Rine Nakanishi

Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone

Importance Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk. Objective To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume. Design, Setting, and Participants Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014. Intervention Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcomes and Measures The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis). Results Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, −27 Agatston units; 95% CI, −80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group. Conclusions and Relevance Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding. Trial Registration clinicaltrials.gov Identifier: NCT00799617

Increase in epicardial fat volume is associated with greater coronary artery calcification progression in subjects at intermediate risk by coronary calcium score: A serial study using non-contrast cardiac CT

OBJECTIVE Epicardial fat volume (EFV) is related to calcified coronary plaques. However, it is unknown whether baseline EFV or changes in EFV affect the progression of coronary artery calcification over time. METHODS We identified 375 consecutive asymptomatic subjects with an intermediate risk of developing coronary artery disease, who underwent serial non-contrast CT at least 3-5 years apart. Subjects were divided into tertiles of CCS progression (% increase) between the 2 scans. Subjects from the upper tertile (High Progressors) were matched by age and gender to 81 subjects from the lower tertile (Low Progressors). All subjects underwent serial measurements of CCS and EFV. Relationships between EFV and CCS progression, and change in plaque number were examined. RESULTS At baseline, there was no difference in EFV, and EFV indexed to body surface area (EFVi) between the groups. At follow-up, EFV, EFVi and percent increase in EFVi-change were higher in High Progressors than Low Progressors (EFV, 102 ± 38 cm(3) vs. 90 ± 35 cm(3), p=0.03; EFVi, 50 ± 16cm(3)/m(2) vs. 46 ± 15 cm(3)/m(2), p=0.03; percent increase in EFVi-change, 15 ± 22% vs. 7 ± 20%, p=0.02). On multivariate analysis, after adjusting for conventional risk factors, EFVi increase ≥15% [odds ratio (OR) 2.3, p<0.05], log (baseline CCS) [OR 0.3, p<0.0001] and scan interval time [p=0.003, OR 1.0] were predictive of being a High Progressor. EFVi increase ≥ 15% (β=3.0, p=0.02) and hypertension (β=3.1, p=0.01) were independent predictors of number of new calcified plaques on follow-up. CONCLUSION Increase in EFV is associated with greater progression of coronary artery calcification in intermediate-risk subjects.

Weight change modulates epicardial fat burden: A 4-year serial study with non-contrast computed tomography

INTRODUCTION Epicardial fat volume (EFV) is linked to cardiovascular event risk. We aimed to investigate the relationships between EFV and weight change. METHODS From the EISNER (Early Identification of Subclinical Atherosclerosis using Non-invasive Imaging Research) Registry with baseline and follow-up coronary calcium scans (1248 subjects), we selected a cohort of 374 asymptomatic subjects matched using age decade, gender and coronary calcium score (CCS) as a measure of subclinical cardiovascular risk, who underwent 2 scans at an interval of 4.1±0.4 years. Using semi-automated validated software, pericardial contours were generated on all slices by spline interpolation from 5 to 10 control points. EFV was computed as fat volume within the pericardial contours. Weight gain/loss was defined as >5% change. RESULTS At baseline, EFV was moderately correlated to weight, body mass index (BMI) and waist circumference (r=0.51, 0.41 and 0.50, p<0.0001). EFV change was weakly correlated to change in weight (r=0.37, p<0.0001), BMI (r=0.39, p<0.0001) and waist circumference (r=0.21, p=0.002). On multivariable linear regression analysis, weight change [β=1.2, 95% confidence interval (CI) 0.9-1.5, p<0.001], BMI change (β=1.2, 95% CI 0.9-1.5, p<0.001), gender (β=-6.4, 95% CI -10.9 to -1.8, p=0.006) and hypertension (β=4.7, 95% CI 0.5-9.0, p=0.03) predicted EFV change. EFV decreased in 54 subjects with weight loss and increased in 71 subjects with weight gain (-2.3±21.1% vs. 23.3±24.4%, p<0.001). CONCLUSIONS EFV is related to body weight, BMI and waist circumference. Reduction in weight may stabilize or reduce EFV, while weight gain may promote EFV increase.

Relation of Diagonal Ear Lobe Crease to the Presence, Extent, and Severity of Coronary Artery Disease Determined by Coronary Computed Tomography Angiography

Controversy exists concerning the relation between diagonal ear lobe crease (DELC) and coronary artery disease (CAD). We examined whether DELC is associated with CAD using coronary computed tomography (CT) angiography. We studied 430 consecutive patients without a history of coronary artery intervention who underwent CT angiography on a dual-source scanner. Presence of DELC was agreed by 2 blinded observers. Two blinded readers evaluated CT angiography images for presence of CAD and for significant CAD (≥50% stenosis). Chi-square and t tests were used to assess demographic differences between subgroups with and without DELC and the relation of DELC to 4 measurements of CAD: any CAD, significant CAD, multivessel disease (cutoff ≥2), and number of segments with plaque (cutoff ≥3). Multivariable logistic regression was performed to adjust for CAD confounders: age, gender, symptoms, and CAD risk factors. Mean age was 61 ± 13 and 61% were men. DELC was found in 71%, any CAD in 71%, and significant CAD in 17% of patients. After adjusting for confounders, DELC remained a significant predictor of all 4 measurements of CAD (odds ratio 1.8 to 3.3, p = 0.002 to 0.017). Sensitivity, specificity, and positive and negative predictive values for DELC in detecting any CAD were 78%, 43%, 77%, and 45%. Test accuracy was calculated at 67%. Area under the receiver operator characteristic curve was 61% (p = 0.001). In conclusion, in this study of patients imaged with CT angiography, finding DELC was independently and significantly associated with increased prevalence, extent, and severity of CAD.

Threshold for the Upper Normal Limit of Indexed Epicardial Fat Volume: Derivation in a Healthy Population and Validation in an Outcome-Based Study

Epicardial fat volume (EFV) quantified on noncontrast cardiac computed tomography relates to cardiovascular prognosis. We sought to define the upper normal limit of body surface area (BSA)-indexed EFV (EFVi) in a healthy population and to validate it as a predictor of major adverse cardiovascular events (MACE). We analyzed noncontrast cardiac computed tomography scans of 226 healthy subjects with a low Framingham Risk Score (FRS; ≤6%) performed for coronary calcium scoring (CCS). EFV was quantified using validated software and indexed to BSA. We defined the 95th percentile as the upper normal limit. Subsequently, we reanalyzed a separate cohort of 232 participants from a previously published case-control study with 4-year follow-up and 58 cases of MACE to test the additive value of an abnormally high EFVi for predicting MACE. Of the 226 healthy participants 51% were men (mean age 52 ± 9 years). EFV correlated to BSA (r = 0.373, p <0.0001). Median, range, and 25th and 75th percentiles of the non-normally distributed EFVi were 33.3, 10.8 to 96.6, and 24.5 and 45.5 cm(3)/m(2). The 95th percentile definition of the upper normal limit of EFVi was 68.1 cm(3)/m(2). For prediction of MACE, EFVi values higher than the newly defined threshold emerged as a significant and independent predictor after controlling for confounders (odds ratio 2.8, 95% confidence interval 1.3 to 6.4, p = 0.012) and trended in its additive value to the combination of CCS ≥400 and FRS (area under the receiver operating characteristic curve 0.714 vs 0.675, p = 0.1277). In conclusion, in a healthy population we determined 68.1 cm(3)/m(2) as the 95th percentile threshold for abnormally high EFVi. EFVi exceeding this value independently predicted MACE and trended to add to CCS and FRS in this prediction.

Myocardial bridging on coronary CTA: An innocent bystander or a culprit in myocardial infarction?

Myocardial bridging describes the clinical entity whereby a segment of coronary artery is either partially or completely covered by surrounding myocardium. It represents the most frequent congenital coronary anomaly and has an estimated prevalence of ≤13% on angiographic series. With the emergence of cardiac computed tomography and its ability to simultaneously image the coronary arteries and also the myocardium, there has been an apparent increase in the detection rates of myocardial bridges (prevalence as high as 44%). It has now become important to evaluate their clinical significance. Myocardial bridging is generally considered a benign entity with survival rates of 97% at 5 years; however, there is now emerging evidence that certain myocardial bridge characteristics may be associated with cardiovascular morbidity. The length and depth of myocardial bridges have been associated with increased atherosclerosis, whereas the degree of systolic compression has been associated with ischemia on myocardial perfusion single-photon emission tomography. On the basis of current evidence, it appears that limiting further testing for ischemia to symptomatic patients with long and/or deep myocardial brides would be appropriate.

Current but not past smoking increases the risk of cardiac events: insights from coronary computed tomographic angiography

AIMS We evaluated coronary artery disease (CAD) extent, severity, and major adverse cardiac events (MACEs) in never, past, and current smokers undergoing coronary CT angiography (CCTA). METHODS AND RESULTS We evaluated 9456 patients (57.1 ± 12.3 years, 55.5% male) without known CAD (1588 current smokers; 2183 past smokers who quit ≥3 months before CCTA; and 5685 never smokers). By risk-adjusted Cox proportional-hazards models, we related smoking status to MACE (all-cause death or non-fatal myocardial infarction). We further performed 1:1:1 propensity matching for 1000 in each group evaluate event risk among individuals with similar age, gender, CAD risk factors, and symptom presentation. During a mean follow-up of 2.8 ± 1.9 years, 297 MACE occurred. Compared with never smokers, current and past smokers had greater atherosclerotic burden including extent of plaque defined as segments with any plaque (2.1 ± 2.8 vs. 2.6 ± 3.2 vs. 3.1 ± 3.3, P < 0.0001) and prevalence of obstructive CAD [1-vessel disease (VD): 10.6% vs. 14.9% vs. 15.2%, P < 0.001; 2-VD: 4.4% vs. 6.1% vs. 6.2%, P = 0.001; 3-VD: 3.1% vs. 5.2% vs. 4.3%, P < 0.001]. Compared with never smokers, current smokers experienced higher MACE risk [hazard ratio (HR) 1.9, 95% confidence interval (CI) 1.4-2.6, P < 0.001], while past smokers did not (HR 1.2, 95% CI 0.8-1.6, P = 0.35). Among matched individuals, current smokers had higher MACE risk (HR 2.6, 95% CI 1.6-4.2, P < 0.001), while past smokers did not (HR 1.3, 95% CI 0.7-2.4, P = 0.39). Similar findings were observed for risk of all-cause death. CONCLUSION Among patients without known CAD undergoing CCTA, current and past smokers had increased burden of atherosclerosis compared with never smokers; however, risk of MACE was heightened only in current smokers.

The relationship between epicardial fat volume and incident coronary artery calcium.

BACKGROUND Epicardial fat volume (EFV) has been associated with prevalent but not incident coronary artery calcium. However, the relationship between EFV and development of incident coronary calcium (incCC) has not been reported. OBJECTIVE We evaluated the relationship between epicardial fat volume and the development of coronary artery calcium over 3-5 years. METHODS From 1248 subjects who underwent 2 serial noncontrast cardiac CT scans 3-5 years (median, 4 years) apart to measure coronary calcium score of 0 who subsequently developed incident coronary calcium (incCC(+)) were matched to 106 controls in whom coronary calcium score remained 0 (incCC(-)). EFV was calculated by determination of the pericardial contour, followed by identification of fat voxels with the use of validated software (QFAT). Baseline EFV and EFV indexed to body surface area (EFVi) and subsequent EFV and EFVi changes were compared between incCC(-) and incCC(+) populations. A significant EFV increase was defined as a ≥10% and ≥25% increase from the baseline value. RESULTS Baseline EFVi was similar between the 2 groups [EFVi, 40.9 ± 17.9 cm³ (median, 38.3 cm³) in incCC(-) vs 40.3 ± 16.3 cm³ (median, 37.0 cm³) in incCC(+); P = 0.96]. On the follow-up CT, EFVi increased in 74.5% of incCC(-) and in 76.4% of incCC(+) (P = 0.75). EFVi changes between the 2 groups were similar [4.9 ± 8.9 cm³ (median, 4.9 cm³) in incCC(-) vs 4.2 ± 8.0 cm³) (median, 3.5 cm³) in incCC(+); P = 0.67]. On multivariate analysis, after adjusting for cardiovascular risk factors, incCC was not related to an increase in EFVi at a 10% or 25% level. CONCLUSIONS In very low-risk subjects with a coronary calcium score of 0, baseline EFVi and change in EFVi after 3-5 years were not related to the development of incidental coronary artery calcium.

The relationship between coronary artery calcium score and the long-term mortality among patients with minimal or absent coronary artery risk factors

BACKGROUND Coronary artery calcium (CAC) is strongly predictive of all-cause mortality in intermediate-risk groups, but this relationship is not well defined in very low-risk individuals. We investigated the relationship between CAC scoring and the long-term all-cause mortality among patients with ≤ 1 cardiovascular disease (CVD) risk factor. METHODS We analyzed a retrospective cohort of 5584 asymptomatic patients with no known CVD (mean 56.6 ± 11.6 years, 69%men) and ≤ 1 risk factor who were physician referred for a CAC scan. Mortality was ascertained through linkage with the Social Security Death Index. We calculated the prevalence of CAC stratified by age and risk factors. We also examined the association between CAC and mortality using multivariable Cox Proportional hazards models. RESULTS During a mean follow-up of 10.4 ± 3.1 years, 168 individuals (3.0%) died. Overall, 54.5% of patients had a CAC >0 and 9.8% had CAC ≥ 400. There was a greater risk of mortality with increasing CAC 1-99 (HR 1.9, 95% CI 1.2-3.1), 100-399 (HR 2.1, 95% CI 1.2-3.6) and ≥ 400 (HR 2.8, 95% CI 1.6-4.8) compared to CAC=0 (p<0.0001 for trend). Similar results were observed when the population was stratified by zero or one risk factor. Among patients < 45 years old, there was a 0.7% incidence of mortality compared to 8.1% for individuals ≥ 65 years old. CONCLUSIONS During long-term follow-up, an increasing CAC was significantly associated with a higher risk of all-cause mortality among patients with a very low CVD risk factor profile. CAC scanning may be a potentially useful tool for risk stratification among low CVD risk individuals who are ≥ 45 years old.

Aged Garlic Extract Reduces Low Attenuation Plaque in Coronary Arteries of Patients with Metabolic Syndrome in a Prospective Randomized Double-Blind Study

BACKGROUND Although several previous studies have demonstrated that aged garlic extract (AGE) inhibits the progression of coronary artery calcification, its effect on noncalcified plaque (NCP) has been unclear. OBJECTIVE This study investigated whether AGE reduces coronary plaque volume measured by cardiac computed tomography angiography (CCTA) in patients with metabolic syndrome (MetS). METHODS Fifty-five patients with MetS (mean ± SD age: 58.7 ± 6.7 y; 71% men) were prospectively assigned to consume 2400 mg AGE/d (27 patients) or placebo (28 patients) orally. Both groups underwent CCTA at baseline and follow-up 354 ± 41 d apart. Coronary plaque volume, including total plaque volume (TPV), dense calcium (DC), NCP, and low-attenuation plaque (LAP), were measured based upon predefined intensity cutoff values. Multivariable linear regression analysis, adjusted for age, gender, number of risk factors, hyperlipidemia medications, history of coronary artery disease, scan interval time, and baseline %TPV, was performed to examine whether AGE affected each plaque change. RESULTS The %LAP change was significantly reduced in the AGE group compared with the placebo group (-1.5% ± 2.3% compared with 0.2% ± 2.0%, P = 0.0049). In contrast, no difference was observed in %TPV change (0.3% ± 3.3% compared with 1.6% ± 3.0%, P = 0.13), %NCP change (0.2% ± 3.3% compared with 1.4% ± 2.9%, P = 0.14), and %DC change (0.2% ± 1.4%, compared with 0.2% ± 1.7%, P = 0.99). Multivariable linear regression analysis found a beneficial effect of AGE on %LAP regression (β: -1.61; 95% CI: -2.79, -0.43; P = 0.008). CONCLUSIONS This study indicates that the %LAP change was significantly greater in the AGE group than in the placebo group. Further studies are needed to evaluate whether AGE has the ability to stabilize vulnerable plaque and decrease adverse cardiovascular events. This trial was registered at clinicaltrials.gov as NCT01534910.