF, potentially explaining distinct responses of the RV to cardiopulmonary disease.
right ventricle; pulmonary heart disease; magnetic resonance imaging; pulmonary hypertension
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
Alcohol use has been consistently found to have a J-shaped association with coronary heart disease, with moderate drinkers exhibiting a decreased risk compared to both heavy drinkers and non-drinkers. However, studies of the association between alcohol use and subclinical coronary artery disease have conflicted.
To determine whether alcohol is associated with the presence, amount, or progression of coronary calcium over a 2- to 4-year period.
MESA is a prospective community-based cohort study of subclinical cardiovascular disease in a multi-ethnic cohort. In 2000–2002, 6814 participants free of clinical cardiovascular disease were enrolled at 6 participating centers.
There were 3766 (55.5%) current drinkers, 1635 (24.1%) former drinkers, and 1390 (20.5%) never drinkers included in the analysis. Although light to moderate alcohol consumption was associated with lower coronary heart disease risk, we found no evidence of a protective or J-shaped association of alcohol and coronary artery calcium (CAC). In fact there was evidence that heavy consumption of hard liquor was associated with greater CAC accumulation. Other alcoholic beverages were not associated with CAC prevalence, incidence or progression.
This is the first large study to evaluate the association of alcohol and coronary artery calcium in four racial/ethnic groups, and to evaluate progression of calcification. These results suggest that the cardiovascular benefits that may be derived from light to moderate alcohol consumption are not mediated through reduced CAC accumulation.
Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent.
We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992–1993 and survived through 1997–1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews.
A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22–2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32–5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95–3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant.
These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.
Telomere; Mortality; Cause of death; Cardiovascular disease; Heart failure
We sought to determine whether insulin resistance predicts the incidence and progression of coronary artery calcification (CAC).
RESEARCH DESIGN AND METHODS
We studied 5,464 participants not on hypoglycemic therapy from the Multi-Ethnic Study of Atherosclerosis (MESA). Each had baseline homeostasis model assessment of insulin resistance (HOMA-IR) and baseline and follow-up CAC scores. Incident CAC was defined as newly detectable CAC; progression was defined as advancing CAC volume score at follow-up.
Median HOMA-IR was 1.2 (0.8–2.0). Across all ethnicities, there was a graded increase in CAC incidence and progression with increasing HOMA-IR. When compared with those in the 1st quartile, participants in the 2nd–4th quartiles had 1.2, 1.5, and 1.8 times greater risk of developing CAC. Median annualized CAC score progression was 8, 14, and 17 higher, respectively. However, HOMA-IR was not predictive after adjustment for metabolic syndrome components.
HOMA-IR predicts CAC incidence and progression, but not independently of metabolic syndrome.
Skeletal muscle (SM) mass decreases with advanced age and with disease in HIV infection. It is unknown whether age-related muscle loss is accelerated in the current era of antiretroviral therapy and which factors might contribute to muscle loss among HIV-infected adults. We hypothesized that muscle mass would be lower and decline faster in HIV-infected adults than in similar-aged controls.
Whole-body 1H-magnetic resonance imaging was used to quantify regional and total SM in 399 HIV-infected and 204 control men and women at baseline and 5 years later. Multivariable regression identified associated factors.
At baseline and Year 5, total SM was lower in HIV-infected than control men. HIV-infected women were similar to control women at both time points. After adjusting for demographics, lifestyle factors, and total adipose tissue, HIV infection was associated with lower Year 5 SM in men and higher SM in women compared with controls. Average overall 5-year change in total SM was small and age related, but rate of change was similar in HIV-infected and control men and women. CD4 count and efavirenz use in HIV-infected participants were associated with increasing SM, whereas age and stavudine use were associated with decreasing SM.
Muscle mass was lower in HIV-infected men compared with controls, whereas HIV-infected women had slightly higher SM than control women after multivariable adjustment. We found evidence against substantially faster SM decline in HIV infected versus similar-aged controls. SM gain was associated with increasing CD4 count, whereas stavudine use may contribute to SM loss.
Sarcopenia; Lipoatrophy; Fat redistribution; Body composition
Rationale: Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.
Objectives: We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease.
Methods: Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.
Measurements and Main Results: Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], −0.87; 95% CI, −1.67 to −0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.
Conclusions: Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
sex; sex hormones; right ventricle
Three types of non-steroidal anti-inflammatory drugs (NSAIDs) can be obtained both over the counter (OTC) and by prescription in the United States. OTC NSAID use is not recorded in prescription claims databases; this might lead to differential misclassification of NSAID exposure status in studies that use computerized pharmacy databases to study NSAID use.
To evaluate characteristics of OTC versus prescription NSAID users
This analysis is set within the Multi-Ethnic Study of Atherosclerosis (MESA) study; a prospective cohort study of 6,814 adults from 4 ethnic groups (European descent, Asian, African-American and Hispanic) with a mean age of 62 years. The cohort was restricted to those who initiated NSAID use (aspirin, ibuprofen or naproxen) during follow-up. We compared information about age, sex, ethnicity, body mass index, smoking, diabetes, medication use, education, income, health insurance status and exercisebetween groups.
OTC NSAID use was prevalent at baseline (25% Aspirin, 9% Ibuprofen, 2% Naproxen). Compared to prescribed NSAID use, OTC NSAID use was lower for users of non-European descent for all classes: aspirin (p<0.0001), ibuprofen (p<0.0001) and naproxen (p=0.0094). For aspirin, differences were seen for male gender (Relative Risk (RR):0.92; 95%(Confidence interval) CI:0.86–0.98), use of lipid lowering drugs (RR:0.88; 95% CI: 0.80–0.96), low income (RR:0.89; 95%CI:0.81–0.97), and participants one standard deviation above average in intentional exercise (RR:1.03; 95%CI:1.01–1.05).
OTC NSAID use is prevalent in an older multi-ethnic population and OTC users differ from prescription NSAID users. Caution should be exercised when using prescribed NSAIDs as a proxy for NSAID use.
Aspirin; over the counter drug use; ethnicity; Multi-Ethnic Study of Atherosclerosis
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
To identify HIV-related risk factors for increased cIMT.
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other race/ethnic groups.
We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n=4764 participants) and two geographically and ethnically diverse cohorts: AGES (Age, Gene/Environment Susceptibility-Reykjavik Study, n=4238), and CHS (Cardiovascular Health Study, n=5410 of whom 874 (16.2%) were African Americans (AA)); aged 45–95 years. The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR-interval, hypertension treatment, and heart failure.
We observed 1359 incident AF events in 100,074 person-years of follow-up. Unadjusted five-year event-rates differed by cohort (AGES 12.8 cases/1000 person-years; CHS whites 22.7 cases/1000 person-years; FHS 4.5 cases/1000 person-years) and race/ethnicity (CHS AA 18.4 cases/1000 person-years).
The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm performed reasonably well in all samples (AGES C-statistic 0.67, 95% confidence interval 0.64–0.71; CHS whites, 0.68, 0.66–0.70; CHS AA 0.66, 0.61–0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population attributable risk.
Risk of incident AF in community-dwelling whites and AA can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% percent of risk.
atrial fibrillation; risk score; epidemiology; cohort study; race/ethnicity
To determine whether nitrogen-containing bisphosphonate (NCBP) therapy is associated with the prevalence of cardiovascular calcification.
Cardiovascular calcification correlates with atherosclerotic disease burden. Experimental data suggest that NCBP may limit cardiovascular calcification, which has implications for disease prevention.
The relationship of NCBP use to the prevalence of aortic valve, aortic valve ring, mitral annulus, thoracic aorta, and coronary artery calcification (AVC, AVRC, MAC, TAC, and CAC, respectively) detected by computed tomography was assessed in 3,636 women within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling.
Analyses were age-stratified because of a significant interaction between age and NCBP use (interaction p-values: AVC p<0.0001; AVRC p<0.0001; MAC p=0.002; TAC p<0.0001; CAC p=0.046). After adjusting for age, body mass index, demographics, diabetes, smoking, blood pressure, cholesterol levels, and statin, hormone replacement, and renin-angiotensin inhibitor therapy, NCBP use was associated with a lower prevalence of cardiovascular calcification in women ≥65 years old (prevalence ratio [95% confidence interval]: AVC 0.68 [0.41, 1.13]; AVRC 0.65 [0.51, 0.84]; MAC 0.54 [0.33, 0.93]; TAC 0.69 [0.54, 0.88]; CAC 0.89 [0.78, 1.02]), whereas calcification was more prevalent in NCBP users among the 2,181 women <65 years old (AVC 4.00 [2.33, 6.89]; AVRC 1.92 [1.42, 2.61]; MAC 2.35 [1.12, 4.84]; TAC 2.17 [1.49, 3.15]; CAC 1.23 [0.97, 1.57]).
Among women in the diverse MESA cohort, NCBPs were associated with decreased prevalence of cardiovascular calcification in older subjects, but more prevalent cardiovascular calcification in younger ones. Further study is warranted to clarify these age-dependent NCBP effects.
bisphosphonate; calcification; coronary artery; valve; vascular
Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065–0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205–0.303) to +0.192 mm (95% CI:0.076–0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.
Carotid intima media thickness; Measurement error; Bias; Carotid ultrasonography
The need for left ventricular mass (LVM) normalization to body size is well recognized. Currently used allometric exponents to normalize LVM may not account for the confounding effect of gender. Since gender is a strong determinant of body size and LVM, we hypothesized that these are subject to potential bias. We analyzed data from 7,528 subjects enrolled in the Asklepios study (n=2,524) and the Multiethnic Study of Atherosclerosis (MESA limited access dataset; n=5,004) in order to assess metric relationships between LVM and body size, generate normative data for indexed LVM and compare the ability of normalization methods to predict cardiovascular events. The allometric exponent that adequately described the LVM-body height relationship was 1.7 in both studies and significantly different from both the unity and 2.7, whereas the LVM-BSA relationship was approximately linear. LVM/height2.7 consistently demonstrated important residual relationships with body height and systematically misclassified subjects regarding the presence of LVH. LVH defined by LVM/height1.7 was more sensitive than LVM/BSA to identify obesity-related LVH and was most consistently associated with cardiovascular events and all-cause death. In contrast to current assumptions, LVM/height2.7 is not an adequate method to normalize LV mass for body size. We provide more appropriate normalization methods, normative data by 2-D-echocardiography and gradient-echo cardiac MRI, and cut-offs for defining LVH, along with prognostic validation data.
left ventricular mass; body size; allometric
Methods to index left ventricular (LV) mass, measured by cardiovascular magnetic resonance (CMR), for body size have not been investigated. The purposes of this study were to develop allometric indices for LV mass measured by CMR and compare estimates of the prevalence and predictive value of LV hypertrophy defined by a new allometric height-weight index, LV mass/body surface area (BSA), height indices (a new allometric height index; and previously derived indices from echocardiographic measurements: LV mass/height2, LV mass/height2.7), and non-indexed LV mass. 5,004 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with CMR measurements of LV mass and no clinical cardiovascular disease at baseline were followed for a median of 4.1 years. The new indices and limits for hypertrophy (95th percentile) were derived from 822 normal-weight, normotensive, non-diabetic MESA participants. 107 events (coronary heart disease or stroke) were observed. The estimated prevalence of hypertrophy at baseline and hazard ratio for event associated with hypertrophy were 8% and 2.4 with the new allometric height-weight index, 11% and 2.2 with LV mass/BSA, 23–24% and 2.0–2.1 with height indices, and 20% and 1.7 with non-indexed LV mass. A statistically significant difference was detected between the hazard ratios based on the new height-weight index and non-indexed LV mass. The prevalence of hypertrophy is higher for indices that do not account for weight. The predictive value of hypertrophy is significantly better with the new allometric height-weight index than with non-indexed LV mass and may be better than indices without weight.
Cardiovascular risk; Hypertension; Hypertrophy; LV mass index; Magnetic resonance imaging; Obesity
Aortic valve calcium (AVC) is common among older adults and shares epidemiologic and histopathologic similarities to atherosclerosis. However, prospective studies have failed to identify meaningful risk-associations with incident (“new”) AVC or its progression. In this study, AVC was quantified from serial computed tomography (CT) images in 5,880 participants (aged 45–84 years) of the Multi-Ethnic Study of Atherosclerosis, using Agatston methodology. Multivariate backwards selection modeling was used to identify risk factors for incident AVC and AVC progression. During a mean follow up of 2.4±0.9 years, 210 subjects (4.0%) developed incident AVC. The incidence rate (mean 1.7 %/year) increased significantly with age (p<0.001). Risk factors for incident AVC included age, male gender, BMI, current smoking, and the use of lipid lowering and antihypertensive medications. Among those with AVC at baseline, the median rate of AVC progression was 2 Agatston units/year [IQR −21, 37]. Baseline Agatston score was a strong, independent predictor of progression, especially among those with high calcium scores at baseline. In conclusion, in this ethnically diverse, pre-clinical cohort, the rate of incident AVC a significantly with age. Incident AVC risk was associated with several traditional cardiovascular risk factors, specifically age, male gender, BMI, current smoking, and the use of both antihypertensive and lipid lowering medications. AVC progression risk was associated with male gender and the baseline Agatston score. Additional research is needed to determine if age- and stage-specific mechanisms underlie risk for AVC progression.
valves; calcium; risk factors; epidemiology; imaging
The purpose of this study was to evaluate the relationship of left ventricular (LV) remodeling assessed by cardiac magnetic resonance to various measures of obesity in a large population-based study.
Obesity is a well-known risk factor for cardiovascular disease, yet its relationship with LV size and function is poorly understood.
A total of 5,098 participants (age 45 to 84 years; 48% men) in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cardiovascular disease underwent cardiac magnetic resonance to assess LV size and function as well as measures of obesity, including body mass index, waist-to-hip ratio and waist circumference, and cardiovascular risk factors. Fat mass (FM) was estimated based on height-weight models derived from bioelectrical impedance studies. The associations of obesity measures with LV size and function were evaluated using linear spline regression models for body mass index and multivariable regression models for other measures of obesity; they were displayed graphically using generalized additive models.
LV mass and end-diastolic volume were positively associated with measures of obesity in both sexes after adjustment for risk factors (e.g., 5.7-g and 6.9-g increase in LV mass per 10-kg increase in FM in women and men, respectively [p < 0.001]). LV mass-to-volume ratio was positively associated with increased body mass index, waist-to-hip ratio, waist circumference, and estimated FM (e.g., 0.02-g/ml and 0.06-g/ml increase in mass-to-volume ratio per 10-kg increase in FM in women and men, respectively [p < 0.001]). The increased mass-to-volume ratio was due to a greater increase in LV mass relative to LV end-diastolic volume. All associations were stronger for men than for women. Ejection fraction showed no significant association with measures of obesity.
Obesity was associated with concentric LV remodeling without change in ejection fraction in a large, multiethnic cohort study.
cardiac magnetic resonance; cardiac morphology; epidemiology; left ventricular function; obesity
The relationship between incident congestive heart failure (CHF) and ethnicity as well as racial/ethnic differences in the mechanisms leading to CHF have not been demonstrated in a multiracial, population-based study. Our objective was to evaluate the relationship between race/ethnicity and incident CHF.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study of 6814 participants of 4 ethnicities: white (38.5%), African American (27.8%), Hispanic (21.9%), and Chinese American (11.8%). Participants with a history of cardiovascular disease at baseline were excluded. Cox proportional hazards models were used for data analysis.
During a median follow-up of 4.0 years, 79 participants developed CHF (incidence rate: 3.1 per 1000 person-years). African Americans had the highest incidence rate of CHF, followed by Hispanic, white, and Chinese American participants (incidence rates: 4.6, 3.5, 2.4, and 1.0 per 1000 person-years, respectively). Although risk of developing CHF was higher among African American compared with white participants (hazard ratio, 1.8; 95% confidence interval, 1.1-3.1), adding hypertension and/or diabetes mellitus to models including ethnicity eliminated statistical ethnic differences in incident CHF. Moreover, African Americans had the highest proportion of incident CHF not preceded by clinical myocardial infarction (75%) compared with other ethnic groups (P = .06).
The higher risk of incident CHF among African Americans was related to differences in the prevalence of hypertension and diabetes mellitus as well as socioeconomic status. The mechanisms of CHF also differed by ethnicity; interim myocardial infarction had the least influence among African Americans, and left ventricular mass increase had the greatest effect among Hispanic and white participants.
To examine the prevalence of left ventricular hypertrophy (LVH) and LV remodeling patterns within Hispanic subgroups compared with non-Hispanic whites in the Multi-Ethnic Study of Atherosclerosis.
Hispanics are the largest and fastest growing ethnic minority in the United States but there are no data on LVH and LV geometry among Hispanic subgroups.
Cardiac magnetic resonance imaging was performed in 4309 men and women aged 45 to 84 years without clinical cardiovascular disease. Hispanics were categorized into subgroups based on self-reported ancestry. LVH was defined as the upper 95th percentile of indexed LV mass in a reference normotensive, non-diabetic, non-obese population, and LV remodeling according to the presence/absence of LVH and abnormal/normal LV mass to LV end-diastolic volume ratio.
Among Hispanic participants, 574 were of Mexican, 329 were of Caribbean, and 161 were of Central/South American origin. On unadjusted analysis, only Caribbean-origin Hispanics (PR 1.2 [95% CI, 1.03–1.4]) had greater prevalence of hypertension than non-Hispanic whites. Hispanic subgroups were more likely to have LVH than non-Hispanic whites after adjustment for hypertension and other covariates (Caribbean-origin Hispanics: OR 1.8 [95% CI 1.1–3.0]; Mexican-origin Hispanics: OR 2.2 [95% CI 1.4–3.3]; Central/South Americans: OR 1.5 [95% CI 0.7–3.1]). All Hispanic subgroups also had a higher prevalence of concentric and eccentric hypertrophy compared to non-Hispanic whites (P<0.001).
Caribbean-origin Hispanics had a higher prevalence of LVH and abnormal LV remodeling compared to non-Hispanic whites. A higher prevalence of LVH and abnormal LV remodeling was also observed among Mexican-origin Hispanics despite a lower prevalence of hypertension. Differences among Hispanic subgroups regarding LVH and LV remodeling should be taken into account when evaluating cardiovascular risk in this population.
hypertension; hypertrophy; remodeling; epidemiology; Hispanics; magnetic resonance imaging