AAS and Cardiovascular/Pulmonary Function

[Michael Scally MD]

[Open Access] Mendelian Randomization Studies In Coronary Artery Disease

Epidemiological research over the last 50 years has discovered a plethora of biomarkers (including molecules, traits or other diseases) that associate with coronary artery disease (CAD) risk. Even the strongest association detected in such observational research precludes drawing conclusions about the causality underlying the relationship between biomarker and disease.

Mendelian randomization (MR) studies can shed light on the causality of associations, i.e whether, on the one hand, the biomarker contributes to the development of disease or, on the other hand, the observed association is confounded by unrecognized exogenous factors or due to reverse causation, i.e. due to the fact that prevalent disease affects the level of the biomarker.

However, conclusions from a MR study are based on a number of important assumptions. A prerequisite for such studies is that the genetic variant employed affects significantly the biomarker under investigation but has no effect on other phenotypes that might confound the association between the biomarker and disease. If this biomarker is a true causal risk factor for CAD, genotypes of the variant should associate with CAD risk in the direction predicted by the association of the biomarker with CAD.

Given a random distribution of exogenous factors in individuals carrying respective genotypes, groups represented by the genotypes are highly similar except for the biomarker of interest. Thus, the genetic variant converts into an unconfounded surrogate of the respective biomarker.

This scenario is nicely exemplified for LDL cholesterol. Almost every genotype found to increase LDL cholesterol level by a sufficient amount has also been found to increase CAD risk. Pending a number of conditions that needed to be fulfilled by the genetic variant under investigation (e.g. no pleiotropic effects) and the experimental set-up of the study, LDL cholesterol can be assumed to act as the functional component that links genotypes and CAD risk and, more importantly, it can be assumed that any modulation of LDL cholesterol-by whatever mechanism-would have similar effects on disease risk.

Therefore, MR analysis has tremendous potential for identifying therapeutic targets that are likely to be causal for CAD. This review article discusses the opportunities and challenges of MR studies for CAD, highlighting several examples that involved multiple biomarkers, including various lipid and inflammation traits as well as hypertension, diabetes mellitus, and obesity.

Jansen H, Samani NJ, Schunkert H. Mendelian randomization studies in coronary artery disease. Eur Heart J 2014;35(29):1917-24. http://eurheartj.oxfordjournals.org/content/35/29/1917

Brief Overview About Candidates Tested In Mendelian Randomization Settings

While many biomarkers suggested a causal role in coronary artery disease in Mendelian randomization studies, others disappointed by negative results.

The effect of diabetes mellitus single nucleotide polymorphisms was by far smaller than expected and barely significant.

Numbers refer to the references in which the Mendelian randomization data have been reported.

 

[Michael Scally MD]

[Open Access] Testosterone Replacement Therapy and Cardiovascular Risk: A Review

Recent reports in the scientific and lay press have suggested that testosterone (T) replacement therapy (TRT) is likely to increase cardiovascular (CV) risk.

In a final report released in 2015, the Food and Drug Administration (FDA) cautioned that prescribing T products is approved only for men who have low T levels due to primary or secondary hypogonadism resulting from problems within the testis, pituitary, or hypothalamus (e.g., genetic problems or damage from surgery, chemotherapy, or infection).

In this report, the FDA emphasized that the benefits and safety of T medications have not been established for the treatment of low T levels due to aging, even if a man's symptoms seem to be related to low T.

In this paper, we reviewed the available evidence on the association between TRT and CV risk.

In particular, data from randomized controlled studies and information derived from observational and pharmacoepidemiological investigations were scrutinized.

The data meta-analyzed here do not support any causal role between TRT and adverse CV events. This is especially true when hypogonadism is properly diagnosed and replacement therapy is correctly performed.

Elevated hematocrit represents the most common adverse event related to TRT. Hence, it is important to monitor hematocrit at regular intervals in T-treated subjects in order to avoid potentially serious adverse events.

Corona GG, Rastrelli G, Maseroli E, Sforza A, Maggi M. Testosterone Replacement Therapy and Cardiovascular Risk: A Review. World J Mens Health 2015;33(3):130-42. Testosterone Replacement Therapy and Cardiovascular Risk: A Review

 

[Michael Scally MD]

Anderson JL, May HT, Lappe DL, et al. Impact of Testosterone Replacement Therapy on Myocardial Infarction, Stroke, and Death in Men With Low Testosterone Concentrations in an Integrated Health Care System. Am J Cardiol. https://www.sciencedirect.com/science/article/pii/S000291491502353X

The aim of this study was to assess the effect of testosterone replacement therapy (TRT) on cardiovascular outcomes. Men (January 1, 1996, to December 31, 2011) with a low initial total testosterone concentration, a subsequent testosterone level, and >3 years of follow-up were studied. Levels were correlated with testosterone supplement use.

The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of death, nonfatal myocardial infarction, and stroke at 3 years.

Multivariate adjusted hazard ratios (HRs) comparing groups of persistent low (<212 ng/dl, n = 801), normal (212 to 742 ng/dl, n = 2,241), and high (>742 ng/dl, n = 1,694) achieved testosterone were calculated by Cox hazard regression. A total of 4,736 men were studied. Three-year rates of MACE and death were 6.6% and 4.3%, respectively.

Subjects supplemented to normal testosterone had reduced 3-year MACE (HR 0.74; 95% confidence interval [CI] 0.56 to 0.98, p = 0.04) compared to persistently low testosterone, driven primarily by death (HR 0.65, 95% CI 0.47 to 0.90). HRs for MI and stroke were 0.73 (95% CI 0.40 to 1.34), p = 0.32, and 1.11 (95% CI 0.54 to 2.28), p = 0.78, respectively. MACE was noninferior but not superior for high achieved testosterone with no benefit on MI and a trend to greater stroke risk.

In conclusion, in a large general health care population, TRT to normal levels was associated with reduced MACE and death over 3 years but a stroke signal with high achieved levels suggests a conservative approach to TRT.

 

[Michael Scally MD]

Pesonen E, Pussinen P, Huhtaniemi I. Adaptation to acute coronary syndrome-induced stress with lowering of testosterone - a possible survival factor. Eur J Endocrinol. Adaptation to acute coronary syndrome-induced stress with lowering of testosterone - a possible survival factor

OBJECTIVES: To explore whether circulating testosterone (T) concentration is associated with the occurrence and risk for acute coronary syndromes (ACS).

METHODS: This case-control study included male patients with acute myocardial infarction (AMI) (n=174) or unstable angina pectoris (UAP) (n=90) and healthy controls (n=238). Patients gave serum samples during the acute phase (n=264) and recovery phase (n=132) after a median of 10.5 months after the incident event. Secondary events (ACS or cardiovascular death) were registered during the following six years.

RESULTS: During the acute phase, AMI and UAP patients had similar significantly reduced concentrations of serum T in comparison to controls. T associated inversely with weight, the degree of inflammation (i.e. CRP concentration), and signs of a chronic infection.

In a multiadjusted Cox regression, when compared to T concentrations considered normal-high (14.91-34.0 nmol/L), low-normal T (9.26-14.90 nmol/L) in the acute phase predicted better prognosis for cardiovascular death rate with a HR of 0.17 (0.04-0.68, p=0.012).

The increased T concentrations after the recovery period did not associate with future CVD events.

CONCLUSIONS: Low-normal T levels in the acute phase of ACS predicted better survival. The observation may indicate better adaptation to stress in survivors and warrants further study.

 

[Michael Scally MD]

Huang C-K, Lee SO, Chang E, Pang H, Chang C. Androgen receptor (AR) in cardiovascular diseases. Journal of Endocrinology. http://joe.endocrinology-journals.org/content/early/2016/01/14/JOE-15-0518.abstract

Cardiovascular diseases (CVDs) are still the highest leading cause of death worldwide. Several risk factors have been linked to CVDs, including smoking, diabetes, hyperlipidemia, and gender. Sex hormones, especially the androgen and its receptor, androgen receptor (AR), have been linked to many diseases with gender difference. Here, we summarize androgen/AR effects on CVDs, including hypertension, stroke, atherosclerosis, abdominal aortic aneurysm (AAA), myocardial hypertrophy, and heart failure, as well as metabolic syndrome/diabetes and their impacts on CVDs. Androgen/AR signaling exacerbates hypertension and anti-androgens may suppress hypertension. Androgen/AR signaling plays dual roles on strokes, dependent on different kinds of factors, but generally male has higher incidence in stroke than female. Androgen and AR differentially modulate atherosclerosis. Androgen deficiency cause elevated lipid accumulation to enhance atherosclerosis, but targeting AR in selective cells without altering serum androgen levels would suppress atherosclerosis progression. Androgen/AR signaling is crucial in abdominal aortic aneurismal (AAA) development and progression, and targeting androgen/AR profoundly restricts AAA progression. Men have increased cardiac hypertrophy as compared to age-matched women and androgen would promote cardiac hypertrophy. Finally, androgen/AR plays important roles in contributing to the obesity and insulin/leptin resistance to increase the metabolic syndrome.

 

[Michael Scally MD]

Pirompol P, Teekabut V, Weerachatayanukul W, Bupha-Intr T, Wattanapermpool J. Supra-physiological dose of testosterone induces pathological cardiac hypertrophy. Journal of Endocrinology. http://joe.endocrinology-journals.org/content/early/2016/02/05/JOE-15-0506.abstract

Testosterone and androgenic anabolic steroids have been misused for enhancement of physical performance despite many reports of cardiac sudden death. While physiological level of testosterone provided many regulatory benefits to human health, including the cardiovascular function, supraphysiological levels of the hormone induce hypertrophy of the heart with unclear contractile activation. In the present study, dose- and time-dependent effects of high testosterone treatment on cardiac structure and function were evaluated. Adult male rats were divided into 4 groups of testosterone treatment for 0, 5, 10, and 20 mg/kg BW for 4, 8, or 12 weeks. Increases in both % heart/body weight ratio and cardiomyocyte cross-sectional area in representing hypertrophy of the heart were significantly shown in all testosterone-treated groups to the same degree. In 4-wk treated rats, physiological cardiac hypertrophy was apparent with an upregulation of α-MHC without any change in myofilament contractile activation. In contrast, pathological cardiac hypertrophy was observed in 8- and 12-wk testosterone-treated groups as indicated by suppression of myofilament activation and myocardial collagen deposition without transition of MHC isoforms. Only in 12-wk testosterone-treated group that eccentric cardiac hypertrophy was demonstrated with unaltered myocardial stiffness but significant reductions in the phosphorylation signals of ERK1/2 and mTOR. Results of our study suggest that the outcome of testosterone-induced cardiac hypertrophy is not dose dependency but is rather relied on the factor of exposure duration in inducing maladaptive responses of the heart.

 

[Michael Scally MD]

Kloner RA, Carson C, 3rd, Dobs A, Kopecky S, Mohler ER, 3rd. Testosterone and Cardiovascular Disease. J Am Coll Cardiol 2016;67(5):545-57. Elsevier: Article Locator

Testosterone (T) is the principal male sex hormone. As men age, T levels typically fall. Symptoms of low T include decreased libido, vasomotor instability, and decreased bone mineral density. Other symptoms may include depression, fatigue, erectile dysfunction, and reduced muscle strength/mass. Epidemiology studies show that low levels of T are associated with more atherosclerosis, coronary artery disease, and cardiovascular events. However, treating hypogonadism in the aging male has resulted in discrepant results in regard to its effect on cardiovascular events. Emerging studies suggest that T may have a future role in treating heart failure, angina, and myocardial ischemia. A large, prospective, long-term study of T replacement, with a primary endpoint of a composite of adverse cardiovascular events including myocardial infarction, stroke, and/or cardiovascular death, is needed. The Food and Drug Administration recently put additional restrictions on T replacement therapy labeling and called for additional studies to determine its cardiac safety.

 

[power36]

Not sure whether to let this thread scare the hell out of me or not...I've been on HRT for a long time now, and once or twice a year do a blast with Mast or Primo, plus maybe some Var, and have tried Winny, Tbol, and a few quick runs with very low dose Tren. And due to the locker room science/myth about Deca I've done it and NPP a few times in low doses for joints. My RBC goes up but I just donate blood every once in a while and it returns to normal levels and my doc has never been worried. Also for those earlier in the thread worried about RBC, you can do double RBC donations and they beg you to do it if you have certain blood types to help save lives. Is there an issue with doing double RBC donations in this scenario?

In my mid 40s so its been harder to train like I used to, but my entire life I have been a strength/power athlete, heavy powerlifting, Olympic lifting, for conditioning strongman type work and lots of intervals. But in past few years nagging injuries have prevented me from doing conditioning. To keep my sanity, my muscle mass, and keep bodyfat down I kept lifting around my injuries. Recently I heard a sports science guy talking about this athlete heart issue with boxers and kickboxers, and the need for steady state cardio rather than just lifting plus intervals, that doing everything anaerobic was not ideal for heart health....so I recently started doing steady state again, and longer intervals, and I feel like complete crap and was like wow either its my age catching up to me or something about HRT not helping my heart health and cardio. Then I read this thread which is hard to digest with all the research that is not exactly done on a bunch of middle aged HRT patients who train regularly, so not sure if it should translate into me worrying about my heart and other health related issues for being on T so long, and for the rest of my life as was the decision I was told I had to make BEFORE I hopped on HRT many years ago.

In my blasts I've never gone above my HRT dose of T, mainly because I do not want to get any bigger (I am 5'10 245ish at 11% BF via DEXA scan), and because I have nagging injuries and worry about connective tissue issues. Again whether its locker room bro science or legit, the whole going over 200mg of T will cause connective tissue issues concerned me so I have not tried the "typical" 500-600mg weekly T cycle. Hence doing blasts with what many consider weak AAS like Primo and Var, at times Mast and tbol, and NPP for joints at low dose. So I have been fairly conservative with AAS but knowing I've been on T so long and will be, if its gonna create major issues I would like to know how to avoid or minimize them. Going off HRT is not an option, as I have tried it a few times after I got healthy and feeling good on HRT, and it felt like crap....the blasts with Primo, Var, Mast, NPP are for times I want better recovery and to hit the gym and MMA more, not for me to get bigger or intentionally cut, but when doing more MMA and the gym while on a blast, I do lean out considerably. So I look forward to the blasts so I can "play" more at the gym and dojo.

How would any of us find a doc who gets all of this and could do an extensive physical once a year to make sure we are not playing Russian Roulete? Seems like docs who would understand all of this are slim to none...

I think it would be impossible for me to give up barbells and meat, and trade it in for being a Vegan and doing steady state cardio 6 days a week...but I certainly want to live as long as possible being as healthy as I can.

 

[Michael Scally MD]

There is a strong inverse association of plasma HDL-C concentrations with CHD,2 which for decades lent credence to the notion that pharmacological raising of HDL-C should protect against CHD. Yet recent genetic analyses have in general failed to support a causal role for HDL-C in CHD.


Musunuru K, Kathiresan S. Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis. Circ Res 2016;118(4):579-85. Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis

Observational epidemiological studies have associated plasma lipid concentrations with risk for coronary heart disease (CHD), but these studies cannot distinguish cause from mere correlation.

Human genetic studies, when considered with the results of randomized controlled trials of medications, can potentially shed light on whether lipid biomarkers are causal for diseases.

Genetic analyses and randomized trials suggest that low-density lipoprotein is causal for CHD, whereas high-density lipoprotein is not.

Surprisingly, human genetic evidence suggests that lipoprotein(a) and triglyceride-rich lipoproteins causally contribute to CHD.

Gene variants leading to higher levels of plasma apolipoprotein B-containing lipoproteins [low-density lipoprotein, triglyceride-rich lipoproteins, or lipoprotein(a)] consistently increase risk for CHD.

For triglyceride-rich lipoproteins, the most compelling evidence revolves around lipoprotein lipase and its endogenous facilitator (APOA5 [apolipoprotein A-V]) and inhibitory proteins (APOC3 [apolipoprotein C-III], ANGPTL4 [angiopoietin like 4]).

Combined, these genetic results anticipate that, beyond low-density lipoprotein, pharmacological lowering of triglyceride-rich lipoproteins or lipoprotein(a) will reduce risk for CHD, but this remains to be proven through randomized controlled trials.

 

[Michael Scally MD]

Lipids, Lipoproteins, and Cardiovascular Disease: Clinical Pharmacology Now and in the Future
[For Full-Text Email mike.scally@asih.net (Include Title)]

Context: While substantial benefit has accrued with respect to prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) since the advent of statin therapy, much remains unknown and there is considerable need to address residual risk beyond statins. Moreover, many individuals are unable to tolerate statins.

Evidence Acquisition: As a result of several recent clinical trials and publications describing early Phase 1–3 clinical trials, the authors briefly discuss the current situation regarding pharmacological management for the prevention and treatment of individuals with disorders of lipid and lipoprotein metabolism, outline some of the unanswered questions, and speculate on where we might expect to be in 5–10 years.

Evidence Synthesis: Fortunately, recent developments in drug therapy hold considerable promise of additional benefits. In addition, new drugs in the pipeline, ongoing clinical trials, and new approaches to treatment hold promise for further improvements in therapy in the foreseeable future.

During the next 5–10 years, we expect to know whether the PCSK9 inhibitors indeed live up to their promise and result in the hoped-for reduction in ASCVD events, whether triglyceride lowering indeed adds additional benefit, how best to approach HDL, and the importance of lipoprotein (a).

Advances in the use of molecular biological approaches such as anti-sense oligonucleotides and RNA silencing, and the use of biological agents such as PSCK9 antibodies, is likely to play an important role in these advances.

Conclusions: The advent of PCSK9 inhibitors is likely to provide a major breakthrough in the management of individuals with heterozygous familial hypercholesterolemia, patients with established ASCVD who are unable to reach targets with other therapies, and high-risk individuals with statin intolerance.

The next 5–10 years should also clarify uncertainties concerning the pharmacological management of individuals with low levels of HDL-cholesterol, hypertriglyceridemia, and elevated lipoprotein (a).

Chait A, Eckel RH. Lipids, Lipoproteins, and Cardiovascular Disease: Clinical Pharmacology Now and in the Future. The Journal of Clinical Endocrinology & Metabolism. http://press.endocrine.org/doi/abs/10.1210/jc.2015-3940

 

[Michael Scally MD]

[Rats] Nandrolone Decanoate Negatively Reverses the Beneficial Effects of Exercise On Cardiac Muscle

ATP-sensitive potassium channels are supposed to have a substantial role in improvement of cardiac performance.

This study was performed to evaluate whether nandrolone decanoate (ND) and (or) exercise training could affect the expression of cardiac KATP channel subunits.

Thirty-five male albino Wistar rats were randomly divided into 5 groups, including sedentary control (SC), sedentary vehicle (SV), sedentary ND (SND), exercise control (EC), and exercise and ND (E+ND).

Exercise training was performed on a treadmill 5 times per week.

ND was injected (10 mg/kg/week, i.m.) to the rats in the SND and E+ND groups.

Following cardiac isolation, the expression of both sarcolemmal and mitochondrial subunits of KATP channel was measured using Western blot method.

The expression of sarcolemmal, but not mitochondrial, subunits of KATP channel (Kir6.2 and SUR2) of EC group was significantly higher compared with SC group while ND administration (SND group) did not show any change in their expression.

In the E+ND group, ND administration led to decrease of the over-expression of sarcolemmal Kir6.2 and SUR2 which was previously induced by exercise.

There was no significant association between the mitochondrial expression of either Kir6.2 or SUR2 proteins and administration of ND or exercise.

Supra-physiological dosage of ND negatively reverses the effects of exercise on the cardiac muscle expression of sarcolemmal, but not mitochondrial, KATP channel subunits.

Bayat G, Javan M, Safari F, et al. Nandrolone decanoate negatively reverses the beneficial effects of exercise on cardiac muscle via sarcolemmal, but not mitochondrial KATP channel. Can J Physiol Pharmacol 2016;94(3):324-31. An Error Occurred Setting Your User Cookie

 

[Michael Scally MD]

Zhao R, Li Y, Dai W. Serum sex hormone and growth arrest-specific protein 6 levels in male patients with coronary heart disease. Asian J Androl. Serum sex hormone and growth arrest-specific protein 6 levels in male patients with coronary heart disease Zhao R, Li Y, Dai W, - J Indian Prosthodont Soc

Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease. Moreover, the tyrosine kinase receptor Axl, the ligand of which is growth arrest-specific protein 6 (GAS6), is expressed in the vasculature, and serum GAS6 levels are associated with endothelial dysfunction and cardiovascular events. Testosterone regulates GAS6 gene transcription directly, which inhibits calcification of vascular smooth muscle cells and provides a mechanistic insight into the cardioprotective action of androgens. This study was designed to determine the correlation between serum GAS6 and testosterone levels in male patients with coronary heart disease (CHD). We recruited 225 patients with CHD and 102 apparently healthy controls. Serum concentrations of GAS6 and soluble Axl were quantified by an enzyme-linked immunosorbent assay. Levels of high-sensitivity C-reactive protein, testosterone, estradiol, and other routine biochemical markers were also measured. Testosterone decreased from 432.69 +/- 14.40 to 300.76 +/- 6.23 ng dl-1 (P < 0.001) and GAS6 decreased from 16.20 +/- 0.31 to 12.51 +/- 0.19 ng ml-1 (P < 0.001) in patients with CHD, compared with control subjects. Multiple linear regression analysis showed that serum testosterone and GAS6 levels were positively associated in male patients with CHD. Alterations in GAS6 levels may influence the development of CHD. Downregulation of GAS6/Axl signaling in the presence of low sex hormone levels during disease progression is a potential mechanism by which GAS6 affects CHD. This study provides novel results regarding the influence of sex hormones on serum GAS6 levels in patients with CHD.

 

[Michael Scally MD]

[Open Access] Serum Sex Hormone and Growth Arrest-Specific Protein 6 Levels in Male Patients with Coronary Heart Disease

Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease. Moreover, the tyrosine kinase receptor Axl, the ligand of which is growth arrest-specific protein 6 (GAS6), is expressed in the vasculature, and serum GAS6 levels are associated with endothelial dysfunction and cardiovascular events.

Testosterone regulates GAS6 gene transcription directly, which inhibits calcification of vascular smooth muscle cells and provides a mechanistic insight into the cardioprotective action of androgens.

This study was designed to determine the correlation between serum GAS6 and testosterone levels in male patients with coronary heart disease (CHD). We recruited 225 patients with CHD and 102 apparently healthy controls.

Serum concentrations of GAS6 and soluble Axl were quantified by an enzyme-linked immunosorbent assay. Levels of high-sensitivity C-reactive protein, testosterone, estradiol, and other routine biochemical markers were also measured.

Testosterone decreased from 432.69 +/- 14.40 to 300.76 +/- 6.23 ng dl-1 (P < 0.001) and GAS6 decreased from 16.20 +/- 0.31 to 12.51 +/- 0.19 ng ml-1 (P < 0.001) in patients with CHD, compared with control subjects. Multiple linear regression analysis showed that serum testosterone and GAS6 levels were positively associated in male patients with CHD.

Alterations in GAS6 levels may influence the development of CHD. Downregulation of GAS6/Axl signaling in the presence of low sex hormone levels during disease progression is a potential mechanism by which GAS6 affects CHD.

This study provides novel results regarding the influence of sex hormones on serum GAS6 levels in patients with CHD.

Zhao R, Li Y, Dai W. Serum sex hormone and growth arrest-specific protein 6 levels in male patients with coronary heart disease. Asian J Androl. Serum sex hormone and growth arrest-specific protein 6 levels in male patients with coronary heart disease Zhao R, Li Y, Dai W, - J Indian Prosthodont Soc

 

[Michael Scally MD]

Travison TG, O'Donnell CJ, Bhasin S, et al. Association between circulating sex steroids and vascular calcification in community dwelling men: The Framingham Heart Study. The Journal of Clinical Endocrinology & Metabolism. http://press.endocrine.org/doi/abs/10.1210/jc.2015-4299

Context: The relationship between sex steroids and atherosclerosis is poorly understood.

Objective: To describe the association of serum total and calculated free testosterone (TT and cFT), estrone (E1), estradiol (E2), and sex hormone binding globulin (SHBG) to vascular calcification in adult men.

Design: Observational study (The Framingham Heart Study; FHS). Analyses are cross-sectional. TT, E1 and E2 were measured by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay, Estimates of association were obtained by Tobit regression, which acknowledges the influence of floor effects on outcomes.

Setting: General community.

Participants: N=1654 community-dwelling men from the Offspring and Third Generation cohorts of the FHS

Main outcome measures: Coronary artery calcification (CAC), abdominal aortic calcification, and thoracic aortic calcification, measured by computed tomography.

Results: Mean (standard deviation) age was 49 (10) years. Mean (SD) TT, cFT, and SHBG were 616 (224) ng/dl, 111 (45) pg/ml, and 46 (23) nmol/l, respectively. Mean (SD) E2 and E1 were 28 (10) and 39 (14) pg/ml. Vascular calcification at all sites was negatively associated with TT and cFT and positively associated with E2 and E1.

A 100-ng/dl between-subject increase in TT was associated with a mean (95% CI) age-adjusted difference in CAC of -23% (-41%, -4%), p=0.02.

After model adjustment for other cardiovascular risk factors, the estimated associations between testosterone and vascular calcification scores were statistically nonsignificant.

Conclusions: Decreased circulating testosterone and estradiol levels are associated with an age-adjusted increase in CAC, but these associations appear to express relationships either attributable to or mediated by established cardiovascular risk factors.

 

[Michael Scally MD]

The Genetics of Dyslipidemia — When Less Is More

An elevated plasma level of low-density lipoprotein (LDL) cholesterol is a major risk factor for coronary heart disease. Whether an elevated plasma triglyceride level and a reduced level of high-density lipoprotein (HDL) cholesterol also carry an increased risk of coronary heart disease has remained a contentious issue.

Two groups of investigators now describe in the Journal important genetic evidence showing a causal role of plasma triglycerides in coronary heart disease.

Stitziel and colleagues tested 54,003 coding-sequence variants covering 13,715 human genes in more than 72,000 patients with coronary artery disease and 120,000 controls. MMS: Error

Dewey and colleagues sequenced the exons of the gene encoding angiopoietin-like 4 (ANGPTL4) in samples obtained from nearly 43,000 participants in the DiscovEHR human genetics study. MMS: Error

The two groups found a significant association between an inactivating mutation (E40K) in ANGPTL4 and both low plasma triglyceride levels and high levels of HDL cholesterol.

ANGPTL4 is an inhibitor of lipoprotein lipase, the enzyme that breaks down plasma triglycerides along the capillaries in heart, muscle, and fat. Extensive research has shown that ANGPTL4 orchestrates the processing of triglyceride-rich lipoproteins during physiologic conditions such as fasting, exercise, and cold exposure.

The E40K mutation in ANGPTL4 was previously shown to nearly eliminate the ability of ANGPTL4 to inhibit lipoprotein lipase, a mechanism that may result in part from the destabilization of ANGPTL4.

The key finding in each study was that carriers of the E40K mutation and other rare mutations in ANGPTL4 had a lower risk of coronary artery disease than did noncarriers, a result that is consistent with the lower triglyceride levels and higher HDL cholesterol levels among mutation carriers.

These findings confirm previous data and provide convincing genetic evidence that an elevated plasma triglyceride level increases the risk of coronary heart disease. In combination with extensive recent data on other genetic variants that modulate plasma triglyceride levels, the studies suggest that lowering plasma triglyceride levels is a viable approach to reducing the risk of coronary artery disease.

Kersten S. The Genetics of Dyslipidemia - When Less Is More. New England Journal of Medicine. MMS: Error

Genetic Variants Affecting the Lipoprotein Lipase Pathway and the Risk of Coronary Artery Disease.

Panel A shows normal physiological function of lipoprotein lipase (LPL) and regulation of LPL by gene products of ANGPTL4, APOC3, and APOA5. LPL, which is both transported across and anchored to capillary endothelial cells by the protein GPIHBP1, normally hydrolyzes the triglycerides that are present in circulating lipoproteins and reduces the plasma triglyceride level. Its activity is reduced by ANGPTL4 and APOC3 and increased by APOA5.

Not shown here are other important regulators of LPL activity, including APOC2 and ANGPTL3.

Green arrows indicate enhancers, and red blocked arrows indicate inhibitors.

IDL denotes intermediate-density lipoprotein, and VLDL very-low-density lipoprotein.

Panel B shows altered function of LPL in mutation carriers. Mutations affecting LPL and proteins interacting with LPL are shown, along with expected effect on LPL activity, plasma triglyceride levels, and risk of coronary artery disease. LPL loss of function refers to p.D36N, and gain of function refers to p.S477*. ANGPTL4 loss of function refers to both p.E40K and loss-of-function mutations. APOC3 17, 18 and APOA5 7 loss of function refers to multiple loss-of-function mutations.

 

[Dr JIM]

[Open Access] Testosterone Replacement Therapy and Cardiovascular Risk: A Review

Recent reports in the scientific and lay press have suggested that testosterone (T) replacement therapy (TRT) is likely to increase cardiovascular (CV) risk.

In a final report released in 2015, the Food and Drug Administration (FDA) cautioned that prescribing T products is approved only for men who have low T levels due to primary or secondary hypogonadism resulting from problems within the testis, pituitary, or hypothalamus (e.g., genetic problems or damage from surgery, chemotherapy, or infection).

In this report, the FDA emphasized that the benefits and safety of T medications have not been established for the treatment of low T levels due to aging, even if a man's symptoms seem to be related to low T.

In this paper, we reviewed the available evidence on the association between TRT and CV risk.

In particular, data from randomized controlled studies and information derived from observational and pharmacoepidemiological investigations were scrutinized.

The data meta-analyzed here do not support any causal role between TRT and adverse CV events. This is especially true when hypogonadism is properly diagnosed and replacement therapy is correctly performed.

Elevated hematocrit represents the most common adverse event related to TRT. Hence, it is important to monitor hematocrit at regular intervals in T-treated subjects in order to avoid potentially serious adverse events.

Corona GG, Rastrelli G, Maseroli E, Sforza A, Maggi M. Testosterone Replacement Therapy and Cardiovascular Risk: A Review. World J Mens Health 2015;33(3):130-42. Testosterone Replacement Therapy and Cardiovascular Risk: A Review

I love this thread and this is another example why, an OUTSTANDING REVIEW ARTICLE on the systemic end-organ effects (with an emphasis on CV disease) of TRT.

My compliments once again @Michael Scally MD, for your tireless efforts to help all Meso members!

 

[Michael Scally MD]

I love this thread and this is another example why, an OUTSTANDING REVIEW ARTICLE on the systemic end-organ effects (with an emphasis on CV disease) of TRT.

My compliments once again @Michael Scally MD, for your tireless efforts to help all Meso members!

And, to you as well.

 

[Michael Scally MD]

Anabolic androgenic steroids are synthetic derivatives of testosterone that promote the growth of skeletal muscles and have many recognised cardiovascular effects.

We report the clinical presentation and pathological findings of an adolescent male whose sudden cardiac arrest following ventricular fibrillation was attributed to anabolic androgenic steroid use.

The age of our patient reflects the usage of anabolic androgenic steroids among younger athletes and highlights the need for increased awareness among practitioners.

Lichtenfeld J, Deal BJ, Crawford S. Sudden cardiac arrest following ventricular fibrillation attributed to anabolic steroid use in an adolescent. Cardiol Young 2016:1-3. Sudden cardiac arrest following ventricular fibrillation attributed to anabolic steroid use in an adolescent

 

[Michael Scally MD]

Anabolic androgenic steroids are synthetic derivatives of testosterone that promote the growth of skeletal muscles and have many recognised cardiovascular effects.

We report the clinical presentation and pathological findings of an adolescent male whose sudden cardiac arrest following ventricular fibrillation was attributed to anabolic androgenic steroid use.

The age of our patient reflects the usage of anabolic androgenic steroids among younger athletes and highlights the need for increased awareness among practitioners.

Lichtenfeld J, Deal BJ, Crawford S. Sudden cardiac arrest following ventricular fibrillation attributed to anabolic steroid use in an adolescent. Cardiol Young 2016:1-3. Sudden cardiac arrest following ventricular fibrillation attributed to anabolic steroid use in an adolescent

So, based on NOTHING!!! "Although we could not confirm the presence of anabolic steroids or their metabolites at the time of our patient’s death."

 

[Michael Scally MD]

Rosenson R. The High-Density Lipoprotein Puzzle: Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict? Arteriosclerosis, Thrombosis, and Vascular Biology. The High-Density Lipoprotein Puzzle

Classical epidemiology has established the incremental contribution of the high-density lipoprotein (HDL) cholesterol measure in the assessment of atherosclerotic cardiovascular disease risk; yet, genetic epidemiology does not support a causal relationship between HDL cholesterol and the future risk of myocardial infarction. Therapeutic interventions directed toward cholesterol loading of the HDL particle have been based on epidemiological studies that have established HDL cholesterol as a biomarker of atherosclerotic cardiovascular risk. However, therapeutic interventions such as niacin, cholesteryl ester transfer protein inhibitors increase HDL cholesterol in patients treated with statins, but have repeatedly failed to reduce cardiovascular events. Statin therapy interferes with ATP-binding cassette transporter–mediated macrophage cholesterol efflux via miR33 and thus may diminish certain HDL functional properties. Unraveling the HDL puzzle will require continued technical advances in the characterization and quantification of multiple HDL subclasses and their functional properties. Key mechanistic criteria for clinical outcomes trials with HDL-based therapies include formation of HDL subclasses that improve the efficiency of macrophage cholesterol efflux and compositional changes in the proteome and lipidome of the HDL particle that are associated with improved antioxidant and anti-inflammatory properties. These measures require validation in genetic studies and clinical trials of HDL-based therapies on the background of statins.