Christopher T. Sibley

Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate-Risk Individuals

CONTEXT Risk markers including coronary artery calcium, carotid intima-media thickness, ankle-brachial index, brachial flow-mediated dilation, high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score (FRS) for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort. OBJECTIVE We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate-risk participants (FRS >5%-<20%) in the Multi-Ethnic Study of Atherosclerosis (MESA). DESIGN, SETTING, AND PARTICIPANTS Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Probability-weighted Cox proportional hazard models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement were used to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. MAIN OUTCOME MEASURES Incident CHD defined as myocardial infarction, angina followed by revascularization, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death. RESULTS After 7.6-year median follow-up (IQR, 7.3-7.8), 94 CHD and 123 CVD events occurred. Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independently associated with incident CHD in multivariable analyses (HR, 2.60 [95% CI, 1.94-3.50]; HR, 0.79 [95% CI, 0.66-0.95]; HR, 1.28 [95% CI, 1.00-1.64]; and HR, 2.18 [95% CI, 1.38-3.42], respectively). Carotid intima-media thickness and brachial flow-mediated dilation were not associated with incident CHD in multivariable analyses (HR, 1.17 [95% CI, 0.95-1.45] and HR, 0.95 [95% CI, 0.78-1.14]). Although addition of the markers individually to the FRS plus race/ethnicity improved AUC, coronary artery calcium afforded the highest increment (0.623 vs 0.784), while brachial flow-mediated dilation had the least (0.623 vs 0.639). For incident CHD, the net reclassification improvement with coronary artery calcium was 0.659, brachial flow-mediated dilation was 0.024, ankle-brachial index was 0.036, carotid intima-media thickness was 0.102, family history was 0.160 and high-sensitivity CRP was 0.079. Similar results were obtained for incident CVD. CONCLUSIONS Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independent predictors of incident CHD/CVD in intermediate-risk individuals. Coronary artery calcium provided superior discrimination and risk reclassification compared with other risk markers.

High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis)

OBJECTIVES The purpose of this study was to evaluate independent associations of high-density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary heart disease (CHD). BACKGROUND HDL-C is inversely related to CHD, and also to triglycerides, low-density lipoprotein particles (LDL-P), and related metabolic risk. HDL-P associations with CHD may be partially independent of these factors. METHODS In a multiethnic study of 5,598 men and women ages 45 to 84 years old, without baseline CHD, excluding subjects on lipid-lowering medications, triglycerides >400 mg/dl, or missing values, we evaluated associations of HDL-C and nuclear magnetic resonance spectroscopy-measured HDL-P with cIMT and incident CHD (myocardial infarction, CHD death, and angina, n = 227 events; mean 6.0 years follow-up). All models were adjusted for age, sex, ethnicity, hypertension, and smoking. RESULTS HDL-C and HDL-P correlated with each other (ρ = 0.69) and LDL-P (ρ = -0.38, -0.25, respectively, p < 0.05 for all). For (1 SD) higher HDL-C (15 mg/dl) or HDL-P (6.64 μmol/l), cIMT differences were - 26.1 (95% confidence interval [CI]: -34.7 to -17.4) μm and -30.1 (95% CI: -38.8 to - 21.4) μm, and CHD hazard ratios were 0.74 (95% CI: 0.63 to 0.88) and 0.70 (95% CI: 0.59 to 0.82), respectively. Adjusted for each other and LDL-P, HDL-C was no longer associated with cIMT (2.3; 95% CI: - 9.5 to 14.2 μm) or CHD (0.97; 95% CI: 0.77 to 1.22), but HDL-P remained independently associated with cIMT (-22.2; 95% CI: - 33.8 to -10.6 μm) and CHD (0.75; 95% CI: 0.61 to 0.93). Interactions by sex, ethnicity, diabetes, and high-sensitivity C-reactive protein were not significant. CONCLUSIONS Adjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL-related risk.

T1 Mapping in Cardiomyopathy at Cardiac MR: Comparison with Endomyocardial Biopsy

PURPOSE To determine the utility of cardiac magnetic resonance (MR) T1 mapping for quantification of diffuse myocardial fibrosis compared with the standard of endomyocardial biopsy. MATERIALS AND METHODS This HIPAA-compliant study was approved by the institutional review board. Cardiomyopathy patients were retrospectively identified who had undergone endomyocardial biopsy and cardiac MR at one institution during a 5-year period. Forty-seven patients (53% male; mean age, 46.8 years) had undergone diagnostic cardiac MR and endomyocardial biopsy. Thirteen healthy volunteers (54% male; mean age, 38.1 years) underwent cardiac MR as a reference. Myocardial T1 mapping was performed 10.7 minutes ± 2.7 (standard deviation) after bolus injection of 0.2 mmol/kg gadolinium chelate by using an inversion-recovery Look-Locker sequence on a 1.5-T MR imager. Late gadolinium enhancement was assessed by using gradient-echo inversion-recovery sequences. Cardiac MR results were the consensus of two radiologists who were blinded to histopathologic findings. Endomyocardial biopsy fibrosis was quantitatively measured by using automated image analysis software with digital images of specimens stained with Masson trichrome. Histopathologic findings were reported by two pathologists blinded to cardiac MR findings. Statistical analyses included Mann-Whitney U test, analysis of variance, and linear regression. RESULTS Median myocardial fibrosis was 8.5% (interquartile range, 5.7-14.4). T1 times were greater in control subjects than in patients without and in patients with evident late gadolinium enhancement (466 msec ± 14, 406 msec ± 59, and 303 msec ± 53, respectively; P < .001). T1 time and histologic fibrosis were inversely correlated (r = -0.57; 95% confidence interval: -0.74, -0.34; P < .0001). The area under the curve for myocardial T1 time to detect fibrosis of greater than 5% was 0.84 at a cutoff of 383 msec. CONCLUSION Cardiac MR with T1 mapping can provide noninvasive evidence of diffuse myocardial fibrosis in patients referred for evaluation of cardiomyopathy.

Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis

BACKGROUND Although dietary recommendations have focused on restricting saturated fat (SF) consumption to reduce cardiovascular disease (CVD) risk, evidence from prospective studies has not supported a strong link between total SF intake and CVD events. An understanding of whether food sources of SF influence these relations may provide new insights. OBJECTIVE We investigated the association of SF consumption from different food sources and the incidence of CVD events in a multiethnic population. DESIGN Participants who were 45-84 y old at baseline (n = 5209) were followed from 2000 to 2010. Diet was assessed by using a 120-item food-frequency questionnaire. CVD incidence (316 cases) was assessed during follow-up visits. RESULTS After adjustment for demographics, lifestyle, and dietary confounders, a higher intake of dairy SF was associated with lower CVD risk [HR (95% CI) for +5 g/d and +5% of energy from dairy SF: 0.79 (0.68, 0.92) and 0.62 (0.47, 0.82), respectively]. In contrast, a higher intake of meat SF was associated with greater CVD risk [HR (95% CI) for +5 g/d and a +5% of energy from meat SF: 1.26 (1.02, 1.54) and 1.48 (0.98, 2.23), respectively]. The substitution of 2% of energy from meat SF with energy from dairy SF was associated with a 25% lower CVD risk [HR (95% CI): 0.75 (0.63, 0.91)]. No associations were observed between plant or butter SF and CVD risk, but ranges of intakes were narrow. CONCLUSION Associations of SF with health may depend on food-specific fatty acids or other nutrient constituents in foods that contain SF, in addition to SF.

Implications of Coronary Artery Calcium Testing Among Statin Candidates According to American College of Cardiology/American Heart Association Cholesterol Management Guidelines: MESA (Multi-Ethnic Study of Atherosclerosis)

BACKGROUND The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guidelines have significantly broadened the scope of candidates eligible for statin therapy. OBJECTIVES This study evaluated the implications of the absence of coronary artery calcium (CAC) in reclassifying patients from a risk stratum in which statins are recommended to one in which they are not. METHODS MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study of 6,814 men and women 45 to 84 years of age without clinical atherosclerotic cardiovascular disease (ASCVD) risk at enrollment. We excluded 1,100 participants (16%) on lipid-lowering medication, 87 (1.3%) without low-density lipoprotein levels, 26 (0.4%) with missing risk factors for calculation of 10-year risk of ASCVD, 633 (9%) >75 years of age, and 209 (3%) with low-density lipoprotein <70 mg/dl from the analysis. RESULTS The study population consisted of 4,758 participants (age 59 ± 9 years; 47% males). A total of 247 (5.2%) ASCVD and 155 (3.3%) hard coronary heart disease events occurred over a median (interquartile range) follow-up of 10.3 (9.7 to 10.8) years. The new ACC/AHA guidelines recommended 2,377 (50%) MESA participants for moderate- to high-intensity statins; the majority (77%) was eligible because of a 10-year estimated ASCVD risk ≥7.5%. Of those recommended statins, 41% had CAC = 0 and had 5.2 ASCVD events/1,000 person-years. Among 589 participants (12%) considered for moderate-intensity statin, 338 (57%) had a CAC = 0, with an ASCVD event rate of 1.5 per 1,000 person-years. Of participants eligible (recommended or considered) for statins, 44% (1,316 of 2,966) had CAC = 0 at baseline and an observed 10-year ASCVD event rate of 4.2 per 1,000 person-years. CONCLUSIONS Significant ASCVD risk heterogeneity exists among those eligible for statins according to the new guidelines. The absence of CAC reclassifies approximately one-half of candidates as not eligible for statin therapy.

Myocardial T1 and Extracellular Volume Fraction Mapping at 3 Tesla

BackgroundTo compare 11 heartbeat (HB) and 17 HB modified lock locker inversion recovery (MOLLI) pulse sequence at 3T and to establish preliminary reference values for myocardial T1 and the extracellular volume fraction (ECV).MethodsBoth phantoms and normal volunteers were scanned at 3T using 11 HB and 17 HB MOLLI sequence with the following parameters: spatial resolution = 1.75 × 1.75 × 10 mm on a 256 × 180 matrix, TI initial = 110 ms, TI increment = 80 ms, flip angle = 35°, TR/TE = 1.9/1.0 ms. All volunteers were administered Gadolinium-DTPA (Magnevist, 0.15 mmol/kg), and multiple post-contrast MOLLI scans were performed at the same pre-contrast position from 3.5-23.5 minutes after a bolus contrast injection. Late gadolinium enhancement (LGE) images were also acquired 12-30 minutes after the gadolinium bolus.ResultsT1 values of 11 HB and 17 HB MOLLI displayed good agreement in both phantom and volunteers. The average pre-contrast myocardial and blood T1 was 1315 ± 39 ms and 2020 ± 129 ms, respectively. ECV was stable between 8.5 to 23.5 minutes post contrast with an average of 26.7 ± 1.0%.ConclusionThe 11 HB MOLLI is a faster method for high-resolution myocardial T1 mapping at 3T. ECV fractions are stable over a wide time range after contrast administration.

Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the Multi-Ethnic Study of Atherosclerosis

AIMS We sought to evaluate the impact of coronary artery calcium (CAC) in individuals at the extremes of risk factor (RF) burden. METHODS AND RESULTS 6698 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) were followed for coronary heart disease (CHD) events over mean 7.1 ± 1 years. Annualized CHD event rates were compared among each RF category (0, 1, 2, or ≥3) after stratification by CAC score (0, 1-100, 101-300, and >300). The following traditional modifiable RFs were considered: cigarette smoking, LDL cholesterol ≥3.4 mmol/L, low HDL cholesterol, hypertension, and diabetes. There were 1067 subjects (16%) with 0 RFs, whereas 1205 (18%) had ≥3 RFs. Among individuals with 0 RFs, 68% had CAC 0, whereas 12 and 5% had CAC >100 and >300, respectively. Among individuals with ≥3 RFs, 35% had CAC 0, whereas 34 and 19% had CAC >100 and >300, respectively. Overall, 339 (5.1%) CHD events occurred. Individuals with 0 RFs and CAC >300 had an event rate 3.5 times higher than individuals with ≥3 RFs and CAC 0 (10.9/1000 vs. 3.1/1000 person-years). Similar results were seen across categories of Framingham risk score. CONCLUSION Among individuals at the extremes of RF burden, the distribution of CAC is heterogeneous. The presence of a high CAC burden, even among individuals without RFs, is associated with an elevated event rate, whereas the absence of CAC, even among those with many RF, is associated with a low event rate. Coronary artery calcium has the potential to further risk stratify asymptomatic individuals at the extremes of RF burden.

T1 mapping of the myocardium: Intra-individual assessment of the effect of field strength, cardiac cycle and variation by myocardial region

BackgroundMyocardial T1 relaxation time (T1 time) and extracellular volume fraction (ECV) are altered in the presence of myocardial fibrosis. The purpose of this study was to evaluate acquisition factors that may result in variation of measured T1 time and ECV including magnetic field strength, cardiac phase and myocardial region.Methods31 study subjects were enrolled and underwent one cardiovascular MR exam at 1.5 T and two exams at 3 T, each on separate days. A Modified Look-Locker Inversion Recovery (MOLLI) sequence was acquired before and 5, 10, 12, 20, 25 and 30 min after administration of 0.15 mmol/kg gadopentetate dimeglumine (Gd-DTPA; Magnevist) at 1.5 T (exam 1). For exam 2, MOLLI sequences were acquired at 3 T both during diastole and systole, before and after administration of Gd-DTPA (0.15 mmol/kg Magnevist).Exam 3 was identical to exam 2 except gadobenate dimeglumine was administered (Gd-BOPTA; 0.1 mmol/kg Multihance). T1 times were measured in myocardium and blood. ECV was calculated by (ΔR1myocardium/ΔR1blood)*(1-hematocrit).ResultsBefore gadolinium, T1 times of myocardium and blood were significantly greater at 3 T versus 1.5 T (28% and 31% greater, respectively, p < 0.001); after gadolinium, 3 T values remained greater than those at 1.5 T (14% and 12% greater for myocardium and blood at 3 T with Gd-DTPA, respectively, p < 0.0001 and 18% and 15% greater at 3 T with Gd-BOPTA, respectively, p < 0.0001). However, ECV did not vary significantly with field strength when using the same contrast agent at equimolar dose (p = 0.2). Myocardial T1 time was 1% shorter at systole compared to diastole pre-contrast and 2% shorter at diastole compared to systole post-contrast (p < 0.01). ECV values were greater during diastole compared to systole on average by 0.01 (p < 0.01 to p < 0.0001). ECV was significantly higher for the septum compared to the non-septal myocardium for all three exams (p < 0.0001-0.01) with mean absolute differences of 0.01, 0.004, and 0.07, respectively, for exams 1, 2 and 3.ConclusionECV is similar at field strengths of 1.5 T and 3 T. Due to minor variations in T1 time and ECV during the cardiac cycle and in different myocardial regions, T1 measurements should be obtained at the same cardiac phase and myocardial region in order to obtain consistent results.

Myocardial T1 Mapping with MRI: comparison of Look-Locker and MOLLI sequences

To evaluate the relationship between “Look‐Locker” (LL) and modified Look‐Locker Inversion recovery (MOLLI) approaches for T1 mapping of the myocardium.

T1 mapping of the myocardium: intra-individual assessment of post-contrast T1 time evolution and extracellular volume fraction at 3T for Gd-DTPA and Gd-BOPTA.

PurposeMyocardial T1 relaxation time (T1 time) and extracellular volume fraction (ECV) are altered in patients with diffuse myocardial fibrosis. The purpose of this study was to perform an intra-individual assessment of normal T1 time and ECV for two different contrast agents.MethodsA modified Look-Locker Inversion Recovery (MOLLI) sequence was acquired at 3 T in 24 healthy subjects (8 men; 28 ± 6 years) at mid-ventricular short axis pre-contrast and every 5 min between 5-45 min after injection of a bolus of 0.15 mmol/kg gadopentetate dimeglumine (Gd-DTPA; Magnevist®) (exam 1) and 0.1 mmol/kg gadobenate dimeglumine (Gd-BOPTA; Multihance®) (exam 2) during two separate scanning sessions. T1 times were measured in myocardium and blood on generated T1 maps. ECVs were calculated as ΔR1myocardium/ΔR1blood*1−hematocrit.ResultsMean pre-contrast T1 relaxation times for myocardium and blood were similar for both the first and second CMR exam (p > 0.5). Overall mean post-contrast myocardial T1 time was 15 ± 2 ms (2.5 ± 0.7%) shorter for Gd-DTPA at 0.15 mmol/kg compared to Gd-BOPTA at 0.1 mmol/kg (p < 0.01) while there was no significant difference for T1 time of blood pool (p > 0.05). Between 5 and 45 minutes after contrast injection, mean ECV values increased linearly with time for both contrast agents from 0.27 ± 0.03 to 0.30 ± 0.03 (p < 0.0001). Mean ECV values were slightly higher (by 0.01, p < 0.05) for Gd-DTPA compared to Gd-BOPTA. Inter-individual variation of ECV was higher (CV 8.7% [exam 1, Gd-DTPA] and 9.4% [exam 2, Gd-BOPTA], respectively) compared to variation of pre-contrast myocardial T1 relaxation time (CV 4.5% [exam 1] and 3.0% [exam 2], respectively). ECV with Gd-DTPA was highly correlated to ECV by Gd-BOPTA (r = 0.803; p < 0.0001).ConclusionIn comparison to pre-contrast myocardial T1 relaxation time, variation in ECV values of normal subjects is larger. However, absolute differences in ECV between Gd-DTPA and Gd-BOPTA were small and rank correlation was high. There is a small and linear increase in ECV over time, therefore ideally images should be acquired at the same delay after contrast injection.