Jeffrey Dach MD » Testosterone Therapy Coronary Plaque and Calcium Score

Testosterone Therapy Coronary Plaque and Calcium Score

by Jeffrey Dach MD

Jim is a retired 72 year old who had a stent placed a few years ago for coronary artery disease. Jim had low testosterone on his initial lab panel, and has been using topical testosterone for a few years now. Last week, Jim’s primary care doctors told him that he should not be taking testoterone, as a new study shows Testosterone increases atherosclerotic plaque formation. This was the Feb 2017 JAMA study by Matt Budoff which reported the Testosterone group has increased non-calcified plaque compared to the placebo group. (1) Paradoxically, Dr. Budoff reported the Testosterone group had less progression of coronary calcium score compared to Placebo group.

Alarm Bells Go Off

Medical writer Eric Barnes declares that,” Testosterone treatment raises levels of heart plaque” (21) Marlene Buskos declares “Atherosclerosis Speeds Up in Older Men on Testosterone” (24) Are these true statements? Below, we will take a critical look at the Budoff study.

A Critical Look at the Budoff Testosterone Study

Study details: 138 males of mean age of 72 years age, with coronary artery disease, and elevated calcium score above 300, were randomized so that 73 received testosterone and 65 placebo for a 12 month time period. The men were given Androgel (TM) 5 grams, which was adjusted to maintain testosterone 280-870 ng/dl. The men tended to have obesity, hypertension, hyperlipidemia, and diabetes.

Primary outcome: Non-calcified plaque

Testosterone Group Increase from 204 mm³ to 232 mm³; change 40 mm³;
Placebo Group Increase from median of 317 mm³ to 325 mm³; change: mean, 4 mm³

Secondary outcome of total plaque volume

Testosterone Group Increased 272 mm³ to 318 mm³; change: 57 mm³; 95% CI, 35 to 78 mm³)
Placebo Group Increased from 499 mm³ to 541 mm³; change: 21 mm³; 95% CI, 0 to 42 mm³) (estimated difference, 47 mm³; 95% CI, 13 to 80 mm³; P = .006).

Calcium score results:

Testosterone group: mean, increased 53 Agatston units.
Placebo group: mean, increased 118 Agatston units;

Testosterone Group median score decreased from 255 to 244
Placebo Group Median score increased from 494 to 503

Problems With the Study:

Number one, if this was a truly randomized study, the starting calcium scores for treatment group and placebo group should be similar. As you can see, they were very different (255 vs. 454) , suggesting some problem with randomization.

Second Problem: It is well known that heavily calcified arteries with high calcium score (as in the Placebo group) cause streak artifact and technical difficulties obtaining accurate readings for non-calcified plaque. This casts doubt on the results for soft non-calcified plaque, suggesting technical errors in the study. Here is a quote from Dr Z. Sun in 2016 in “Coronary CT angiography in coronary artery disease”.(2) (CCTA = coronary CT angiography, CAD=coronary artery diease)

“extensive coronary artery calcification (coronary calcium score >400) still limits the diagnostic accuracy of CCTA in CAD, in particular, reducing the sensitivity to some extent due to high rate of false positive results.“….”clinical value of CCTA is controversial as FACTOR64 and PROMISE trials concluded that CCTA did not improve clinical outcomes as compared with functional testing or did not reduce all cause mortality.”(2)

Third problem: The clinical relevance of coronary artery calcium score is well established, and in routine use. The clinical relevance of non-calcified plaque is controversial and not in routine clinical use. Look at the chart below showing the robust predictive ability of the calcium score. No such chart exists for non-calcified plaque. Dr Budoff’s study showed a clear benefit for the Testosterone group in terms of Calcium Score, the more accepted predictor of cardiovascular risk. This was not a surprise as previous studies showed similar improvement in calcium scores in men on tesosterone.(22)

The Robust Predictive Ability of Coronary Calcium Score

Here is a quote from Dr. Stephan Achenbach in 2010 “Imaging of coronary atherosclerosis by computed tomography.(4)

“So far, the available clinical data are not sufficient to draw specific conclusions as to the risk–benefit ratio of contrast-enhanced coronary CTA (computed tomography) for risk prediction, especially for asymptomatic individuals. Hence, CTA is currently not recommended for risk stratification purposes.(4)

Rather than used as a stand alone tool, CAT scan detection of non-calcified plaque is useful as an add on to the calcium score to improve discriminatory value.(3)

Results Are Discordant: CAT scan calcium score is the best predictor on non-calcified plaque in patients with low calcium score.(28) Calcium score and total plaque measurements should be trending in the same direction. Therefore, the results of the Budoff study are discordant and suspect.

Fourth Problem with Budoff Study:

Another red warning flag: Dr Budoff is concluding from his study that testosterone increases plaque formation in men with coronary artery disease. However, Dr Budoff reports in his study, over12 months of testosterone use, there were no cardiovascular events. If testosterone was as bad as he says, where are the worsening ischemic events, myocardial infarctions and increased mortality in the testosterone treated group? There were none.

My most significant criticism of the Budoff study is that it contradicts forty years of previous medical studies on the effect of testosterone on the cardiovascular system. According to Dr A. Traish in 2016 (5)

“There is no credible evidence to indicate that T therapy increases the risk of CVD (cardiovascular disease). On the contrary, T therapy may be protective ” …” T therapy has been used as early as 1940s with no reported adverse effects on the CV (cardiovascular)system.”(5)… Recent observational, registry studies, clinical trials, and meta-analyses, all revealed no increase in CV (cardiovascular) risks in men receiving T therapy.(6)

If Dr Budoff’s study was true, then this implies that Testosterone worsens coronary artery disease in males by causing more plaque formation, more myocardial ischemia, more arterial occlusion, more myocardial infarction and increased mortality from heart disease. As we can clearly see from a real life experience at the two Urology clinics over 8 years treating 77 males with known coronary artery disease, none of this actually happens as reported by Dr.Haider.(8) Not only were no cardiovascular events in the Testosterone treated group, various cardiovascular risk parameters were improved. Here is a quote from Dr Haider(8):

“Over 8 years, the men experienced weight loss (from 114 kg to 91 kg), decreased waist circumference (112 cm to 99 cm), decreased BMI from 37 to 29. Cardio-metabolic parameters such as lipid profile, glycemic control, blood pressure, heart rate, and pulse pressure all improved significantly and sustainably. No patient suffered a major adverse cardiovascular event during the full observation time. Testosterone therapy …. may be effective as an add-on treatment for secondary prevention of cardiovascular events in testosterone deficient men with a history of cardiovascular disease.”(8)

Testosterone (8 years) in Males With Coronary Artery Disease

Younger men without heart disease

If testosterone increases plaque formation in a clinically significant way, as Dr Budoff is suggesting, then this should result in increased myocardial ischemic, myocardial infarction and death in healthy males of any age who receive testosterone treatment. In reviewing registries for 20,000 males receiving testosterone therapy, average age of 46, Dr. Robert Tan had this to say:”There was no evidence of worsening preexisting MI or stroke in patients treated with testosterone.”(9)

If testosterone is an evil hormone that makes men die of coronary artery disease, then surely men with low testosterone should be protected from this evil drug, and men with high testosterone should succumb to its adverse effects. Studies show just the opposite is true. (11-13)

Here is a quote from Dr Haider:(8) (note TD=testosterone deficiency, TTh=Testosterone Therapy):

Mortality in men with TD was reduced subsequent to TTh.32,33 Shores et al32 demonstrated that mortality in T-treated men was 10.3% compared with 20.7% in untreated hypogonadal men (P<0.0001). Muraleedharan et al33 demonstrated, in hypogonadal men with type 2 diabetes mellitus, reduced mortality of 8.4% in men receiving TTh compared with 19.2% in untreated men. These findings are consistent with several studies summarized by Morgentaler et al.1 CV benefits of TTh have been shown in interventional studies, including benefits in men with congestive heart failure, cardiac ischemia/angina, including a reduction in carotid intima–media thickness.1 Most studies identified an inverse association between serum T concentration and all-cause or CV mortality.(8)

If Testosterone is the evil drug that worsens plaque formation in men with coronary artery disease, then one would expect men with angina should be made worse by testosterone. The opposite is true. Numerous studies show testosterone improves ischemic threshold in men with angina and improves quality of life (14-15)

In conclusion:

The Budoff study reports discordant results which are suspect for technical error. The study contradicts forty years of published data on Testosterone and Cardiovascular disease. Real world data from two Urology Clinics treating males with cardiovascular disease with testosterone for eight years contradicts Dr Bufoff’s conclusions. It is the physician’s job to read these types of studies with a critical eye, and to reject studies which do not pass muster. This is one of them.

Articles with Related Interest

Increased Survival in Men Using Testosterone Replacement

Testosterone Found Beneficial for Diabetes

Testosterone and the Heart

Testosterone and the Heart Part Two

Links and References

1) Original Investigation February 21, 2017
Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone
Matthew J. Budoff, MD1; wt al. JAMA. 2017;317(7):708-716. Question Is testosterone treatment of older men with low testosterone associated with a decrease in noncalcified coronary artery plaque volume? Findings In a controlled clinical trial, 1 year of testosterone treatment of men aged 65 years or older with a low serum testosterone level was associated with a significant increase in noncalcified coronary artery plaque volume of 41 mm3 more than placebo.

Meaning Testosterone treatment of older men was associated with an increase in coronary artery plaque volume, but additional studies are needed to determine the clinical significance.
Abstract
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.
Although testosterone replacement is increasingly being used clinically,1 the cardiovascular benefits and risks of testosterone administration to older men with age-related decline in testosterone levels remain uncertain. Several observational studies show an inverse association between serum testosterone concentration and adverse cardiovascular outcomes, the metabolic syndrome, diabetes, and mortality,2- 5 independent of traditional cardiovascular risk factors.

Studies of the effects of testosterone on clinical cardiovascular outcomes are conflicting.6 Meta-analyses of clinical trials have shown no association between testosterone treatment and cardiovascular adverse events, but none of the individual trials included in the meta-analyses were designed to assess these events prospectively. A clinical trial in older men with mobility limitation showed an excess of cardiovascular adverse events in men treated with testosterone compared with placebo,7 but another trial in a similar population did not.8 These trials were also not designed to assess cardiovascular adverse events. Retrospective analyses of electronic medical records to evaluate the possible association of testosterone treatment with cardiovascular adverse events have also yielded conflicting results.9- 13
The Testosterone Trials (TTrials), a group of 7 placebo-controlled, coordinated trials, were designed to determine the efficacy of testosterone treatment of men aged 65 years or older with low testosterone concentrations for no apparent reason other than age. The Cardiovascular Trial was designed to test the hypothesis that testosterone treatment of older men with low testosterone slows the progression of noncalcified coronary artery plaque volume, assessed by coronary computed tomographic angiography (CCTA), as an indicator of coronary atherosclerosis.

2) Sun, Zhonghua. “Coronary CT angiography in coronary artery disease: Opportunities and challenges.” Australasian Medical Journal 9.5 (2016).Coronary CT angiography in coronary artery disease Sun Zhonghua Australasian Medical Journal 2016

Second, extensive coronary artery calcification (coronary calcium score >400) still limits the diagnostic accuracy of CCTA in CAD, in particular,
reducing the sensitivity to some extent due to high rate of false positive results.
It has been reported that highly calcified plaques (high calcium in the plaques) significantly lowered the specificity of CCTA to between 18 per cent and 44 per cent

This is represented by some randomised controlled trials available in the recent literature, including FACTOR64 Randomized Clinical Trial, PROMISE Clinical Trial, PLATFORM Clinical Trial and SCOT-HEART trial.

7376Table 3 summarises key findings of these four multicentre trials.

As shown in the table, clinical value of CCTA is controversial as FACTOR64 and PROMISE trials concluded that CCTA did not improve clinical outcomes as compared with functional testing or did not reduce all cause mortality.

3) Does coronary CT angiography improve risk stratification over coronary calcium scoring in symptomatic patients with suspected coronary artery disease? Results from the prospective multicenter international CONFIRM registry. Mouaz H. Al-Mallah Eur Heart J Cardiovasc Imaging (2014) 15 (3): 267-274.
In symptomatic patients with suspected CAD, CCTA adds incremental discriminatory power over CAC for discrimination of individuals at risk of death or MI.

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4) Achenbach, Stephan, and Paolo Raggi. “Imaging of coronary atherosclerosis by computed tomography.” European heart journal (2010): ehq150.

So far, the available clinical data are not sufficient to draw specific conclusions as to the risk–benefit ratio of contrast-enhanced coronary CTA for risk prediction, especially for asymptomatic individuals. Hence, CTA is currently not recommended for risk stratification purposes.

5) Traish, Abdulmaged. “Testosterone therapy men testosterone deficiency :Are we beyond the point of no return?.” Investigative and Clinical Urology 57.6 (2016): 384-400.

Thus, there is no credible evidence to indicate that T therapy increases the risk of CVD. On the contrary, T therapy may be protective [9-15].

the scientific evidence that restoration of physiological levels of T are
critical for maintaining men’s health. Interestingly, T therapy has been used as early as 1940s with no reported adverse effects on the CV system [1,2,16,18]. On the contrary, T therapy has been shown to improve the symptoms of angina pectoris and peripheral vascular disease [16,18].

A spectrum of recent studies (Table 5) have shown that T therapy does not increase the risk of CVD.

6) Traish, Abdulmaged M. “Testosterone therapy in men with testosterone deficiency: are the benefits and cardiovascular risks real or imagined?.” American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. Vol. 311. No. 3. American Physiological Society, 2016.
In the adult male, testosterone (T) deficiency (TD) also known as male hypogonadism, is a well-established medical condition, which has been recognized for more than a century. T therapy in men with TD was introduced as early as 1940s and was reported to improve overall health with no concomitant serious adverse effects. A wealth of recent studies demonstrated that T therapy in men with TD is associated with increased lean body mass, reduced fat mass and waist circumference, improvement in glycemic control, and reduced obesity. T therapy is also associated with improvements in lipid profiles, amelioration of metabolic syndrome (Met S) components, reduced inflammatory biomarkers, reduced systolic and diastolic blood pressure, and improvements in sexual function. More importantly, T therapy is associated with amelioration of diabetes and reduced mortality. However, few studies, marred with serious methodological and analytical flaws reported between 2010 and 2014, suggested that T therapy is associated with increased cardiovascular (CV) risk. As summarized in this review, a thorough and critical analysis of these studies showed that the risks purported are unsubstantiated and such studies lacked credible scientific and clinical evidence. Moreover, recent observational, registry studies, clinical trials, and meta-analyses, all revealed no increase in CV risks in men receiving T therapy. In this review, the benefits of T therapy in adult men with TD and the lack of credible evidence suggesting that T therapy is linked to increased CV risks are discussed. It should be noted that the literature is replete with studies demonstrating beneficial effects of T therapy on CV and overall health.

7) Nebido Web Site
The topic of testosterone and cardiovascular disease has been receiving a lot of attention over the past years. Despite the common belief that testosterone may increase the incidence of coronary artery disease, the scientific evidence shows the opposite; testosterone deficiency is associated with increased prevalence and severity of coronary atherosclerosis and testosterone therapy is associated with beneficial cardiovascular outcomes.1

To date, no long-term studies have assessed the effects of testosterone therapy in men with a history of cardiovascular disease. Here we summarise the results of an observational study that investigated the effects of long-term testosterone therapy – up to 8 years – in hypogonadal men with a history of cardiovascular disease.2

Long term Testo-Undecanoate q 3 months -Urology Clinic Men with CV disease 8 year follow up

GOOD CHARTS !!!!

8) Haider, Ahmad, et al. “Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study.” Vascular health and risk management 12 (2016): 251.
Long-term TTh in men with hypogonadism and a history of CVD appears to be an effective approach to achieve sustained improvements in anthropometric parameters and cardiometabolic function, with no reported increases in CVD events. The fact that none of these high-risk patients had another CV event may suggest that TTh can have beneficial effects in men with a history of CVD, provided comprehensive secondary prevention therapy is already in place.
We and others have reported that TTh produces positive effects on blood pressure, glucose levels, insulin sensitivity, HbA1c levels, and MetS components.19–27 Diabetes is a major risk factor for CVD, and the majority of patients in this study were diabetics receiving standard treatment but with limited success according to their baseline HbA1c levels of 7.6%. Our findings corroborate previous reports that TTh ameliorates hyperglycemia and insulin resistance, which are sustained for a period of 8 years. This is of critical importance, because diabetes is a chronic, progressive disease, and TTh seems to successfully control it.

In men with testosterone deficiency and a history of cardiovascular disease, who received testosterone therapy for up to 8 years, a significant weight loss (from 114 kg to 91 kg) and a decrease in waist circumference (112 cm to 99 cm) was observed. BMI decreased from 37 to 29.
Cardio-metabolic parameters such as lipid profile, glycemic control, blood pressure, heart rate, and pulse pressure all improved significantly and sustainably.
No patient suffered a major adverse cardiovascular event during the full observation time.
In men with testosterone deficiency, testosterone therapy appears to be effective in achieving sustained improvements in all cardiometabolic risk factors, and may be effective as an add-on treatment for secondary prevention of cardiovascular events in testosterone deficient men with a history of cardiovascular disease.

9) Tan, Robert S., Kelly R. Cook, and William G. Reilly. “Myocardial Infarction and Stroke Risk in Young Healthy Men Treated with Injectable Testosterone.” (2015). Myocardial Infarction and Stroke Risk in Young Healthy Men Treated with Injectable Testosterone Tan Robert Kelly Cook 2015
This study was conducted to examine the association between testosterone therapy and new myocardial infarction (MI) and stroke events in a series of patients treated at Low T Centers across the United States, consisting of mainly young (mean age = 46), otherwise, healthy men. Electronic medical records were queried between the years 2009 and 2014 to identify patients diagnosed with hypogonadism, MI, and stroke, as indicated by ICD-9 codes. The incidence of MI and stroke events was compared to community-based registries. 39,936 patients recruited from 40 Low T Centers across the United States were treated and 19,968 met eligibility criteria for receiving testosterone treatment. The incidence rate ratio (IRR) for MI in testosterone- (T-) treated versus nontreated patients was 0.14 (C.I. = 0.08 to 0.18, ) whereas the IRR for stroke for T-treated versus nontreated patients was 0.11 (C.I. = 0.02 to 0.13, ).

There was no evidence of worsening preexisting MI or stroke in patients treated with testosterone.

The experience in Low T Centers shows that, in an injectable testosterone patient registry, testosterone is generally safe for younger men who do not have significant risk factors. Of patients that developed MI with testosterone, there was no association with testosterone or hematocrit levels.

10) Kelly, Daniel M., and T. Hugh Jones. “Testosterone and cardiovascular risk in men.” Cardiovascular Issues in Endocrinology. Vol. 43. Karger Publishers, 2014. 1-20. Myocardial Infarction and Stroke Risk in Young Healthy Men Treated with Injectable Testosterone Tan Robert Kelly Cook 2015

11) Park, Byoung-Jin, et al. “Inverse relationship between bioavailable testosterone and subclinical coronary artery calcification in non-obese Korean men.” Asian journal of andrology 14.4 (2012): 612-615. Inverse relationship testosterone and coronary artery calcification in men Park Byoung-Jin Asian journal andrology 2012

12) Morgentaler, Abraham, Allison Feibus, and Neil Baum. “Testosterone and cardiovascular disease–the controversy and the facts.” Postgraduate medicine 127.2 (2015): 159-165. Testosterone and cardiovascular disease controversy and the facts Morgentaler Abraham Postgraduate medicine 2015

In a group of men with angiographically confirmed CV disease, those with normal levels of T had a significantly longer survival than those with lower levels of T. Also, men with type 2 diabetes mellitus who had low T had a shorter survival than men with normal T but with type 2 diabetes mellitus. It is also of interest that a subgroup of men who had received treatment to normalize the decrease in their T levels had the same survival as those men who had a normal T level [20]. This study concluded that men with endogenous high T concentrations are inversely related to mortality due to CV disease and all causes. In fact, low T may be a predictive marker for those at high risk of CV disease.

Standard cautions are to avoid use of T in men with elevated hematocrit or prostate specific anti-gen, moderate-to-severe lower urinary tract symptoms, or obstructive sleep apnea.
Certainly there is controversy in the relationship between T and CV disease,but there exists good evidence that T is associated with a decrease in atherosclerosis, hypertension, IMT of the carotid arteries, insulin resistance, and mortality in men of all causes.

13) Morgentaler, Abraham. “Testosterone deficiency and cardiovascular mortality.” Asian journal of andrology 17.1 (2015): 26. Testosterone deficiency and cardiovascular mortality Asian journal of andrology Morgentaler Abraham 2015

14) English, Katherine M., et al. “Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina.” Circulation 102.16 (2000): 1906-1911.Testosterone improves angina threshold in men chronic stable angina English Katherine Circulation 2000

15) Malkin, C. J., et al. “Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life.” Heart 90.8 (2004): 871-876.Testosterone replacement in hypogonadal men with angina improves ischaemic threshold Malkin C J Heart

16) Khaw, Kay-Tee, et al. “Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men.” Circulation 116.23 (2007): 2694-2701. Endogenous testosterone mortality cardiovascular disease cancer men EPIC Khaw KayTee Circulation 2007

17) Gururani, Kunal, John Jose, and Paul V. George. “Testosterone as a marker of coronary artery disease severity in middle aged males.” Indian Heart Journal 68 (2016): S16-S20.
Historically, higher levels of serum testosterone were presumed deleterious to the cardiovascular system. In the last two decades, studies have suggested that low testosterone levels are associated with increased prevalence of risk factors for cardiovascular disease (CVD), including dyslipidemia and diabetes. This is a cross sectional study. The aim of our study was to determine the relationship between serum testosterone levels and angiographic severity of coronary artery disease (CAD). Serum testosterone levels were also correlated with flow mediated dilation of brachial artery (BAFMD) – an indicator of endothelial function. Consecutive male patients, aged 40-60 years, admitted for coronary angiography (CAG) with symptoms suggestive of CAD, were included in the study. Out of the 92 patients included in the study, 32 patients had normal coronaries and 60 had CAD on coronary angiography. Severity of CAD was determined by Gensini coronary score. The group with CAD had significantly lower levels of total serum testosterone (363±147.1 vs 532.09±150.5ng/dl, p<0.001), free testosterone (7.1215±3.012 vs 10.4419±2.75ng/dl, p<0.001) and bioavailable testosterone (166.17±64.810 vs 247.94±62.504ng/dl, p<0.001) when compared to controls. Adjusting for the traditional risk factors for CAD, a multiple linear regression analysis showed that low testosterone was an independent predictor of severity of CAD (β=-0.007, p<0.001). This study also showed that levels of total, free and bioavailable testosterone correlated positively with BAFMD %.

18) Li, Z. B., et al. “Testosterone therapy improves cardiac function of male rats with right heart failure.” Zhonghua nan ke xue= National journal of andrology 15.11 (2009): 994-1000.

19) Malkin, C. J., et al. “Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial.” European heart journal 27.1 (2006): 57. Testosterone therapy men moderate heart failure randomized trial Malkin C J European heart journal 2006

20) Pugh, P. J., et al. “Testosterone treatment for men with chronic heart failure.” Heart 90.4 (2004): 446-447.Testosterone treatment for men with chronic heart failure Pugh PJ Heart 2004

Aunt Minnie

21) Testosterone treatment raises levels of heart plaque
By Eric Barnes, AuntMinnie.com staff writer

“That might be overreplacing some of the necessary testosterone,” Budoff said. “I’m not saying testosterone in all forms of replacement is bad, I’m just suggesting that making a 70-year-old into a 45-year-old again may not be the healthiest thing for the coronary arteries. And that’s what our study suggests. There are some large-scale studies underway that will look at overall effect of testosterone supplementation on heart attack and stroke, and I think this study supports earlier data from the [Testosterone in Older Men (TOM)] trial showing some harm from taking testosterone.”

22) JAMA. 2015 Aug 11;314(6):570-81.
Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial.
Basaria S1, Bhasin S1 et al.
Testosterone use in older men is increasing, but its long-term effects on progression of atherosclerosis are unknown.
OBJECTIVE:To determine the effect of testosterone administration on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels.
DESIGN, SETTING, AND PARTICIPANTS:Testosterone’s Effects on Atherosclerosis Progression in Aging Men (TEAAM) was a placebo-controlled, double-blind, parallel-group randomized trial involving 308 men 60 years or older with low or low-normal testosterone levels (100-400 ng/dL; free testosterone <50 pg/mL), recruited at 3 US centers. Recruitment took place between September 2004 and February 2009; the last participant completed the study in May 2012.
INTERVENTIONS:One hundred fifty-six participants were randomized to receive 7.5 g of 1% testosterone and 152 were randomized to receive placebo gel packets daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL.
MAIN OUTCOMES AND MEASURES:Coprimary outcomes included common carotid artery intima-media thickness and coronary artery calcium; secondary outcomes included sexual function and health-related quality of life.
RESULTS:Baseline characteristics were similar between groups: patients were a mean age of 67.6 years; 42% had hypertension; 15%, diabetes; 15%, cardiovascular disease; and 27%, obesity. The rate of change in intima-media thickness was 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group (mean difference adjusted for age and trial site, 0.0002 mm/year; 95% CI, -0.003 to 0.003, P = .89). The rate of change in the coronary artery calcium score was 41.4 Agatston units/year in the placebo group and 31.4 Agatston units/year in the testosterone group (adjusted mean difference, -10.8 Agatston units/year; 95% CI, -45.7 to 24.2; P = .54). Changes in intima-media thickness or calcium scores were not associated with change in testosterone levels among individuals assigned to receive testosterone. Sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life did not differ significantly between groups. Hematocrit and prostate-specific antigen levels increased more in testosterone group.
CONCLUSIONS AND RELEVANCE:Among older men with low or low-normal testosterone levels, testosterone administration for 3 years vs placebo did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium nor did it improve overall sexual function or health-related quality of life. Because this trial was only powered to evaluate atherosclerosis progression, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men.

23) Coronary Artery Calcium Scoring Can Help Guide Statin Therapy
Matthew J. Budoff, MD January 14, 2016

CAC scores of either > 75th percentile for age and gender or ≥ 300 (Agatston units) are deemed high risk per the 2013 cholesterol guidelines[23] and warrant high-dose statins. In the St Francis Heart randomized study, atorvastatin reduced cardiovascular events by 42% in those with scores > 400, with an NNT to reduce one myocardial infarction or death of only 17.[24] On the basis of current guidelines from both NCEP and ACC/AHA:
CAC scores < 75th percentile and < 300 are to be treated with low- to moderate-dose statins.
CAC scores > 75th percentile or ≥ 300 are to be treated with high-dose statins.
CAC score of zero should be considered for lifestyle modification, unless a compelling indication for statin already exists.

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24) Atherosclerosis Speeds Up in Older Men on Testosterone: T Trial
Marlene Busko February 24, 2017

Most were obese (mean body-mass index [BMI] 30), hypertensive (66%), or former smokers (66%), and close to a third had type 2 diabetes (30%). The men had an average coronary artery calcium score of 250 Agatston units, which is “pretty high but not an outrageous number; you would expect a 70-year-old man to have some coronary calcium,” according to Budoff.

serum testosterone levels in the normal range for young men (280–873 ng/dL

From baseline to 12 months, the median volume of noncalcified plaque increased from 204 mm3 to 232 mm3 in the treatment group but only from 317 mm3 to 325 mm3 in the placebo group—a difference of 41 mm3 (P=0.003).

During the same time, the median total plaque volume increased from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm 3 to 541 mm3 in the placebo group (P=0.006).

The increased plaque progression in the testosterone group was similar after adjustment for higher baseline plaque values in the placebo group.

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 (P=0.31).

25) Snyder, Peter J., et al. “THE TESTOSTERONE TRIALS: THE DESIGN OF SEVEN COORDINATED TRIALS TO DETERMINE IF TESTOSTERONE TREATMENT BENEFITS ELDERLY MEN.” Clinical trials (London, England) 11.3: 362.

26) February 21, 2017 Testosterone and Male Aging Faltering Hope for Rejuvenation. David J. Handelsman, JAMA. 2017;317(7)
Glueck, Charles J., et al. “Thrombophilia in 67 patients with thrombotic events after starting testosterone therapy.” Clinical and Applied Thrombosis/Hemostasis 22.6 (2016): 548-553.

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27) February 21, 2017. jama, Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone
Matthew J. Budoff, MD1M, Shalender Bhasin, MD6; Elizabeth Barrett-Connor, MD7; Shehzad Basaria, ET AL
JAMA. 2017;317(7):708-716.
Question Is testosterone treatment of older men with low testosterone associated with a decrease in noncalcified coronary artery plaque volume?
Findings In a controlled clinical trial, 1 year of testosterone treatment of men aged 65 years or older with a low serum testosterone level was associated with a significant increase in noncalcified coronary artery plaque volume of 41 mm3 more than placebo.
Meaning Testosterone treatment of older men was associated with an increase in coronary artery plaque volume, but additional studies are needed to determine the clinical significance.
Abstract
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
Although testosterone replacement is increasingly being used clinically,1 the cardiovascular benefits and risks of testosterone administration to older men with age-related decline in testosterone levels remain uncertain. Several observational studies show an inverse association between serum testosterone concentration and adverse cardiovascular outcomes, the metabolic syndrome, diabetes, and mortality,2- 5 independent of traditional cardiovascular risk factors.
Studies of the effects of testosterone on clinical cardiovascular outcomes are conflicting.6 Meta-analyses of clinical trials have shown no association between testosterone treatment and cardiovascular adverse events, but none of the individual trials included in the meta-analyses were designed to assess these events prospectively. A clinical trial in older men with mobility limitation showed an excess of cardiovascular adverse events in men treated with testosterone compared with placebo,7 but another trial in a similar population did not.8 These trials were also not designed to assess cardiovascular adverse events. Retrospective analyses of electronic medical records to evaluate the possible association of testosterone treatment with cardiovascular adverse events have also yielded conflicting results.9- 13
The Testosterone Trials (TTrials), a group of 7 placebo-controlled, coordinated trials, were designed to determine the efficacy of testosterone treatment of men aged 65 years or older with low testosterone concentrations for no apparent reason other than age. The Cardiovascular Trial was designed to test the hypothesis that testosterone treatment of older men with low testosterone slows the progression of noncalcified coronary artery plaque volume, assessed by coronary computed tomographic angiography (CCTA), as an indicator of coronary atherosclerosis.

28) Tam, Lori M., et al. “Absolute coronary artery calcium score is the best predictor of non-calcified plaque involvement in patients with low calcium scores (1e100).” Atherosclerosis 230.7 (2013): 6e79.
Our results suggest that the absolute calcium score is the best predictor of NCP burden in patients with low CAC scores. Absolute coronary artery calcium score is the best predictor of non-calcified plaque involvement in patients with low calcium scores Tam Lori Atherosclerosis 2013

29) Int J Cardiovasc Imaging. 2011 Dec;27 Suppl 1:27-35. doi: 10.1007/s10554-011-9968-1. Epub 2011 Nov 24.
Significance of noncalcified coronary plaque in asymptomatic subjects with low coronary artery calcium score: assessment with coronary computed tomography angiography. Yoo DH1, Chun EJ, Choi SI, Kim JA, Jin KN, Yeon TJ, Choi DJ.

We aimed to investigate the prevalence and severity of noncalcified coronary plaques (NCP) using coronary CT angiography (CCTA) and analyze predictors of significant coronary stenosis by NCP in asymptomatic subjects with low coronary artery calcium score (CACS). The institutional review board approved this retrospective study and all patients gave written, informed consent. The presence of plaque, severity of stenosis, plaque characteristics, and CACS were assessed in 7,515 asymptomatic subjects. We evaluated the prevalence and severity of NCP in subjects having low CACS (707 subjects; men with CACS from 1 to 50 and women from 1 to 10) in comparison to those having 0 CACS (6,040 subjects) as the reference standard. Conventional risk factors were assessed for predictors of NCP and significant stenosis by NCP. We also investigated the cardiac events of the patients through medical records. Compared to subjects with 0 CACS, those with low CACS showed higher prevalence of NCP (6.9% vs. 31.5%, P < 0.001) and significant stenosis caused by NCP (0.8% vs. 7.5%, P < 0.001). In the low CACS group, independent predictors for significant NCP included diabetes mellitus (DM), hypertension, and elevated low-density lipoprotein (LDL)-cholesterol (all P < 0.05). However, 47.2% of subjects with significant NCP were classified into the low to intermediate risk according to Framingham Risk Score. At the median follow up of 42 months (range: 3-60 months), cardiac events were significantly higher in the low CACS group compared to the 0 CACS group (2.6% vs. 0.27%, P < 0.001). In asymptomatic subjects having low CACS, the prevalence and severity of NCP were higher as compared to subjects having zero CACS and predictors of significant stenosis by NCP were DM, hypertension and LDL-Cholesterol. Therefore, CCTA may be useful for risk stratification of coronary artery disease as added value over CACS in selected populations with low CACS who have predictors of significant NCP.

30) J Am Coll Cardiol. 2011 Oct 18; 58(17): 1807–1816.
Quantitative Relationship Between the Extent and Morphology of Coronary Atherosclerotic Plaque and Downstream Myocardial Perfusion
Masanao Naya, MD, PhD, Venkatesh L. Murthy, MD, PhD, Ron Blankstein, MD, Arkadiusz Sitek, PhD, Jon Hainer, BS, Courtney Foster, CNMT, Mariya Gaber, MLA, Jolene M. Fantony, CNMT, Sharmila Dorbala, MD, and Marcelo F. Di Carli, MD
The purpose of this study was to quantify the effects of coronary atherosclerosis morphology and extent on myocardial flow reserve (MFR).
Background Although the relationship between coronary stenosis and myocardial perfusion is well established, little is known about the contribution of other anatomic descriptors of atherosclerosis burden to this relationship.
MethodsWe evaluated the relationship between atherosclerosis plaque burden, morphology, and composition and regional MFR (MFRregional) in 73 consecutive patients undergoing Rubidium-82 positron emission tomography and coronary computed tomography angiography for the evaluation of known or suspected coronary artery disease.
Results
Atherosclerosis was seen in 51 of 73 patients and in 107 of 209 assessable coronary arteries. On a per-vessel basis, the percentage diameter stenosis (p = 0.02) or summed stenosis score (p = 0.002), integrating stenoses in series, was the best predictor of MFRregional. Importantly, MFRregional varied widely within each coronary stenosis category, even in vessels with nonobstructive plaques (n = 169), 38% of which had abnormal MFRregional (<2.0). Total plaque length, composition, and remodeling index were not associated with lower MFR. On a per-patient basis, the modified Duke CAD (coronary artery disease) index (p = 0.04) and the number of segments with mixed plaque (p = 0.01) were the best predictors of low MFRglobal.
Conclusions Computed tomography angiography descriptors of atherosclerosis had only a modest effect on downstream MFR. On a per-patient basis, the extent and severity of atherosclerosis as assessed by the modified Duke CAD index and the number of coronary segments with mixed plaque were associated with decreased MFR.

31) Gaur, Sara, et al. “Coronary plaque quantification and fractional flow reserve by coronary computed tomography angiography identify ischaemia-causing lesions.” European heart journal 37.15 (2016): 1220-1227.

32) Noncalcified Atherosclerotic Plaque Burden at Coronary CT Angiography: A Better Predictor of Ischemia at Stress Myocardial Perfusion Imaging Than Calcium Score and Stenosis Severity
Ralf W. Bauer1 2, Christian Thilo1, Salvatore A. Chiaramida3, Thomas J. Vogl2, Philip Costello1 and U. Joseph Schoepf1 3

33) Mathur, Atish, et al. “Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men.” European Journal of Endocrinology 161.3 (2009): 443-449.

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34) Toma, Mustafa, et al. “Testosterone Supplementation in Heart Failure Clinical Perspective.” Circulation: Heart Failure 5.3 (2012): 315-321.
Tone 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.

Trial Registration clinicaltrials.gov Identifier: NCT00799617
Introduction

Although testosterone replacement is increasingly being used clinically,1 the cardiovascular benefits and risks of testosterone administration to older men with age-related decline in testosterone levels remain uncertain. Several observational studies show an inverse association between serum testosterone concentration and adverse cardiovascular outcomes, the metabolic syndrome, diabetes, and mortality,2- 5 independent of traditional cardiovascular risk factors.

The Testosterone Trials (TTrials), a group of 7 placebo-controlled, coordinated trials, were designed to determine the efficacy of testosterone treatment of men aged 65 years or older with low testosterone concentrations for no apparent reason other than age. The Cardiovascular Trial was designed to test the hypothesis that testosterone treatment of older men with low testosterone slows the progression of noncalcified coronary artery plaque volume, assessed by coronary computed tomographic angiography (CCTA), as an indicator of coronary atherosclerosis.

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