Raymond T. Yan

Reduced Ascending Aortic Strain and Distensibility Earliest Manifestations of Vascular Aging in Humans

Arterial stiffness predicts cardiovascular events beyond traditional risk factors. However, the relationship with aging of novel noninvasive measures of aortic function by MRI and their interrelationship with established markers of vascular stiffness remain unclear and currently limit their potential impact. Our aim was to compare age-related changes of central measures of aortic function with carotid distensibility, global carotid–femoral pulse wave velocity, and wave reflections. We determined aortic strain, distensibility, and aortic arch pulse wave velocity by MRI, carotid distensibility by ultrasound, and carotid–femoral pulse wave velocity by tonometry in 111 asymptomatic subjects (54 men, age range: 20 to 84 years). Central pressures were used to calculate aortic distensibility. Peripheral and central pulse pressure, augmentation index, and carotid–femoral pulse wave velocity increased with age, but aortic strain and aortic arch PWV were most closely and specifically related to aging. Ascending aortic (AA) strain and distensibility decreased, respectively, by 5.3±0.5% (R2=0.54, P<0.0001) and 13.6±1 kPa−1×10−3 (R2=0.62, P<0.0001), and aortic arch pulse wave velocity increased by 1.6±0.13 m/sec (R2=0.60, P<0.0001) for each decade of age after adjustment for gender, body size, and heart rate. We demonstrate in this study a dramatic decrease in AA distensibility before the fifth decade of life in individuals with diverse prevalence of risk factors free of overt cardiovascular disease. In particular, compared with other measures of aortic function, the best markers of subclinical large artery stiffening, were AA distensibility in younger and aortic arch pulse wave velocity in older individuals.

Prognostic value of myocardial circumferential strain for incident heart failure and cardiovascular events in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis

AIMSnLeft ventricular (LV) circumferential strain (Ecc) is a sensitive index of regional myocardial function. Currently, no studies have assessed its prognostic value in general population. We sought to investigate whether Ecc has a prognostic value for predicting incident heart failure (HF) and other major cardiovascular events in asymptomatic individuals without a history of previous cardiovascular diseases.nnnMETHODS AND RESULTSnWe, prospectively, assessed incident HF and atherosclerotic events during a 5.5 ± 1.3-year period in 1768 asymptomatic individuals aged 45-84 (mean age 65 years; 47% female) who underwent tagged magnetic resonance imaging for strain determination. During the follow-up period, 39 (2.2%) participants experienced incident HF and 108 (6.1%) participants had atherosclerotic cardiovascular events. Average of peak Ecc of 12-LV segments (Ecc-global) and mid-slice (Ecc-mid) was -17.0 ± 2.4 and -17.5 ± 2.7%, respectively. Participants with average absolute Ecc-mid lower than -16.9% had a higher cumulative hazard of incident HF (log-rank test, P = 0.001). In cox regression analysis, Ecc-mid predicted incident HF independent of age, diabetes status, hypertension, interim myocardial infarction, LV mass index, and LV ejection fraction (hazard ratio 1.15 per 1%, 95% CI: 1.01-1.31, P = 0.03). This relationship remained significant after adjustment for LV-end-systolic wall stress into covariates. In addition, by adding Ecc-mid to risk factors, LV ejection fraction, and the LV mass index, both the global χ(2) value (76.6 vs. 82.4, P = 0.04) and category-less net-reclassification index (P = 0.01, SE = 0.18, z = 2.53) were augmented for predicting HF. Circumferential strain was also significantly related to the composite atherosclerotic cardiovascular events, but its relationship was attenuated after introducing the LV mass index.nnnCONCLUSIONnCircumferential shortening provides robust, independent, and incremental predictive value for incident HF in asymptomatic subjects without any history of previous clinical cardiovascular disease.nnnCLINICAL TRIAL REGISTRATIONnhttp://www.clinicaltrials.gov. Unique identifier: NCT00005487.

Relationship of interleukin-6 with regional and global left-ventricular function in asymptomatic individuals without clinical cardiovascular disease: insights from the Multi-Ethnic Study of Atherosclerosis

AIMSnWe sought to examine the relationship between circulating interleukin-6 (IL-6) level and regional left-ventricular (LV) function among apparently healthy individuals free of cardiovascular disease.nnnMETHODS AND RESULTSnUsing magnetic resonance myocardial tagging, we determined peak systolic circumferential strain (Ecc) as a measure of regional systolic function in 894 asymptomatic participants in the Multi-Ethnic Study of Atherosclerosis. Ecc was analysed by harmonic phase imaging separately in the LV anterior wall, septum, lateral wall, and inferior wall. Global Ecc was calculated as the average of Ecc in all myocardial segments. We performed multivariable linear regression to evaluate the independent associations between log IL-6 and Ecc, after adjusting for demographic features, cardiovascular risk factors, and markers of subclinical atherosclerosis. The inverse relationships between IL-6 and absolute Ecc were similar in both genders. In multivariable analysis, higher IL-6 level was independently associated with reduced systolic function (less negative Ecc) in the septum [regression coefficient = 1.03 per unit higher log IL-6, 95% confidence interval (CI) 0.26-1.79, P = 0.008] and inferior wall (regression coefficient = 1.65, 95% CI 0.74-2.56, P < 0.001), but not in the anterior wall (P = 0.27) or lateral wall (P = 0.52). Overall, there was an independent inverse association between IL-6 and global Ecc (regression coefficient = 0.94, 95% CI 0.37-1.51, P = 0.001). Compared with C-reactive protein, higher IL-6 level demonstrates a stronger independent association with reduced regional systolic function.nnnCONCLUSIONnIn asymptomatic men and women without documented cardiovascular disease, there is a strong, independent, inverse relationship between IL-6 and regional LV systolic function. These findings suggest that IL-6 may underlie the pathogenetic link between inflammation, LV dysfunction and incipient heart failure. The observed variable relationships between IL-6 and systolic function across different LV regions warrant further investigations.

Inter-study reproducibility of cardiovascular magnetic resonance tagging

BackgroundThe aim of this study is to determine the test-retest reliability of the measurement of regional myocardial function by cardiovascular magnetic resonance (CMR) tagging using spatial modulation of magnetization.MethodsTwenty-five participants underwent CMR tagging twice over 12u2009±u20097xa0days. To assess the role of slice orientation on strain measurement, two healthy volunteers had a first exam, followed by image acquisition repeated with slices rotated ±15 degrees out of true short axis, followed by a second exam in the true short axis plane. To assess the role of slice location, two healthy volunteers had whole heart tagging. The harmonic phase (HARP) method was used to analyze the tagged images. Peak midwall circumferential strain (Ecc), radial strain (Err), Lambda 1, Lambda 2, and Angle α were determined in basal, mid and apical slices. LV torsion, systolic and early diastolic circumferential strain and torsion rates were also determined.ResultsLV Ecc and torsion had excellent intra-, interobserver, and inter-study intra-class correlation coefficients (ICC range, 0.7 to 0.9). Err, Lambda 1, Lambda 2 and angle had excellent intra- and interobserver ICC than inter-study ICC. Angle had least inter-study reproducibility. Torsion rates had superior intra-, interobserver, and inter-study reproducibility to strain rates. The measurements of LV Ecc were comparable in all three slices with different short axis orientations (standard deviation of mean Ecc was 0.09, 0.18 and 0.16 at basal, mid and apical slices, respectively). The mean difference in LV Ecc between slices was more pronounced in most of the basal slices compared to the rest of the heart.ConclusionsIntraobserver and interobserver reproducibility of all strain and torsion parameters was excellent. Inter-study reproducibility of CMR tagging by SPAMM varied between different parameters as described in the results above and was superior for Ecc and LV torsion. The variation in LV Ecc measurement due to altered slice orientation is negligible compared to the variation due to slice location.Trial registrationThis trial is registered as NCT00005487 at National Heart, Lung and Blood institute.

Fibrinogen and left ventricular myocardial systolic function: The Multi-Ethnic Study of Atherosclerosis (MESA)

BACKGROUNDnIncreasing evidence suggests that elevated plasma fibrinogen is associated with incident heart failure. However, the underlying pathophysiological mechanisms have not been well elucidated.nnnMETHODSnWe examined the relationship between plasma fibrinogen level and peak systolic midwall circumferential strain (Ecc) at the base, mid cavity, and apex of the left ventricle measured by magnetic resonance imaging myocardial tagging in 1096 participants without clinical cardiovascular disease enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA).nnnRESULTSnAfter adjustment for demographics, established risk factors and body mass index, elevated fibrinogen was independently associated with reductions in absolute Ecc indicative of impaired systolic function in all regions (all P < or = .015). The relationships were consistently significant upon further adjustment for measures of atherosclerosis (all P < .024) and were modestly attenuated with regional heterogeneity after additional adjustment for other inflammatory biomarker and N-terminal pro-brain natriuretic peptide. In this fully-adjusted model, every 1-SD (74 mg/dL) increment in plasma fibrinogen was independently associated with a reduction in left ventricular absolute Ecc of 0.29% (95% CI 0.03%-0.59%, P = .048) at the base, 0.22% (95% CI 0.006%-0.43%, P = .044) at mid cavity, 0.20% (95% CI = -0.035% to 0.43%, P = .097) at the apex, and 0.24% (95% CI = 0.05%-0.43%, P = .015) overall.nnnCONCLUSIONSnAmong asymptomatic individuals without clinical cardiovascular disease, elevated fibrinogen is independently associated with impaired myocardial systolic function. These findings support roles of inflammation, procoagulation, and hyperviscosity underlying hyperfibrinogenemia in the pathogenesis of incipient myocardial dysfunction.

Predictors of Inaccurate Coronary Arterial Stenosis Assessment by CT Angiography

OBJECTIVESnThis study sought to investigate the clinical and imaging characteristics associated with diagnostic inaccuracy of computed tomography angiography (CTA) for detecting obstructive coronary artery disease (CAD) defined by quantitative coronary angiography (QCA).nnnBACKGROUNDnAlthough diagnostic performance metrics of CTA have been reported, there are sparse data on predictors of diagnostic inaccuracy by CTA.nnnMETHODSnThe clinical characteristics of 291 patients (mean age: 59 ± 10 years; female: 25.8%) enrolled in the multicenter CorE-64 (Coronary Artery Evaluation Using 64-Row Multi-detector Computed Tomography Angiography) study were examined. Pre-defined CTA segment-level characteristics of all true-positive (N = 237), false-positive (N = 115), false-negative (FN) (N = 159), and a random subset of true-negative segments (N = 511) for ≥50% stenosis with QCA as the reference standard were blindly abstracted in a central core laboratory. Factors independently associated with corresponding levels of CTA diagnostic inaccuracies on a patient level and coronary artery segment level were determined using multivariable logistic regression models and generalized estimating equations, respectively.nnnRESULTSnAn Agatston calcium score of ≥1 per patient (odds ratio [OR]: 5.2; 95% confidence interval [CI]: 1.1 to 24.6) and the presence of within-segment calcification (OR: 10.2; 95% CI: 5.2 to 19.8) predicted false-positive diagnoses. Conversely, absence of within-segment calcification was an independent predictor of an FN diagnosis (OR: 2.0; 95% CI: 1.2 to 3.5). Prior percutaneous revascularization was independently associated with patient-level misdiagnosis of obstructive CAD (OR: 4.2; 95% CI: 1.6 to 11.2). Specific segment characteristics on CTA, notably segment tortuosity (OR: 3.5; 95% CI: 2.4 to 5.1), smaller luminal caliber (OR: 0.48; 95% CI: 0.36 to 0.63 per 1-mm increment), and juxta-arterial vein conspicuity (OR: 2.1; 95% CI: 1.4 to 3.2), were independently associated with segment-level misdiagnoses. Attaining greater intraluminal contrast enhancement independently lowered the risk of an FN diagnosis (OR: 0.96; 95% CI: 0.94 to 0.99 per 10-Hounsfield unit increment).nnnCONCLUSIONSnWe identified clinical and readily discernible imaging characteristics on CTA predicting inaccurate CTA diagnosis of obstructive CAD defined by QCA. Knowledge and appropriate considerations of these features may improve the diagnostic accuracy in clinical CTA interpretation. (Diagnostic Accuracy of Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors [CORE-64]; NCT00738218).

Regional left ventricular myocardial dysfunction as a predictor of incident cardiovascular events: MESA (Multi-Ethnic Study of Atherosclerosis)

OBJECTIVESnWe sought to examine the prognostic value of subclinical left ventricular (LV) regional myocardial dysfunction (RMD) measured by magnetic resonance imaging (MRI) among asymptomatic individuals.nnnBACKGROUNDnLV RMD, defined as segmental impairment in systolic wall thickening, predicts adverse events in patients with established cardiovascular disease. MRI is highly accurate for detecting subtle RMD, of which the prognostic significance in a large multiethnic asymptomatic population is not known.nnnMETHODSnWe used MRI to evaluate baseline regional LV myocardial function and prospectively followed a multiethnic (African American, Caucasian, Chinese, and Hispanic) population-based sample of 4,510 men and women without cardiovascular disease for a mean of 4.6 years. Regional myocardial dysfunction was defined as the presence of impaired systolic wall thickening (<10th percentile of segment-specific population distribution) in ≥2 contiguous LV segments within any given coronary artery territory.nnnRESULTSnBaseline prevalence of RMD was 25.6%. Heart failure developed in 34 (1.0%) and 30 (2.6%) participants without and with RMD, respectively (p < 0.001). After adjustment for demographics and traditional risk factors, RMD remained independently associated with incident heart failure (hazard ratio [HR]: 2.62; 95% confidence interval [CI]: 1.56 to 4.39; p < 0.001). The relationship persisted after further adjustment for biomarkers of reported association with cardiovascular disease and indexes of global LV systolic dysfunction and hypertrophy (HR: 1.80; 95% CI: 1.02 to 3.20; p = 0.044). Similarly, RMD independently conferred an increased risk for hard coronary events (myocardial infarction or death from coronary heart disease; HR: 1.75; 95% CI: 1.06 to 2.89; p = 0.029), the composite of hard coronary events and stroke (HR: 1.72; 95% CI: 1.16 to 2.56; p = 0.005), and all atherosclerotic cardiovascular events (HR: 1.50; 95% CI: 1.09 to 2.07; p = 0.012).nnnCONCLUSIONSnAmong an asymptomatic multiethnic American cohort, RMD is an independent predictor beyond traditional risk factors and global LV assessment for incident heart failure and atherosclerotic cardiovascular events. The clinical utility of early recognition of this subclinical phenotype deserves further investigation. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

High-sensitivity C-reactive protein as an independent predictor of progressive myocardial functional deterioration: The multiethnic study of atherosclerosis

BACKGROUNDnSystemic inflammation has been linked to the development of heart failure in population studies including Multi-Ethnic Study of Atherosclerosis (MESA), but little evidence exists regarding potential mechanism of this relationship. In this study, we used longitudinal magnetic resonance imaging follow-up analysis to examine whether C-reactive protein (CRP) levels relate to progressive myocardial functional deterioration as a potential mechanism of incident heart failure.nnnMETHODSnRegional myocardial functional data from MESA participants who had baseline CRP measurement and also underwent tagged cardiac magnetic resonance imaging both at baseline and at 5-year follow-up were analyzed. Left ventricular midwall and midslice peak circumferential strain (Ecc), of which a more negative value denotes stronger regional myocardial function, was measured. Circumferential strain change was calculated as the difference between baseline and follow-up Ecc.nnnRESULTSnDuring the follow-up period, participants (n = 785) with elevated CRP experienced a decrease in strain, independent of age, gender, and ethnicity (B = 0.081, ∆Ecc change per 1 mg/L CRP change, 95% CI 0.036-0.126, P < .001, model 1) and, additionally, beyond systolic blood pressure, heart rate, diabetes, smoking status, body mass index, current medication, and glomerular filtration rate (B = 0.099, 0.052-0.145, P < .001, model 2). The relationship remained statistically significant after further adjustment for left ventricular mass, coronary calcium score, and interim clinical coronary events (B = 0.098, 0.049-0.147, P < .001, model 3).nnnCONCLUSIONnHigher CRP levels are related to progressive myocardial functional deterioration independent of subclinical atherosclerosis and clinical coronary events in asymptomatic individuals without previous history of heart disease.