Suguru Matsumoto

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

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.

Effect of treatment with 5‐lipoxygenase inhibitor VIA‐2291 (atreleuton) on coronary plaque progression: a serial CT angiography study

Inflammation has a key role in the process of atherosclerosis. Production of leukotrienes by 5‐lipoxygenase has been linked to atherosclerotic plaques and cardiovascular events.

The Cardiovascular Trial of the Testosterone Trials: rationale, design, and baseline data of a clinical trial using computed tomographic imaging to assess the progression of coronary atherosclerosis.

BackgroundData from prior studies have yielded inconsistent results on the association of serum testosterone levels with the risk for cardiovascular disease. There are no clinical trial data on the effects of testosterone replacement therapy on plaque progression. ObjectiveWe designed a study to investigate the effect of testosterone therapy on coronary artery plaque progression using serial coronary computed tomographic angiography (CCTA). In this paper, we describe the study design, methods, and characteristics of the study population. MethodsThe Cardiovascular Trial of the Testosterone Trials (TTrials; NCT00799617) is a double-blind, placebo-controlled trial of 1 year of testosterone therapy in men 65 years or older with clinical manifestations of androgen deficiency and unequivocally low serum testosterone concentrations (<275 ng/dl). CCTA performed at baseline and after 12 months of therapy will determine the effects of testosterone on the progression of the total volume of noncalcified plaques. All scans are evaluated at a central reading center by an investigator blinded to treatment assignment. ResultsA total of 165 men were enrolled. The average age is 71.1 years, and the average BMI is 30.7. About 9% of men had a history of myocardial infarction, 6% angina, and 10% coronary artery revascularization. A majority reported hypertension and/or high cholesterol; 31.8% reported diabetes. Total noncalcified plaque at baseline showed a slight but nonsignificant trend toward lower plaque volume with higher serum testosterone concentrations (P=0.12). ConclusionThe Cardiovascular Trial will test the hypothesis that testosterone therapy inhibits coronary plaque progression, as assessed by serial CCTA.

The relationship between cardio-ankle vascular index and subclinical atherosclerosis evaluated by cardiac computed tomographic angiography

The cardio‐ankle vascular index (CAVI) is a new noninvasive index to evaluate arterial stiffness. We investigated whether CAVI can predict severity, extent, and burden of coronary artery disease by comparing results with cardiac computed tomographic angiography (CCTA).

Association of Vitamin D Level and Subclinical Coronary Artery Disease

Background: The role of vitamin D level in subclinical atherosclerosis remains controversial. We aimed to investigate the relationship between vitamin D level and coronary artery calcium score (CACS). Patients methods: We investigated 303 consecutive patients referred to an outpatient clinic for CACS. The 25-hydroxy vitamin D [25(OH) D] levels were checked within three months of CACS evaluation. Vitamin D levels of <30 and <20 ng/mL were used as thresholds of vitamin D insufficiency and deficiency, respectively. The correlation between CACS and vitamin D was assessed. Unadjusted and covariate-adjusted logistic regression analyses were used to predict positive CACS. Results: The mean age in this study is 61.8 ± 11.8 years (39.9% female). The majority of patients enrolled were Caucasian (87.4%). Median (interquartile range) serum 25(OH) D concentration was 30.0 (23.0, 39.0) ng/ml. Vitamin D was insufficient ( 0) was prevalent in 206 (68%) participants. In the unadjusted model, the 25 (OH) D levels were not associated with the prevalence of CACS among all cases or among patients with positive CACS. Logistic regression models, after controlling for risk factors, did not change the results. In addition, among the 206 participants with prevalent CACS, 25 (OH) D levels were not associated with CACS severity. Conclusions: Our single centre retrospective study in a population with low prevalence of vitamin D deficiency failed to find a significant relation between 25(OH) D level and CACS even when adjusted for risk factors.

Changes in Coronary Plaque Volume: Comparison of Serial Measurements on Intravascular Ultrasound and Coronary Computed Tomographic Angiography

Serial measurements of coronary plaque volume have been used to evaluate drug efficacy in atherosclerotic progression. However, the usefulness of computed tomography for this purpose is unknown. We investigated whether the change in total plaque volume on coronary computed tomographic angiography is associated with the change in segment plaque volume on intravascular ultrasound. We prospectively enrolled 11 consecutive patients (mean age, 56.3 ± 5 yr; 6 men) who were to undergo serial invasive coronary angiographic examinations with use of grayscale intravascular ultrasound and coronary computed tomography, performed <180 days apart at baseline and from 1 to 2 years later. Subjects underwent 186 serial measurements of total plaque volume on coronary computed tomography and 22 of segmental plaque volume on intravascular ultrasound. We used semiautomated software to examine percentage relationships and changes between total plaque and segmental plaque volumes. No significant correlations were found between percentages of total coronary and segment coronary plaque volume, nor between normalized coronary plaque volume. However, in the per-patient analysis, there were strong correlations between the imaging methods for changes in total coronary and segment coronary plaque volume (r=0.62; P=0.04), as well as normalized plaque volume (r=0.82; P=0.002). Per-patient change in plaque volume on coronary computed tomography is significantly associated with that on intravascular ultrasound. Computed tomographic angiography may be safer and more widely available than intravascular ultrasound for evaluating atherosclerotic progression in coronary arteries. Larger studies are warranted.

Coronary artery-positive remodeling in current smokers

Background This study aims to evaluate the association of the coronary artery-positive remodeling (CAPR) observed on cardiac computed tomography angiography (CCTA) with cigarette smoking. Patients and methods This retrospective case–control study enrolled 178 consecutive patients with CAPR plaque (case group) and 180 consecutive patients with coronary artery plaque, but no positive remodeling (control group). CAPR was evaluated in CCTA images and defined as at least 10% larger vessel diameter at the plaque site compared with a normal reference segment. Results The average age of this population was 61.8±11.5 years (30.4% women). In the case group, the prevalences of current smokers, former smokers, and nonsmokers were 15.7, 26.4, and 57.9%, respectively. In the control group, the prevalences were 6.1, 20.6, and 73.3%, respectively, which were significantly different from the control group (P=0.002 for all). In a subanalysis of the CAPR location in the CAPR group, CAPR was more prevalent in the proximal than the distal segments of the major coronary arteries. Most of the patients in the case group had only one segment involvement with CAPR (71.35%). Logistic regression analyses showed that a history of current smoking has a significant correlation with CAPR in both unadjusted and adjusted models after controlling for risk factors. Current smokers have a 3.5-fold higher risk of having CAPR compared with nonsmokers (P<0.01). Conclusion There is a significant independent association between a history of cigarette smoking and CAPR evaluated by CCTA. Current cigarette smokers have a 3.5 times higher risk of having CAPR.

Massive left ventricular calcification.

Author(s): Alani, Anas; Nakanishi, Rine; Matsumoto, Suguru; Abraham, Jeby; Budoff, Matthew J