AAS and Cardiovascular/Pulmonary Function

[Michael Scally MD]

[OA] Kerroumi A, Majdoub K, Guennoun Z, Doghmi N, Cherti M. Myocarditis Associated with Anabolic Steroid Abuse Report of Two Cases. IOSR Journal of Dental and Medical Sciences. 2019;18(6): 55-61. https://www.iosrjournals.org/iosr-jdms/papers/Vol18-issue6/Series-7/L1806075561.pdf

It is obvious that the abuse of anabolic steroids to improve physical performance has been widely implicated in several cardiovascular events, especially myocardial infarction; However, according to the literature, there is currently no report describing myocarditis due to the abuse of anabolic steroids to our knowledge, unless animal experiments or Post mortem autopsy which were carried out at young athletes. We report two cases of young bodybuilders who were complaining about chest pain. They did not have traditional cardiovascular risk factors, however they admitted the intermittent abuse of anabolic steroids. In both instances, electrocardiography, blood chemistry, Transthoracic echocardiography and cardiac magnetic resonance imaging where performed. Our results support the theory of the cause-effect relationship between anabolic steroid abuse and cardiovascular events, especially their direct cardiac toxicity, by demonstrating myocarditis in both patients through cardiac magnetic resonance imaging

 

[Michael Scally MD]

[OA] Uncovering Sex-Specific Mechanisms of Action of Testosterone and Redox Balance

The molecular and pharmacological manipulation of the endogenous redox system is a promising therapy to limit myocardial damage after a heart attack; however, antioxidant therapies have failed to fully establish their cardioprotective effects, suggesting that additional factors, including antioxidant system interactions with other molecular pathways, may alter the pharmacological effects of antioxidants.

Since gender differences in cardiovascular disease (CVD) are prevalent, and sex is an essential determinant of the response to oxidative stress, it is of particular interest to understand the effects of sex hormone signaling on the activity and expression of cellular antioxidants and the pharmacological actions of antioxidant therapies.

In the present review, we briefly summarize the current understanding of testosterone effects on the modulation of the endogenous antioxidant systems in the CV system, cardiomyocytes, and the heart.

We also review the latest research on redox balance and sexual dimorphism, with particular emphasis on the role of the natural antioxidant system glutathione (GSH) in the context of myocardial infarction, and the pro- and antioxidant effects of testosterone signaling via the androgen receptor (AR) on the heart.

Finally, we discuss future perspectives regarding the potential of using combing antioxidant and testosterone replacement therapies to protect the aging myocardium.

Cruz-Topete D, Dominic P, Stokes KY. Uncovering sex-specific mechanisms of action of testosterone and redox balance. Redox Biology 2020:101490. Uncovering sex-specific mechanisms of action of testosterone and redox balance - ScienceDirect

 

[Michael Scally MD]

Clinical Review on Triglycerides
Clinical Review on Triglycerides - American College of Cardiology

Hypertriglyceridemia (HTG) is a very common problem in clinical practice with a prevalence of approximately 10%.1 Plasma triglyceride (TG) concentration is a biomarker for TG rich lipoproteins (TRL) and their remnants, which have emerged as important contributors to atherosclerotic cardiovascular disease and pancreatitis. This summary reviews the underlying biochemistry, etiologies, current treatments and emerging therapies that was discussed in detail in Clinical review on triglycerides by Ulrich Laufs et al. published in the European Heart Journal early in 2020.

 

[Michael Scally MD]

Clomiphene Misuse and Risk of Severe Cardiovascular Events

Dear Editor,

Clomiphene is a selective oestrogen receptor modulator usually used to treat subfertility in women. However, misuse of clomiphene was recently reported in men by bodybuilders, and to treat infertility [1]. Here, we present the case of 2 subjects with severe cardiovascular complications due to clomiphene misuse in a performance-enhancing drug context that occurred in 2019 in a French area.

Case 1

A 24-year-old man presented at 2:00 p.m. to the emergency unit for tachycardia and palpitations. The patient reported intense strength activity using anabolic-androgenic steroids periodically (2 or 3 months ago) for several months and was currently on clomiphene. On admission, the physical examination revealed a heart rate of 108 beats/min and elevated blood pressure of 183/99 mmHg. Cardiac examination revealed a regular rate and rhythm, and electrocardiography revealed sinus tachycardia.

Cardiac biomarkers and chest radiography were normal. Troponin value was 5 ng/ml (normal value < 14) and creatinine-kinase was 330 U/ml. Electrolyte levels and renal function were normal. No other medical history was noted. The last clomiphene intake was in the morning at 8 a.m. (one 50-mg tablet). His symptoms improved without treatment a few hours later, and he was discharged at 6:00 p.m. with the recommendation to stop clomiphene use.

Case 2

A 30-year-old man was hospitalized for acute myocardial infarction (MI) complicated by recovered cardiac arrest. Coronary angiography showed a suspended thrombus into the inter-anterior ventricular with no sign of atheromatous coronary artery disease. A bolus of eptifibatide (Integrelin®) was administered followed by a thromboaspiration, and a stent was placed. Aspirin, ticagrelor, heparin, and bisoprolol were started.

The patient had a history of testosterone injections as doping substances. He recognized tobacco and cannabis smoking (10 pack-year and 3–4 cannabis uses/day). Except for being overweight (body mass index 29.3), no other conventional risk factor for MI was detected in this very young patient. The day before, he had taken 2 pills of 50 mg of clomiphene and one the day of the event.

Urine toxicological analyses were positive for cannabinoids, and negative for amphetamines, cocaine, and ethanol. After 1 day in the intensive care unit (ICU), the patient was transferred to cardiac inpatient services. Intracardiac echocardiography showed a left ventricle ejection fraction at 45%. At day 4, the patient was discharged against medical advice.

Both cases were reported anonymously according to national law to the French medicines regulatory authorities (ANSM) via the Pharmacovigilance and Addictovigilance centres as serious adverse drug reactions resulting froma drug misuse [2]. Clomiphene is misused in male bodybuilders to counteract hypogonadism induced by exogenous testosterone [1]. Clomiphene increases endogenous oestrogens in women and testosterone production levels in men, via an increased release of gonadotropins, which results in a thrombogenic effect.

A total of 10 other reports of clomiphene misuse by men (median age 30 years old) was collected in the French Pharmacovigilance and Addictovigilance database, 4 in a context of doping, 3 to treat subfertility (2 unknown).

Cardiovascular effects reported in 5/10 cases (2 tachycardia/palpitation, 1 hypertension, 1 chest pain, and 1 pulmonary embolism). In the worldwide Pharmacovigilance database (VigiBase®), since 2012, 17 other cases have been reported (research criteria: “men” and “cardiac disorder”) with a recent increase of reports (4 in 2018, 6 in 2019), with fatal issue in 7 cases (in association with anabolic steroids in 6).

In the literature, cases of acute cardiovascular complications after the initiation of clomiphene in the context of ovulatory dysfunction have been reported [3–6], as well as cases of deep venous thrombosis in the context of male hypogonadism and infertility [7].

The use of appearance- and performance-enhancing drugs is increasing and exposes patients to potential life-threatening complications. Clomiphene is usually associated with other drugs to enhance androgen production that could also predispose patients to cardiovascular risk.

Eiden C, Pinzani V, Laureau M, et al. Clomiphene misuse and risk of severe cardiovascular events [published online ahead of print, 2020 Mar 17]. Eur J Clin Pharmacol. 2020;10.1007/s00228-020-02858-4. doi:10.1007/s00228-020-02858-4 Clomiphene misuse and risk of severe cardiovascular events

 

[Old]

misuse of clomiphene was recently reported in men by bodybuilders, and to treat infertility

Misuse use of a fertility drug for fertility?

As to "misused in male bodybuilders to counteract hypogonadism induced by exogenous testosterone", in the course "#91513: Medical and Illicit Use of Anabolic Steroids" [ See this post Medical and Illicit Use of Anabolic Steroids Course ] it specifically states:

"AAS-induced hypogonadism during withdrawal may require treatment with human chorionic gonadotropin or clomiphene to reactivate neuroendocrine function"​

In the end, clomid (like all meds) has risk. But the tenure of this article is poorly biased ... and uninformed.

 

[Michael Scally MD]

[OA] Rate and Extent of Recovery from Reproductive and Cardiac Dysfunction Due to Androgen Abuse

Context: Androgen abuse impairs male reproductive and cardiac function but the rate, extent and determinants of recovery are not understood.

Objective: To investigate recovery of male reproductive and cardiac function after ceasing androgen intake in current and past androgen abusers compared with healthy non-users.

Methods: Cross-sectional, observational study recruited via social media 41 current and 31 past users (≥3 months since last use, median 300 days since last use) with 21 healthy, eugonadal non-users. Each provided a history, examination, serum and semen sample and underwent testicular ultrasound, body composition analysis and cardiac function evaluation.

Results: Current abusers had suppressed reproductive function, impaired cardiac systolic function and lipoprotein parameters compared with non or past users. Past users did not differ from non-users suggesting full recovery of suppressed reproductive and cardiac functions after ceasing androgen abuse, other than residual reduced testicular volume. Mean time to recovery was faster for reproductive hormones (AMH, 7.3 months; LH, 10.7 months) than for sperm variables (output, 14.1 months) whereas spermatogenesis (serum FSH, inhibin B, inhibin) took longer. The duration of androgen abuse was the only other variable associated with slower recovery of sperm output (but not hormones).

Conclusion: Suppressed testicular and cardiac function due to androgen abuse is effectively fully reversible (apart from testis volume and serum SHBG) with recovery taking between 6 to 18 months after ceasing androgen intake with possible cumulative effects on spermatogenesis. Suppressed serum AMH, LH and FSH represent convenient, useful and underutilized markers of recovery from androgen abuse.

Shankara-Narayana N, Yu C, Savkovic S, et al. Rate and Extent of Recovery from Reproductive and Cardiac Dysfunction Due to Androgen Abuse in Men [published online ahead of print, 2020 Feb 7]. J Clin Endocrinol Metab. 2020;dgz324. Rate and Extent of Recovery from Reproductive and Cardiac Dysfunction Due to Androgen Abuse in Men

[Opinion] Recovery of Reproductive and Cardiac Function in Past Androgen Users

Conclusion: Cumulative data suggest that the hypothalamic-pituitary-testis axis recovers in former androgenic steroid abusers with Leydig cell function recovering faster than spermatogenesis. The recovery may be prolonged taking a few years and may depend on the duration and dosage of androgens used.

Handelsman et al further showed that the adverse cardiovascular effects that are associated with androgen abuse are at least partially reversible. Cross-sectional studies cannot provide causal relationships between androgen abuse and off target adverse effects because of potential confounding factors.

These observational studies in androgen abuser provide further evidence that recovery of endogenous testosterone production and spermatogenesis and other off target adverse effects are reversible when androgens are used as potential hormonal male contraceptives in healthy men. For hypogonadal men who have residual pituitary or testicular function, withdrawal of androgen replacement should result in return to their pretreatment state with time.

Wang C. Recovery of reproductive and cardiac function in past androgen users. The Journal of clinical endocrinology and metabolism 2020. Recovery of reproductive and cardiac function in past androgen users

 

[Michael Scally MD]

Cardiovascular Side Effects of Commonly Prescribed Medications and Performance Enhancing Drugs and Special Considerations for the Athlete

Side effects of commonly prescribed cardiac medications such as anti-arrhythmics have specific implications for athletic performance in athletes with cardiovascular disease. Similarly, non-cardiac medications such as stimulants and anti-depressants may have more pronounced side effects in the setting of athletic activity due to the combination of endogenous and exogenous sympathetic stimulation and altered thermoregulation.

This chapter is a summary of the available literature on (a) the implications of prescription medications, both cardiac and non-cardiac, on cardiovascular performance and cardiovascular health of athletic persons, and (b) the implications of potentially performance enhancing drugs known to be widely used by elite and recreational athletes on cardiovascular performance and cardiovascular health.

Maria Joan Brosnan, Paolo Emilio Adami. Cardiovascular Side Effects of Commonly Prescribed Medications and Performance Enhancing Drugs and Special Considerations for the Athlete. Textbook of Sports and Exercise Cardiology, 2020:513-530. Cardiovascular Side Effects of Commonly Prescribed Medications and Performance Enhancing Drugs and Special Considerations for the Athlete

 

[Michael Scally MD]

Acute Myocardial Infarction in Young Newbie Bodybuilder Using Multiple Steroid and Protein Supplements

Coronary artery disease (CAD), the major reason of deaths worldwide is generally known as a disease of the elderly, however it is grasping the youth too. The most common etiology of young CAD is lifestyle changes, smoking, and development of other comorbid conditions such as diabetes and hypertension at an early age. There has been an upward trend in youngsters regarding consciousness about their body build and thus use of various protein supplements and anabolic steroids for faster results.

The present case reports a young patient presenting with severe retrosternal left-sided chest pain for 15-20 min to the emergency department. His electrocardiogram was suggestive of acute anterolateral wall ST segment elevation myocardial infarction for which he underwent urgent coronary angiography and percutaneous coronary intervention.

His personal history revealed a significant use of steroids, proteins, and other supplements in supraphysiological doses for instant body building efforts without any other significant past medical, surgical, or family history.

He showed good recovery and was strongly recommended to stop steroids and protein supplements. In conclusion, supraphysiological doses of protein supplements, anabolic steroids, and other nutritional products bear a risk factor for CAD.

Learning objective: This is evident from the case report that excessive supplements use by body builders for immediate mass gain and performance enhancement may lead to adverse cardiovascular complications. This is mostly prescribed by peer groups or untrained gym professionals without judging their adverse effects so we recommend a detailed history for steroid use and protein supplements in young patients presenting with acute myocardial infarction without other significant risk factors and need for counselling for use of such substances.

Jain V, Goel G. Acute myocardial infarction in young newbie bodybuilder using multiple steroid and protein supplements. Journal of cardiology cases 2020;21:134-6. https://www.journalofcardiologycases.com/article/S1878-5409(19)30119-7/pdf

 

[Michael Scally MD]

Testosterone Concentrations and Risk of Cardiovascular Events in Androgen-Deficient Men with Atherosclerotic Cardiovascular Disease

Background: Whether androgen deficiency among men increases the risk of cardiovascular (CV) events or is merely a disease marker remains a subject of intense scientific interest.

Objectives: Among male subjects in the AIM-HIGH Trial with metabolic syndrome and low baseline levels of high-density lipoprotein (HDL)-cholesterol who were randomized to niacin or placebo plus simvastatin, we examined the relationship between low baseline testosterone (T) concentrations and subsequent CV outcomes during a mean 3-year follow-up.

Methods: In this post hoc analysis of men with available baseline plasma T concentrations, we examined the relationship between clinical/demographic characteristics and T concentrations both as a continuous and dichotomous variable (<300 ng/dL ["low T"] vs. ≥300 ng/dL ["normal T"]) on rates of pre-specified CV outcomes, using Cox proportional hazards models.

Results: Among 2118 male participants in whom T concentrations were measured, 643 (30%) had low T and 1475 had normal T concentrations at baseline. The low T group had higher rates of diabetes mellitus, hypertension, elevated body mass index, metabolic syndrome, higher blood glucose, hemoglobin A1c, and triglyceride levels, but lower levels of both low-density lipoprotein and HDL-cholesterol, and a lower rate of prior myocardial infarction (MI).

Men with low T had a higher risk of the primary composite outcome of coronary heart disease (CHD) death, MI, stroke, hospitalization for acute coronary syndrome, or coronary or cerebral revascularization (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07, and a higher risk of the CHD death, MI, and stroke composite endpoint (11.8% vs. 8.2%; final adjusted HR 1.37, P = .04), respectively.

Conclusions: In this post hoc analysis, there was an association between low baseline testosterone concentrations and increased risk of subsequent CV events in androgen-deficient men with established CV disease and metabolic syndrome, particularly for the composite secondary endpoint of CHD death, MI, and stroke.

Condensed abstract: In this AIM-HIGH Trial post hoc analysis of 2118 men with metabolic syndrome and low HDL-cholesterol with available baseline plasma testosterone (T) samples, 643 males (30%) had low T (mean: 229 ng/dL) and 1475 (70%) had normal T (mean: 444 ng/dL) concentrations.

The "low T" group had a 24% higher risk of the primary 5-component endpoint (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07). There was also a 31% higher risk of the secondary composite endpoint: coronary heart disease death, myocardial infarction, and stroke (11.8% vs. 8.2%, final adjusted HR 1.37, P = .04) in the low vs. normal T group, respectively.

Boden WE, Miller MG, McBride R, et al. Testosterone concentrations and risk of cardiovascular events in androgen-deficient men with atherosclerotic cardiovascular disease [published online ahead of print, 2020 Mar 20]. Am Heart J. 2020;224:65–76. doi:10.1016/j.ahj.2020.03.016 Testosterone concentrations and risk of cardiovascular events in androgen-deficient men with atherosclerotic cardiovascular disease - ScienceDirect

 

[Michael Scally MD]

Exogenous Testosterone Abuse and Myocardial Infarction in A Young Bodybuilder

A 25-year-old man presented with new-onset substernal chest pain. The pain was dull, and radiated to his neck and left jaw. ECG showed diffuse ST elevation without reciprocal changes (Figure 1A). Troponin level was 4.76 ng/mL (normal: 0 – 0.09). He was started on colchicine and aspirin for the treatment of suspected pericarditis. Repeat troponin level in six hours was greater than 50 ng/mL. Contrast echocardiography showed left ventricular (LV) ejection fraction of 45% and akinesis of all apical segments without left ventricular thrombus.

He underwent emergent coronary angiography, which revealed a large thrombus in proximal left anterior descending artery (LAD) (Figure 1B). Apical left anterior descending artery was noted to be occluded due to a thrombus. Proximal left anterior descending artery thrombus was treated with aspiration thrombectomy without stent placement. Aspiration thrombectomy was attempted for the distal lesion, but the vessel was too small to accommodate the catheter.

Tan BEX, Chowdhury M, Hall C, Baibhav B. Exogenous testosterone abuse and myocardial infarction in a young bodybuilder. The American Journal of Medicine. Redirecting



Figure 1 A: ECG showed diffuse ST-elevation (II, III, aVF, V2, V3, V4, V5) without reciprocal ST depression. Figure 1B: Coronary angiography showed large thrombus in proximal left anterior descending artery without atherosclerotic coronary artery disease.

 

[Michael Scally MD]

Just wondering about future reports wrt AAS and cardiac issues.

“An apple a day may keep myocardial infarction away.”

[OA] Drexler M, Elsner C, Gabelmann V, Gori T, Münzel T. Apple Watch detecting coronary ischaemia during chest pain episodes or an apple a day may keep myocardial infarction away. European Heart Journal 2020. Apple Watch detecting coronary ischaemia during chest pain episodes or an apple a day may keep myocardial infarction away

An 80-year-old lady with a work history as engineer presented with typical angina symptoms Canadian Cardiovascular Society Class III in our chest pain unit (CPU). She also complained of two episodes of praesyncopy. There reported no vegetative symptoms. Previous history included a diagnosis of arterial hypertension, paroxysmal atrial fibrillation, and an episode of pulmonary embolism 2 years ago. Her current medication included aspirin, telmisartan, nebivolol, atorvastatin, and the organic nitrate pentaerythritol tetranitrate (PETN).

The initial 12-channel ECG revealed no evidence for ischaemia. High-sensitive troponin I was also negative. The patient also complained about previous frequent episodes of ectopic beats which were recorded with her Apple watch. Further, Apple watch recordings included tracings with marked ST-segment depression (Panel).

Based on this evidence of ischaemia, further diagnostic in the CPU was omitted and the patient was transferred to the catheterization laboratory, where a left main stem stenosis and a left anterior descending/diagonal bifurcation lesion (Panel). Accordingly, the patient was treated with coronary artery stenting and left the hospital a day later.

The development of smart technologies paves the way for new diagnostic possibilities. In the case of the Apple watch, after the mobile application is installed, the records an ECG when a finger is placed on the watch’s digital crown. A 30-s tracing is stored in a PDF file that can be retrieved from the application.

Thus, the Apple watch may be used not only to detect atrial fibrillation or atrioventricular-conduction disturbances but also to detect myocardial ischaemia.

An apple a day may keep myocardial infarction away.

 

[Millard]

Just wondering about future reports wrt AAS and cardiac issues.

Thus, the Apple watch may be used not only to detect atrial fibrillation or atrioventricular-conduction disturbances but also to detect myocardial ischaemia.

Cool tech for AAS users! @Michael Scally MD said it first!

I didn't realize there were FDA-cleared ECG apps. In addition to Apple Watch ECG app, there is the Alivecor KardiaMobile for iOS and Android smartphones

 

[Michael Scally MD]

Herculean Mistake: Mephentermine Associated Cardiomyopathy

Case presentation: A 32-year-old professional bodybuilder presented with acute decompensated heart failure. He gave a history of anabolic androgenic steroids (AAS) use for >2 years and mephentermine use for the preceding 3 months.

Management: Transthoracic echocardiography showed severe left ventricular (LV) dysfunction with a large pedunculated, mobile thrombus attached to the ventricular apex. The patient had an embolic stroke during the hospital stay, with complete neurological recovery. Following the cessation of mephentermine use, there was a steady improvement in LV function over a follow-up of 2 months. However, at 3 months, his ventricular function showed deterioration, which coincided with mephentermine reuse.

Take home message: Though AAS abuse by athletes leading to such a presentation has been documented, to the best of our knowledge, a similar role of mephentermine has not been reported.

Singal AK, Deepti S, Sharma G, Kothari SS. Herculean mistake: mephentermine associated cardiomyopathy [published online ahead of print, 2020 May 13]. Phys Sportsmed. 2020;1‐7. doi:10.1080/00913847.2020.1763146 https://www.tandfonline.com/doi/abs/10.1080/00913847.2020.1763146?journalCode=ipsm20

 

[Michael Scally MD]

Anabolic Steroid Excess and Myocardial Infarction: From Ischemia to Reperfusion Injury

Anabolic steroids (AS) are synthetic testosterone-derivatives developed by the pharmaceutical industry to mimic testosterone biological effects. So far, AS have been implicated in the treatment of pathological conditions, such as hypogonadism, anemia, and cachexia.

Since their discovery, though, AS have been illicitly used by elite and recreational athletes, bodybuilders and weightlifters in order to enhance athletic and aesthetic performance. This practice is characterized by cycles of administration and withdrawal, the combination of different AS compounds, and administration of doses 50 - 1000 times higher than those recommended for therapeutic purposes.

AS excess has been correlated to cardiovascular detrimental effects, including cardiac hypertrophy, arrhythmias, and hypertension. Particularly, acute myocardial infarction (AMI) has been extensively reported by clinical and post-mortem studies. Atherosclerosis, hypercoagulability state, increased thrombogenesis and vasospasm have arisen as potential causes of myocardial ischemia in AS users.

Additionally, several experimental reports have demonstrated that AS can increase the susceptibility to cardiac ischemia/reperfusion injury, whereas the cardioprotection elicited by physical exercise and ischemic postconditioning is blunted.

Altogether, these factors can contribute to increased AMI morbidity and mortality during AS excess, particularly when AS are combined with other compounds, such as thyroid hormones, growth hormones, insulin, and diuretics.

Seara FAC, Olivares EL, H M Nascimento J. Anabolic steroid excess and myocardial infarction: from ischemia to reperfusion injury [published online ahead of print, 2020 May 31]. Steroids. 2020;108660. doi:10.1016/j.steroids.2020.108660 Anabolic steroid excess and myocardial infarction: from ischemia to reperfusion injury - ScienceDirect

 

[Michael Scally MD]

[OA] Androgen-Regulated Cardiac Metabolism in Aging Men.

The prevalence of cardiovascular mortality is higher in men than in age-matched premenopausal women. Gender differences are linked to circulating sex-related steroid hormone levels and their cardio-specific actions, which are critical factors involved in the prevalence and features of age-associated cardiovascular disease.

In women, estrogens have been described as cardioprotective agents, while in men, testosterone is the main sex steroid hormone. The effects of testosterone as a metabolic regulator and cardioprotective agent in aging men are poorly understood.

With advancing age, testosterone levels gradually decrease in men, an effect associated with increasing fat mass, decrease in lean body mass, dyslipidemia, insulin resistance and adjustment in energy substrate metabolism. Aging is associated with a decline in metabolism, characterized by modifications in cardiac function, excitation-contraction coupling, and lower efficacy to generate energy.

Testosterone deficiency -as found in elderly men- rapidly becomes an epidemic condition, associated with prominent cardiometabolic disorders. Therefore, it is highly probable that senior men showing low testosterone levels will display symptoms of androgen deficiency, presenting an unfavorable metabolic profile and increased cardiovascular risk.

Moreover, recent reports establish that testosterone replacement improves cardiomyocyte bioenergetics, increases glucose metabolism and reduces insulin resistance in elderly men. Thus, testosterone-related metabolic signaling and gene expression may constitute relevant therapeutic target for preventing, or treating, age- and gender-related cardiometabolic diseases in men.

Here, we will discuss the impact of current evidence showing how cardiac metabolism is regulated by androgen levels in aging men.

Barrientos G, Llanos P, Basualto-Alarcón C, Estrada M. Androgen-Regulated Cardiac Metabolism in Aging Men. Front Endocrinol (Lausanne). 2020;11:316. Published 2020 May 15. doi:10.3389/fendo.2020.00316 Androgen-Regulated Cardiac Metabolism in Aging Men

 

[Michael Scally MD]

Aortic Root Dilation and Testosterone Use: Are They Associated?

Aortic root dilation and thoracic aortic aneurysms are relatively rare in young and healthy patient populations. However, a number of observed incidental cases regarding young males and testosterone use raises suspicion of a potential risk factor for aortic root dilation.

The authors' patient, a healthy 40-year-old man with a significant history of testosterone use who developed a massively dilated aortic root, is sufficiently alarming to report. Notwithstanding anecdotal cases, there exists a well-known association between elite strength athletes and aortic root dilation.

Nevertheless, very little clinical research exists on the relationship between testosterone use and aortic root dilation and/or thoracic aortic aneurysms. Furthermore, a small number of animal studies showed a relationship between testosterone and vascular dilation, particularly the aorta.

Although testosterone may play a role in the development of aortic pathologies, further research is necessary to clarify the possible relationship if cases such as these are to be prevented.

Goitom B, Thom D, Emerson D, Henderson L, Grant JD, D'Attellis N. Aortic Root Dilation and Testosterone Use: Are They Associated? [published online ahead of print, 2020 May 15]. J Cardiothorac Vasc Anesth. 2020;S1053-0770(20)30423-7. doi:10.1053/j.jvca.2020.05.003 https://www.jcvaonline.com/article/S1053-0770(20)30423-7/pdf

 

[Michael Scally MD]

Mortality, Major Adverse Cardiovascular Events (MACDE), and Diabetic Complications in Men with Hypogonadism and Type 2 Diabetes (T2DM) Receiving Long-Term Treatment with Testosterone Undecanoate Injections (TU): 11-Year Real-World Data
401-P: Mortality, Major Adverse Cardiovascular Events (MACDE), and Diabetic Complications in Men with Hypogonadism and Type 2 Diabetes (T2DM) Receiving Long-Term Treatment with Testosterone Undecanoate Injections (TU): 11-Year Real-World Data

Background: Men with hypogonadism are at increased risk of MACE and mortality. Studies in men with T2DM show that testosterone therapy (TTh) reduces both MACE and mortality.

Methods: In a registry of 858 men with hypogonadism, 356 men (41.5%) had T2DM. 178 received testosterone undecanoate injections (TU) 1000 mg/12 weeks (T-group) and 178 opted against treatment (CTRL). MACE, mortality, and diabetic complications were recorded and compared between groups.

Results: Mean baseline age in the T-group and CTRL was 61.8±5.1 and 63.6±4.9 years, respectively. Mean follow-up in T-group vs. CTRL was 7.4 and 8.3 years, respectively. 69 patients (38.8%) in the T-group and 70 (39.3%) in CTRL had a history of cardiovascular disease (myocardial infarction, stroke, or coronary artery disease diagnosis) (p=0.9135). Baseline smoking prevalence was 41.6% (74 men) in the T-group and 38.2% (68 men) in CTRL (p=0.5161).

The T-group had significantly worse baseline risk factor profile than CTRL: BMI (36.5±4.5 vs. 33.4±5.3 kg/m²), systolic blood pressure (163.0±13.3 vs. 145.6±14.6 mmHg), LDL (4.7±0.9 vs. 4.1±1.4 mmol/L), HbA1c 9.4±1.4 vs. 7.8±0.7% (p<0.0001 for all).

Mortality: during the entire observation period, 13 patients (7.3%) died in the T-group vs. 48 (27.0%) in CTRL (p<0.0001).

MACE: in the T-group, there were no cases of myocardial infarction or stroke. In CTRL, there were 55 cases of myocardial infarction (30.9%) and 45 cases of stroke (25.3%).

Diabetic complications: in the T-group vs. CTRL, the incidence of retinopathy was 3.4% and 16.9% (p<0.0001), nephropathy 0.6% and 4% (p<0.05), polyneuropathy 6.2% and 54.8% (p<0.0001), diabetic foot syndrome 0% and 9.6% (p<0.0001).

Conclusions: Long-term treatment with TU in men with hypogonadism and T2DM significantly reduces MACE and mortality, as well as diabetic complications compared to untreated controls.

 

[Michael Scally MD]

Association of Normal Systolic Blood Pressure Level With Cardiovascular Disease in the Absence of Risk Factors

Key Points

Question Is there an association between normal systolic blood pressure values as currently defined and atherosclerotic cardiovascular disease among persons without traditional cardiovascular disease risk factors?

Findings In this cohort study including 1457 participants without atherosclerotic cardiovascular disease, beginning with a systolic blood pressure level of 90 mm Hg, there was a stepwise increase in the prevalence of traditional atherosclerotic cardiovascular disease risk factors, coronary artery calcium, and the risk of atherosclerotic cardiovascular disease. For every 10-mm Hg increase in systolic blood pressure, there was a 53% higher risk for atherosclerotic cardiovascular disease.

Meaning These results highlight the importance of primordial prevention to maintain optimal systolic blood pressure levels as well as optimal values of other traditional atherosclerotic cardiovascular disease, all of which generally have similar trajectories of risk within conventionally considered normal ranges.

Whelton SP, McEvoy JW, Shaw L, et al. Association of Normal Systolic Blood Pressure Level With Cardiovascular Disease in the Absence of Risk Factors. JAMA Cardiol. Published online June 10, 2020. https://jamanetwork.com/journals/jamacardiology/article-abstract/2766469

Importance The risk of atherosclerotic cardiovascular disease (ASCVD) at currently defined normal systolic blood pressure (SBP) levels in persons without ASCVD risk factors based on current definitions is not well defined.

Objective To examine the association of SBP levels with coronary artery calcium and ASCVD in persons without hypertension or other traditional ASCVD risk factors based on current definitions.

Design, Setting, and Participants A cohort of 1457 participants free of ASCVD from the Multi-Ethnic Study of Atherosclerosis who were without dyslipidemia (low-density lipoprotein cholesterol level ≥160 mg/dL or high-density lipoprotein cholesterol level <40 mg/dL), diabetes (fasting glucose level ≥126 mg/dL), treatment for hyperlipidemia or diabetes, or current tobacco use, and had an SBP level between 90 and 129 mm Hg. Participants receiving hypertension medication were excluded. Coronary artery calcium was classified as absent or present and adjusted hazard ratios (aHRs) were calculated for incident ASCVD. The study was conducted from March 27, 2018, to February 12, 2020.

Exposures Systolic blood pressure.

Main Outcomes and Measures Presence or absence of coronary artery calcium and incident ASCVD events.

Results Of the 1457 participants, 894 were women (61.4%); mean (SD) age was 58.1 (9.8) years and mean (SD) follow-up was 14.5 (3.9) years. There was an increase in traditional ASCVD risk factors, coronary artery calcium, and incident ASCVD events with increasing SBP levels. The aHR for ASCVD was 1.53 (95% CI, 1.17-1.99) for every 10-mm Hg increase in SBP levels. Compared with persons with SBP levels 90 to 99 mm Hg, the aHR for ASCVD risk was 3.00 (95% CI, 1.01-8.88) for SBP levels 100 to 109 mm Hg, 3.10 (95% CI, 1.03-9.28) for SBP levels 110 to 119 mm Hg, and 4.58 (95% CI, 1.47-14.27) for SBP levels 120 to 129 mm Hg.

Conclusions and Relevance Beginning at an SBP level as low as 90 mm Hg, there appears to be a stepwise increase in the presence of coronary artery calcium and the risk of incident ASCVD with increasing SBP levels. These results highlight the importance of primordial prevention for SBP level increase and other traditional ASCVD risk factors, which generally seem to have similar trajectories of graded increase in risk within values traditionally considered to be normal.

 

[Michael Scally MD]

Association of Normal Systolic Blood Pressure Level With Cardiovascular Disease in the Absence of Risk Factors

Key Points

Question Is there an association between normal systolic blood pressure values as currently defined and atherosclerotic cardiovascular disease among persons without traditional cardiovascular disease risk factors?

Findings In this cohort study including 1457 participants without atherosclerotic cardiovascular disease, beginning with a systolic blood pressure level of 90 mm Hg, there was a stepwise increase in the prevalence of traditional atherosclerotic cardiovascular disease risk factors, coronary artery calcium, and the risk of atherosclerotic cardiovascular disease. For every 10-mm Hg increase in systolic blood pressure, there was a 53% higher risk for atherosclerotic cardiovascular disease.

Meaning These results highlight the importance of primordial prevention to maintain optimal systolic blood pressure levels as well as optimal values of other traditional atherosclerotic cardiovascular disease, all of which generally have similar trajectories of risk within conventionally considered normal ranges.

Whelton SP, McEvoy JW, Shaw L, et al. Association of Normal Systolic Blood Pressure Level With Cardiovascular Disease in the Absence of Risk Factors. JAMA Cardiol. Published online June 10, 2020. https://jamanetwork.com/journals/jamacardiology/article-abstract/2766469

Importance The risk of atherosclerotic cardiovascular disease (ASCVD) at currently defined normal systolic blood pressure (SBP) levels in persons without ASCVD risk factors based on current definitions is not well defined.

Objective To examine the association of SBP levels with coronary artery calcium and ASCVD in persons without hypertension or other traditional ASCVD risk factors based on current definitions.

Design, Setting, and Participants A cohort of 1457 participants free of ASCVD from the Multi-Ethnic Study of Atherosclerosis who were without dyslipidemia (low-density lipoprotein cholesterol level ≥160 mg/dL or high-density lipoprotein cholesterol level <40 mg/dL), diabetes (fasting glucose level ≥126 mg/dL), treatment for hyperlipidemia or diabetes, or current tobacco use, and had an SBP level between 90 and 129 mm Hg. Participants receiving hypertension medication were excluded. Coronary artery calcium was classified as absent or present and adjusted hazard ratios (aHRs) were calculated for incident ASCVD. The study was conducted from March 27, 2018, to February 12, 2020.

Exposures Systolic blood pressure.

Main Outcomes and Measures Presence or absence of coronary artery calcium and incident ASCVD events.

Results Of the 1457 participants, 894 were women (61.4%); mean (SD) age was 58.1 (9.8) years and mean (SD) follow-up was 14.5 (3.9) years. There was an increase in traditional ASCVD risk factors, coronary artery calcium, and incident ASCVD events with increasing SBP levels. The aHR for ASCVD was 1.53 (95% CI, 1.17-1.99) for every 10-mm Hg increase in SBP levels. Compared with persons with SBP levels 90 to 99 mm Hg, the aHR for ASCVD risk was 3.00 (95% CI, 1.01-8.88) for SBP levels 100 to 109 mm Hg, 3.10 (95% CI, 1.03-9.28) for SBP levels 110 to 119 mm Hg, and 4.58 (95% CI, 1.47-14.27) for SBP levels 120 to 129 mm Hg.

Conclusions and Relevance Beginning at an SBP level as low as 90 mm Hg, there appears to be a stepwise increase in the presence of coronary artery calcium and the risk of incident ASCVD with increasing SBP levels. These results highlight the importance of primordial prevention for SBP level increase and other traditional ASCVD risk factors, which generally seem to have similar trajectories of graded increase in risk within values traditionally considered to be normal.

Jones DW. What Is a Normal Blood Pressure? JAMA Cardiol. Published online June 10, 2020. https://jamanetwork.com/journals/jamacardiology/article-abstract/2766467

In this issue of JAMA Cardiology, Whelton et al1 report an analysis of data from the Multi-Ethnic Study of Atherosclerosis Study that provides insight into the association between blood pressure (BP) and incident atherosclerotic cardiovascular disease (ASCVD), as well as the prevalence of coronary artery calcium. The key finding in the analysis is that, in persons free of hypertension as currently defined, free of known ASCVD, and free of other risk factors as currently defined, the risk imposed by a BP level below the currently defined hypertensive level is continuous beginning at a systolic BP level as low as 90 mm Hg.

 

[Michael Scally MD]

Kharaba ZJ, Buabeid MA, Ibrahim NA, et al. Testosterone therapy in hypogonadal patients and the associated risks of cardiovascular events. Biomedicine & Pharmacotherapy 2020;129:110423. Testosterone therapy in hypogonadal patients and the associated risks of cardiovascular events - ScienceDirect

Highlights
· Clinical trials have shown presence and absence of correlation between cardiovascular risks and testosterone therapy.
· Such contradictions have reduced certainty in predicting cardiovascular risks during testosterone replacement therapy.
· The cardiovascular risk of such therapy was found to be associated with age.
· The risk was even more severe in patients who had a previous history of myocardial infarction or stroke.

Since the male secondary sex characters, libido and fertility are attributed to their major androgen hormone testosterone, the sub-optimum levels of testosterone in young adults may cause infertility and irregularities in their sexual behaviour. Such deficiency is often secondary to maladies involving testes, pituitary or hypothalamus that could be treated with an administration of exogenous testosterone.

In the last few decades, the number of testosterone prescriptions has markedly increased to treat sub-optimal serum levels even though its administration in such conditions is not yet approved. On account of its associated cardiovascular hazards, the food and drug authority in the United States has issued safety alerts on testosterone replacement therapy (TRT).

Owing to a great degree of conflict among their findings, the published clinical trials seem struggling in presenting a decisive opinion on the matter. Hence, the clinicians remain uncertain about the possible cardiovascular adversities while prescribing TRT in hypogonadal men. The uncertainty escalates even further while prescribing such therapy in older men with a previous history of cardiovascular ailments.

In the current review, we analysed the pre-clinical and clinical studies to evaluate the physiological impact of testosterone on cardiovascular and related parameters. We have enlisted studies on the association of cardiovascular health and endogenous testosterone levels with a comprehensive analysis of epidemiological studies, clinical trials, and meta-analyses on the cardiovascular risk of TRT. The review is aimed to assist clinicians in making smart decisions regarding TRT in their patients.