AAS and Cardiovascular/Pulmonary Function

[Michael Scally MD]

Cecchi R, Muciaccia B, Ciallella C, et al. Ventricular androgenic-anabolic steroid-related remodeling: an immunohistochemical study. Int J Legal Med. https://link.springer.com/article/10.1007%2Fs00414-017-1589-3

BACKGROUND: Several fatal cases of bodybuilders, following a myocardial infarction after long exposure to androgenic-anabolic steroids (AAS), are reported. In recent years, evidence has emerged of cases of heart failure related to AAS consumption, with no signs of coronary or aorta atherosclerosis. This study aims to further investigate the pathogenesis of the ventricular AAS-related remodeling performing immunohistochemistry (IHC).

METHOD: In order to examine innate immunity activity and myocytes and endothelial cell apoptosis, IHC analyses were performed on heart tissue of two cases of bodybuilders who died after years of supratherapeutic use of metelonone and nandrolone and where no atherosclerosis or thrombosis were found, using the following antibodies: anti-CD68, anti-iNOS, anti-CD163, anti-CD 15, anti-CD8, anti-CD4, anti-HIF1 alpha, and in situ TUNEL staining.

RESULTS: Results confirm the experimental findings of recent research that, in the absence of other pathological factors, if intensive training is combined with AAS abuse, myocytes and endothelial cells undergo apoptotic alterations. The absence of inflammatory reactions and the presence of an increased number of M2 macrophages in the areas of fibrotic remodeling confirm that the fibrotic changes in the heart are apoptosis-related and not necrosis-related.

CONCLUSIONS: In conclusion, the study indicates that, in very young subjects with chronic hypoxia-related alterations of the heart, signs of a heart failure in the other organs and a history of AAS abuse, death can be ascribed to progressive heart failure due to the direct apoptotic cardiac and endothelial changes produced by AAS.

 

[Michael Scally MD]

Pergolizzi B, Carriero V, Abbadessa G, et al. Subchronic nandrolone administration reduces cardiac oxidative markers during restraint stress by modulating protein expression patterns. Mol Cell Biochem. https://link.springer.com/article/10.1007%2Fs11010-017-3036-7

Nandrolone decanoate (ND), an anabolic-androgenic steroid prohibited in collegiate and professional sports, is associated with detrimental cardiovascular effects through redox-dependent mechanisms.

We previously observed that high-dose short-term ND administration (15 mg/kg for 2 weeks) did not induce left heart ventricular hypertrophy and, paradoxically, improved postischemic response, whereas chronic ND treatment (5 mg/kg twice a week for 10 weeks) significantly reduced the cardioprotective effect of postconditioning, with an increase in infarct size and a decrease in cardiac performance.

We wanted to determine whether short-term ND administration could affect the oxidative redox status in animals exposed to acute restraint stress. Our hypothesis was that, depending on treatment schedule, ND may have a double-edged sword effect.

Measurement of malondialdehyde and 4-hydroxynonenal, two oxidative stress markers, in rat plasma and left heart ventricular tissue, revealed that the levels of both markers were increased in animals exposed to restraint stress, whereas no increase in marker levels was noted in animals pretreated with ND, indicating a possible protective action of ND against stress-induced oxidative damage.

Furthermore, isolation and identification of proteins extracted from the left heart ventricular tissue samples of rats pretreated or not with ND and exposed to acute stress showed a prevalent expression of enzymes involved in amino acid synthesis and energy metabolism.

Among other proteins, peroxiredoxin 6 and alpha B-crystallin, both involved in the oxidative stress response, were predominantly expressed in the left heart ventricular tissues of the ND-pretreated rats.

In conclusion, ND seems to reduce oxidative stress by inducing the expression of antioxidant proteins in the hearts of restraint-stressed animals, thus contributing to amelioration of postischemic heart performance.

 

[JRA]

Did these article authors go to same writing class as attorneys? Also, and sorry if I missed the conversion, but what is the human male equivalent amount of "Chronic administration of anabolic androgenic steroids (AAS) in adult rats"?

Edit: "
Let's see so @ 10mg/kg THREE times a WEEK the "average" 80kg BB would be pinning
TWO THOUSAND FOUR-HUNDRED mg of DECA !! (compare that to the average therapeutic dose in humans of between 50-100 mg/wk AND an "average BB dose" of between 200-800mg/wk)"

Thanks Dr. Jim

 

[JRA]

Which in my opinion keeps proper studies of AAS use in humans in the dark. Obviously science isn't about to take human guinea pigs and inject those doses. I wonder if we will ever truly get an unbiased opinion on AAS use that actually uses BB doses? Wishful thinking on my part. To both doctors, I am going up to Harvard University the week after Thanksgiving. They are going to perform some genetic testing on me. I won't have answers right away, but I'll let you know how it goes. Hope all is well Doc.

Maybe, like in the NFL for concussions, doctors could be allowed by families to perform autopsies for AAS abuse in certain cases.

 

[hurricane]

Pergolizzi B, Carriero V, Abbadessa G, et al. Subchronic nandrolone administration reduces cardiac oxidative markers during restraint stress by modulating protein expression patterns. Mol Cell Biochem. https://link.springer.com/article/10.1007%2Fs11010-017-3036-7

Nandrolone decanoate (ND), an anabolic-androgenic steroid prohibited in collegiate and professional sports, is associated with detrimental cardiovascular effects through redox-dependent mechanisms.

We previously observed that high-dose short-term ND administration (15 mg/kg for 2 weeks) did not induce left heart ventricular hypertrophy and, paradoxically, improved postischemic response, whereas chronic ND treatment (5 mg/kg twice a week for 10 weeks) significantly reduced the cardioprotective effect of postconditioning, with an increase in infarct size and a decrease in cardiac performance.

We wanted to determine whether short-term ND administration could affect the oxidative redox status in animals exposed to acute restraint stress. Our hypothesis was that, depending on treatment schedule, ND may have a double-edged sword effect.

Measurement of malondialdehyde and 4-hydroxynonenal, two oxidative stress markers, in rat plasma and left heart ventricular tissue, revealed that the levels of both markers were increased in animals exposed to restraint stress, whereas no increase in marker levels was noted in animals pretreated with ND, indicating a possible protective action of ND against stress-induced oxidative damage.

Furthermore, isolation and identification of proteins extracted from the left heart ventricular tissue samples of rats pretreated or not with ND and exposed to acute stress showed a prevalent expression of enzymes involved in amino acid synthesis and energy metabolism.

Among other proteins, peroxiredoxin 6 and alpha B-crystallin, both involved in the oxidative stress response, were predominantly expressed in the left heart ventricular tissues of the ND-pretreated rats.

In conclusion, ND seems to reduce oxidative stress by inducing the expression of antioxidant proteins in the hearts of restraint-stressed animals, thus contributing to amelioration of postischemic heart performance.

I think I told you before @Dr. Scally but I have the B protein disorder. I am deficient in it. I've never really had a long discussion about it with my cardiologist or EP. I'm assuming its because I've been tested for CHF and don't have it. Also my dangerous rhythms don't come from the lower chambers. If I remember correctly my Doctors said that would be much worse. Anyways I'm doing well. Saw my EP last Monday and everything is pretty well. EF is staying around 40-45 and have had fewer episodes of a fib and flutter(I'm assuming because of the ablation). I remain on xarelto, coreg, and ivabradine. Hope all is well.

 

[Michael Scally MD]

Ference BA, Ginsburg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Euro Heart J. 2017. https://academic.oup.com/eurheartj/article/3745109/Low-density-lipoproteins-cause-atherosclerotic?searchresult=1

Aims - To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).

Methods and results - We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies.

In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD.

Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C.

Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects.

Conclusion - Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.

 

[Michael Scally MD]

[OA] Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration

PURPOSE: Undertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk.

DESIGN: Two-sample Mendelian randomization investigation using published data.

PARTICIPANTS: A total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium.

METHODS: We consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD.

We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy.

We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk.

We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison.

MAIN OUTCOME MEASURES: Diagnosis of AMD.

RESULTS: We find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol.

No causal effect of LDL-cholesterol or triglycerides was found.

Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD.

CONCLUSIONS: Some genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk.

Burgess S, Davey Smith G. Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration. Ophthalmology. http://www.aaojournal.org/article/S0161-6420(16)32310-7/fulltext

 

[Michael Scally MD]

Stroke In The Setting Of Testosterone Abuse [Abstract #900]

Case Presentation: A 28 year-old male presented with complaint of acute-onset vertigo while lifting weights. He also had associated nausea, emesis and an unsteady gait. His exam was notable for ataxia on the right during finger-to-nose testing. Imaging studies included magnetic resonance imaging of the brain which revealed small acute infarcts involving the left cerebellum and brainstem and was suggestive of an embolic pattern.

He was found to have total testosterone 2626 ng/dL, calculated free testosterone 5104 pmol/L and estradiol level 22.3 pg/mL. His lipid profile revealed LDL 186 mg/dL, triglycerides 104 mg/dL, total cholesterol 225 mg/dL, and HDL 18 mg/dL His liver function studies revealed AST 47 IU/L and ALT 51 IU/L.

Extensive testing for pro-thrombotic disorders was unrevealing. A trans-thoracic echocardiogram revealed mild concentric left ventricular hypertrophy with ejection fraction of 50-55%. A trans-esophageal echocardiogram (TEE) was also performed with agitated saline which did suggest a small patent foramen ovale (PFO).

Further history revealed that the patient was otherwise healthy but had been abusing testosterone and trenbolone (an oral androgen resistant to aromatase) for at least six years. He was self-administering testosterone injections of 325mg every other day and using unspecified amounts of trenbolone. The patient denied having a family history of stroke or myocardial infarction.

The patient was started on Atorvastatin 80 mg daily. He was also discharged on Eliquis because of the cryptogenic nature of the stroke and presence of a PFO. He was strongly advised to stop testosterone therapy.

Discussion: This case describes a cerebrovascular event related to exogenous testosterone use in an otherwise healthy young male. The patient may have had a deep vein thrombosis that embolized to his brain in the setting of a pre-existing PFO. Testosterone supplementation has been associated with both erythrocytosis and dyslipidemia, specifically increased LDL and reduced HDL cholesterol.

Previous case reports and case series studies have also suggested a correlation between thrombophilia and exogenous testosterone use, generally in the setting of a preexisting prothrombotic disorder. These events typically manifest as deep vein thrombosis or pulmonary embolus. In 2014 the FDA also added a general warning requirement in testosterone drug labeling about the risk of venous thromboembolism.

Conclusion: The case demonstrates a serious adverse effect of exogenous testosterone use. A careful review of a patient’s risk status including prior history of thrombotic events and stroke as well as a discussion of risk and benefit is important before initiating testosterone therapy.

 

[Michael Scally MD]

Testosterone Replacement Therapy for Secondary Hypogonadism and Risk of Myocardial Infarction, Stroke or All-Cause Mortality [Abstract #906]
http://am.aace.com/files/Abstract-Book_ALL.pdf

Objective: To evaluate the effect of testosterone replacement therapy (TRT) on the risk of myocardial infarction (MI), stroke (CVA) or all-cause mortality, in men with secondary hypogonadism.

Methods: We conducted a retrospective cohort study using the electronic health record in a large, integrated healthcare system. Men ≥ 40 years of age, with at least two testosterone levels < 220 ng/dL, with one level obtained between 7am and 10am, were identified.

Men with primary hypogonadism, secondary hypogonadism related to overt hypothalamic pituitary pathology, Human Immunodeficiency Virus infection, metastatic cancer, history of prostate cancer, prostate specific antigen > 4ng/mL, elevated hematocrit, or history of previous thromboembolic disease were excluded.

Men exposed to TRT were matched 1:1 with replacement to controls that were not exposed on the following variables: duration of low testosterone, age, income, diabetes diagnosis, smoking status, LDL cholesterol, hypertension diagnosis, statin use, body mass index, and history of established cardiovascular or cerebrovascular disease. A survival analysis was performed on the composite outcome of MI, CVA, or all-cause mortality.

Results: 418 patients exposed to TRT were matched with 283 controls. The median (IQR) age (years), and the prevalence of established CVD (%), in the TRT exposed group vs. the control group were 53.8 (47.3, 60.1) vs. 54.9 (49.9, 61.4), P=0.04 and 9.8% vs. 12.7%, P=0.23, respectively. The median duration of follow-up (years) for the TRT exposed group was 3.8 vs. 3.4 in the control group (P=0.02).

The event rate (composite outcome) of the TRT exposed group was 3.3% vs. 6.4% in the control group (P=0.06). Exposure to TRT reduced the odds of the combined cardiovascular endpoint (Hazard Ratio: 0.49; 95% CI: 0.24 to 0.99; p=0.046).

Discussion: TRT in hypogonadal men has become a controversial topic over the past decade. There has been continued concern regarding whether or not TRT increases the risk of adverse cardiovascular outcomes or mortality. The available data has been conflicting. The effect of TRT may vary considerably depending on the etiology of low testosterone, the patient’s age, and whether or not they have established CV disease.

Our study adds to the growing body of evidence which has suggested TRT may afford a protective effect in certain populations of hypogonadal men.

Conclusion: In a population of hypogonadal men with a rather low prevalence of established CVD, TRT may confer a protective effect on the risk of MI, CVA or mortality. These results would support future prospective studies evaluating the effect of TRT in men with secondary hypogonadism.

 

[Michael Scally MD]

Age Distribution of Myocardial Infarction Patients on Testosterone: The Low T Experience [Abstract #922]
http://am.aace.com/files/Abstract-Book_ALL.pdf

Objective: There are ongoing concerns for safety with testosterone therapy. Our goal was to assess if MI occur at an earlier age in patents with testosterone therapy among our Low T Center patients. These 48 community based centers across the United States have strict protocols requiring regular 1-2 week monitoring in the office for efficacy and safety.

Methods: Following IRB application and GCP training, we conducted a retrospective analysis of patients that had MI post testosterone therapy. Data was extracted from our electronic health record (Advance MD) of the multi-site Low T Centers. Prior to extraction of data; ICD-9 were updated to ICD-10, with attention to MI. We also did case findings on patients that had MI and reviewed risk factors.

Results: A total of 96,065 charts of patients seen between years 2009-2016 were reviewed. Using ICD definition of MI (ICD 9: 412 & ICD-10: I21.29), there were 174 identified cases of MI, giving an overall prevalence of 1.8 cases per 1000 male adults.

The rate of MI by age is reported below: <40= 0.03%, 40-60= 0.2%, 61-80= 0.62%, > 80= 0. The rate of MI was compared to the NHANES data set which was <40= 0.3%, 40-60= 3.3%, 61-80= 11.3%, > 80= 17.3% respectively. Comparative statistics were applied for the 2 groups and the rate ratio (RR) for MI in the Low T group versus the NHANES group was 0.1, 0.06, 0.05, 0 (p= 0.0001) respectively. The rate of increase of MI with age in both data set was compared for those <40 to 80 years (R2= 0.99, C.I. 14-74-22.7)

Discussion: Patients who get MIs may or may not be receiving testosterone concurrently. The rate of MI appears to be a function of age. We find that our rate of MI increases with age, akin to other population data sets, except after 80. We postulate that we have few patients (147) in that age group and hence did not detect MI. Testosterone treated patients in our cohort have consistently lower rates of MI than community based models at every age group.

Conclusion: This study further supports a non-associative role of testosterone with MI, and even suggesting a protective effect of testosterone against MI, considering finding lower rates of MI in all age groups with patients on testosterone as compared to a general community sample.

Our study shows that there is no evidence to suggest that testosterone leads to the development of MI at an earlier age. MI rates rises with age in testosterone treated patients like in community models. There are limitations to this observational study and causal links cannot be established.

 

[hurricane]

Stroke In The Setting Of Testosterone Abuse [Abstract #900]

Case Presentation: A 28 year-old male presented with complaint of acute-onset vertigo while lifting weights. He also had associated nausea, emesis and an unsteady gait. His exam was notable for ataxia on the right during finger-to-nose testing. Imaging studies included magnetic resonance imaging of the brain which revealed small acute infarcts involving the left cerebellum and brainstem and was suggestive of an embolic pattern.

He was found to have total testosterone 2626 ng/dL, calculated free testosterone 5104 pmol/L and estradiol level 22.3 pg/mL. His lipid profile revealed LDL 186 mg/dL, triglycerides 104 mg/dL, total cholesterol 225 mg/dL, and HDL 18 mg/dL His liver function studies revealed AST 47 IU/L and ALT 51 IU/L.

Extensive testing for pro-thrombotic disorders was unrevealing. A trans-thoracic echocardiogram revealed mild concentric left ventricular hypertrophy with ejection fraction of 50-55%. A trans-esophageal echocardiogram (TEE) was also performed with agitated saline which did suggest a small patent foramen ovale (PFO).

Further history revealed that the patient was otherwise healthy but had been abusing testosterone and trenbolone (an oral androgen resistant to aromatase) for at least six years. He was self-administering testosterone injections of 325mg every other day and using unspecified amounts of trenbolone. The patient denied having a family history of stroke or myocardial infarction.

The patient was started on Atorvastatin 80 mg daily. He was also discharged on Eliquis because of the cryptogenic nature of the stroke and presence of a PFO. He was strongly advised to stop testosterone therapy.

Discussion: This case describes a cerebrovascular event related to exogenous testosterone use in an otherwise healthy young male. The patient may have had a deep vein thrombosis that embolized to his brain in the setting of a pre-existing PFO. Testosterone supplementation has been associated with both erythrocytosis and dyslipidemia, specifically increased LDL and reduced HDL cholesterol.

Previous case reports and case series studies have also suggested a correlation between thrombophilia and exogenous testosterone use, generally in the setting of a preexisting prothrombotic disorder. These events typically manifest as deep vein thrombosis or pulmonary embolus. In 2014 the FDA also added a general warning requirement in testosterone drug labeling about the risk of venous thromboembolism.

Conclusion: The case demonstrates a serious adverse effect of exogenous testosterone use. A careful review of a patient’s risk status including prior history of thrombotic events and stroke as well as a discussion of risk and benefit is important before initiating testosterone therapy.

Holy shit! He's lucky to be alive. When I had my PE I thought I was dead. I was at a friends watching the Orioles when my left side went numb and I couldn't breathe. I told him to dial 911. The police were first to arrive and I kept going in and out of consciousness. I was trying so hard not to act like a pussy(the woman officer was HOT). when the paramedics showed up they said they needed me to walk down the stairs because they couldn't carry me. LOL. I weighed about 270 and was only on test. I was rushed to Yale where Dr Marieb found the PE. Scariest day of my life. Thank GOD it didn't get to my heart. I am surprised he had a relatively good EF. I also had very high cholesterol which through diet has become normal. This is a wonderful article Dr. Scally. It should be read before you can even join the forum. I'm serious. 90% have zero idea what they may be setting themselves up for. Thanks for caring about us. Best Wishes. HC.

 

[Michael Scally MD]

Sharma R, Oni OA, Gupta K, et al. Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. J Am Heart Assoc 2017;6(5). Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation | Journal of the American Heart Association

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac dysrhythmia associated with significant morbidity and mortality. Several small studies have reported that low serum total testosterone (TT) levels were associated with a higher incidence of AF. In contrast, it is also reported that anabolic steroid use is associated with an increase in the risk of AF. To date, no study has explored the effect of testosterone normalization on new incidence of AF after testosterone replacement therapy (TRT) in patients with low testosterone.

METHODS AND RESULTS: Using data from the Veterans Administrations Corporate Data Warehouse, we identified a national cohort of 76 639 veterans with low TT levels and divided them into 3 groups. Group 1 had TRT resulting in normalization of TT levels (normalized TRT), group 2 had TRT without normalization of TT levels (nonnormalized TRT), and group 3 did not receive TRT (no TRT). Propensity score-weighted stabilized inverse probability of treatment weighting Cox proportional hazard methods were used for analysis of the data from these groups to determine the association between post-TRT levels of TT and the incidence of AF. Group 1 (40 856 patients, median age 66 years) had significantly lower risk of AF than group 2 (23 939 patients, median age 65 years; hazard ratio 0.90, 95% CI 0.81-0.99, P=0.0255) and group 3 (11 853 patients, median age 67 years; hazard ratio 0.79, 95% CI 0.70-0.89, P=0.0001). There was no statistical difference between groups 2 and 3 (hazard ratio 0.89, 95% CI 0.78- 1.0009, P=0.0675) in incidence of AF.

CONCLUSIONS: These novel results suggest that normalization of TT levels after TRT is associated with a significant decrease in the incidence of AF.

 

[hurricane]

Sharma R, Oni OA, Gupta K, et al. Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. J Am Heart Assoc 2017;6(5). Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation | Journal of the American Heart Association

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac dysrhythmia associated with significant morbidity and mortality. Several small studies have reported that low serum total testosterone (TT) levels were associated with a higher incidence of AF. In contrast, it is also reported that anabolic steroid use is associated with an increase in the risk of AF. To date, no study has explored the effect of testosterone normalization on new incidence of AF after testosterone replacement therapy (TRT) in patients with low testosterone.

METHODS AND RESULTS: Using data from the Veterans Administrations Corporate Data Warehouse, we identified a national cohort of 76 639 veterans with low TT levels and divided them into 3 groups. Group 1 had TRT resulting in normalization of TT levels (normalized TRT), group 2 had TRT without normalization of TT levels (nonnormalized TRT), and group 3 did not receive TRT (no TRT). Propensity score-weighted stabilized inverse probability of treatment weighting Cox proportional hazard methods were used for analysis of the data from these groups to determine the association between post-TRT levels of TT and the incidence of AF. Group 1 (40 856 patients, median age 66 years) had significantly lower risk of AF than group 2 (23 939 patients, median age 65 years; hazard ratio 0.90, 95% CI 0.81-0.99, P=0.0255) and group 3 (11 853 patients, median age 67 years; hazard ratio 0.79, 95% CI 0.70-0.89, P=0.0001). There was no statistical difference between groups 2 and 3 (hazard ratio 0.89, 95% CI 0.78- 1.0009, P=0.0675) in incidence of AF.

CONCLUSIONS: These novel results suggest that normalization of TT levels after TRT is associated with a significant decrease in the incidence of AF.

Very interesting study being a veteran myself. Not in my 60's yet. My test levels when they were checked in October was 593 TT. I don't remember my free test but I know it was right in the middle. I know myself and my doctors will never know, but I wish I knew definitively if it was AAS use or genetics or something else. I know it wouldn't change my course of treatment but it would be nice to know.

 

[Michael Scally MD]

Rasmussen JJ, Schou M, Selmer C, et al. Insulin sensitivity in relation to fat distribution and plasma adipocytokines among abusers of anabolic androgenic steroids. Clinical Endocrinology. Insulin sensitivity in relation to fat distribution and plasma adipocytokines among abusers of anabolic androgenic steroids

Objective: Abuse of anabolic androgenic steroids (AAS) is prevalent among young men, but information regarding effects on insulin sensitivity and fat distribution is limited. The objective was to investigate insulin sensitivity in relation to fat distribution and adipocytokines among current and former AAS abusers compared with controls.

Design: Cross-sectional study among men involved in recreational strength training. Current and former AAS abusers (n=37 and n=33) and controls (n=30) volunteered from the community.

Methods: We assessed insulin sensitivity by Matsuda index (oral glucose tolerance test). Using overnight fasting blood samples, adiponectin and leptin were measured. Body composition and fat distribution, including visceral adipose tissue (VAT), were assessed by dual energy x-ray absorptiometry.

Results: Current and former AAS abusers displayed lower Matsuda index than controls (%-difference (95%CI) from controls, -26% (-45; -1) and -39% (-55; -18)). Testosterone was markedly higher among current AAS abusers and subnormal among former AAS abusers compared with controls.

Current AAS abusers displayed higher mean VAT than controls (388 (17) versus 293 (12) cm3, P < 0.001) whereas body fat %, adiponectin and leptin concentrations were lower.

In contrast, former AAS abusers showed highest leptin concentrations and body fat %.

Multivariate linear regressions identified VAT as independent predictor of lower Matsuda index among current AAS abusers compared with controls; while body fat % independently predicted lower Matsuda index among former AAS abusers.

Conclusions: Both current and former AAS abusers displayed lower insulin sensitivity which could be mediated by higher VAT and total body fat %, respectively.

 

[Michael Scally MD]

Corona G, Dicuio M, Rastrelli G, et al. Testosterone treatment and cardiovascular and venous thromboembolism risk: what is 'new'? J Investig Med. Testosterone treatment and cardiovascular and venous thromboembolism risk: what is ‘new’? | JIM

In men, testosterone (T) production declines as a function of ageing. Late-onset hypogonadism (LOH) is the most commonly used term to indicate this age-related condition. In LOH, the relative clinical significance and the potential benefit of testosterone treatment (TTh) are still the subject of strong criticisms in the scientific community.

The debate is further complicated by the recent position statement of the US Food and Drug Administration (FDA) emphasizing that, in LOH, the benefits and safety of TTh have not been fully established. Hence, the FDA required a labeling change to inform patients about a possible increased cardiovascular (CV) risk of TTh.

Similar considerations were previously released by the FDA and by Health Canada concerning a TTh-related venous thromboembolism (VTE) risk. In this review, we will summarize the available evidence concerning a possible link among TTh and CV and VTE risks.

For this purpose, data derived from epidemiological studies analyzing relationships between the aforementioned risks and endogenous T levels will be analyzed. In addition, evidence deriving from interventional studies including pharmacoepidemiological and placebo-controlled randomized controlled trials (RCTs) will be examined.

Our analysis shows that available data do not support an increased CV risk related to TTh. Similar considerations can be drawn for the relationship between TTh and VTE. The previously reported cases of TTh-related VTE were frequently related to a previously undiagnosed thrombophilia-hypofibrinolysis status.

Hence, an anamnestic screening for thrombophilia before starting TTh is recommended, just as it is for the use of oral contraceptives.

 

[Michael Scally MD]

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease


LDL drops by 30%; HDL more than doubles. But drug (evacetrapib) has no effect on events/outcomes.

“The negative results of the current trial therefore reinforce the principle that biologic plausibility and beneficial effects on surrogate end points do not obviate the need for adequately powered outcome trials of new therapeutic agents.”

Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease. New England Journal of Medicine 2017;376(20):1933-42. http://www.nejm.org/doi/full/10.1056/NEJMoa1609581

BACKGROUND - The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease.

METHODS - In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease.

Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy.

The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.

RESULTS - At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo.

After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy.

After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91).

CONCLUSIONS - Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.

 

[Michael Scally MD]

Baggish AL, Weiner RB, Kanayama G, et al. Cardiovascular Toxicity of Illicit Anabolic-Androgenic Steroid Use. Circulation 2017;135(21):1991-2002. Cardiovascular Toxicity of Illicit Anabolic-Androgenic Steroid UseClinical Perspective | Circulation

BACKGROUND: Millions of individuals have used illicit anabolic-androgenic steroids (AAS), but the long-term cardiovascular associations of these drugs remain incompletely understood.

METHODS: Using a cross-sectional cohort design, we recruited 140 experienced male weightlifters 34 to 54 years of age, comprising 86 men reporting >/=2 years of cumulative lifetime AAS use and 54 nonusing men. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: left ventricular (LV) systolic function (left ventricular ejection fraction), LV diastolic function (early relaxation velocity), and coronary atherosclerosis (coronary artery plaque volume).

RESULTS: Compared with nonusers, AAS users demonstrated relatively reduced LV systolic function (mean+/-SD left ventricular ejection fraction = 52+/-11% versus 63+/-8%; P<0.001) and diastolic function (early relaxation velocity = 9.3+/-2.4 cm/second versus 11.1+/-2.0 cm/second; P<0.001). Users currently taking AAS at the time of evaluation (N=58) showed significantly reduced LV systolic (left ventricular ejection fraction = 49+/-10% versus 58+/-10%; P<0.001) and diastolic function (early relaxation velocity = 8.9+/-2.4 cm/second versus 10.1+/-2.4 cm/second; P=0.035) compared with users currently off-drug (N=28). In addition, AAS users demonstrated higher coronary artery plaque volume than nonusers (median [interquartile range] 3 [0, 174] mL3 versus 0 [0, 69] mL3; P=0.012). Lifetime AAS dose was strongly associated with coronary atherosclerotic burden (increase [95% confidence interval] in rank of plaque volume for each 10-year increase in cumulative duration of AAS use: 0.60 SD units [0.16-1.03 SD units]; P=0.008).

CONCLUSIONS: Long-term AAS use appears to be associated with myocardial dysfunction and accelerated coronary atherosclerosis. These forms of AAS-associated adverse cardiovascular phenotypes may represent a previously underrecognized public-health problem.

 

[Michael Scally MD]

[OA] Lacey B, Herrington WG, Preiss D, Lewington S, Armitage J. The Role of Emerging Risk Factors in Cardiovascular Outcomes. Current Atherosclerosis Reports 2017;19(6):28. The Role of Emerging Risk Factors in Cardiovascular Outcomes

Purpose of Review - This review discusses the recent evidence for a selection of blood-based emerging risk factors, with particular reference to their relation with coronary heart disease and stroke.

Recent Findings - For lipid-related emerging risk factors, recent findings indicate that increasing high-density lipoprotein cholesterol is unlikely to reduce cardiovascular risk, whereas reducing triglyceride-rich lipoproteins and lipoprotein(a) may be beneficial. For inflammatory and hemostatic biomarkers, genetic studies suggest that IL-6 (a pro-inflammatory cytokine) and several coagulation factors are causal for cardiovascular disease, but such studies do not support a causal role for C-reactive protein and fibrinogen. Patients with chronic kidney disease are at high cardiovascular risk with some of this risk not mediated by blood pressure. Randomized evidence (trials or Mendelian) suggests homocysteine and uric acid are unlikely to be key causal mediators of chronic kidney disease-associated risk and sufficiently large trials of interventions which modify mineral bone disease biomarkers are unavailable. Despite not being causally related to cardiovascular disease, there is some evidence that cardiac biomarkers (e.g. troponin) may usefully improve cardiovascular risk scores.

Summary - Many blood-based factors are strongly associated with cardiovascular risk. Evidence is accumulating, mainly from genetic studies and clinical trials, on which of these associations are causal. Non-causal risk factors may still have value, however, when added to cardiovascular risk scores. Although much of the burden of vascular disease can be explained by ‘classic’ risk factors (e.g. smoking and blood pressure), studies of blood-based emerging factors have contributed importantly to our understanding of pathophysiological mechanisms of vascular disease, and new targets for potential therapies have been identified.

 

[Michael Scally MD]

Genomic and Non-Genomic Effects of Androgens in The Cardiovascular System: Clinical Implications

The principle steroidal androgens are testosterone and its metabolite 5alpha-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5alpha-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively.

AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues.

It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation].

This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function.

Herald AKL, Alves-Lopes R, Montezano AC, Ahmed SF, Touyz RM. Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications. Clin Sci (Lond) 2017;131(13):1405-18. http://www.clinsci.org/content/131/13/1405

 

[Robfromga]

So after reading through all these studies, and admittedly I have trouble absorbing so much info, is there's a cliff notes to what we can do to protect our hearts?

Personally I don't do huge cycles. I'm on trt and usually add one compound for one cycle a year, and usually at a low dose. Then nothing but trt. Aside from a good diet/rest/recovery what can we add or do? Plant sterols for cholesterol?