AAS and Cardiovascular/Pulmonary Function

Long-Term Testosterone Supplementation in Older Men Attenuates Age-Related Decline in Aerobic Capacity

Context - Testosterone increases skeletal muscle mass and strength, but long-term effects of testosterone supplementation on aerobic capacity (V˙O2peak) in healthy older men with low testosterone have not been evaluated.

Objective - To determine the effects of testosterone supplementation on V˙O2peak during incremental cycle ergometry.

Design - Testosterone’s Effects on Atherosclerosis Progression in Aging Men trial: double-blind, randomized, placebo-controlled, parallel-group trial.

Setting - Exercise physiology laboratory.

Participants - Healthy men aged ≥60y with total testosterone levels of 100-400 ng/dL (3.5 – 13.9 nmol/L) or free testosterone <50 pg/mL (174 pmol/L).

Interventions - Randomization to 1% transdermal testosterone gel adjusted to achieve serum levels of 500-950 ng/dL or placebo applied daily for 3 years.

Main Outcome Measures - Change in V˙O2peak .

Results - Mean (SD) baseline V˙O2peak was 24.2 (5.2) and 23.6 (5.6) mL/kg/min for testosterone and placebo respectively.

V˙O2peak did not change in testosterone treated men but fell significantly in men receiving placebo [average 3-year decrease = 0.88 mL/kg/min (95% CI = -1.39 to 0.38) (P=0.035)]; the difference in change in V˙O2peak between groups was significant, [average 3-year difference = 0.91 mL/kg/min (95% CI = 0.010 to 0.122)], P=0.008. The 1 g/dL mean increase in hemoglobin (P<0.001) was significantly associated with changes in V˙O2peak in testosterone-treated men.

Conclusion - The mean 3-year change in V˙O2peak was significantly less in testosterone-treated men than in men receiving placebo and was associated with increases in hemoglobin.

The difference in V˙O2peak change between groups may indicate attenuation of its expected age-related decline; the clinical meaningfulness of the modest treatment effect remains to be determined.

Traustadóttir T, Harman SM, Tsitouras P, et al. Long-Term Testosterone Supplementation in Older Men Attenuates Age-Related Decline in Aerobic Capacity. The Journal of Clinical Endocrinology & Metabolism 2018. Long-Term Testosterone Supplementation in Older Men Attenuates Age-Related Decline in Aerobic Capacity | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic
 
@Michael Scally MD
I recently came across a study on dogs using Rapamycin. I know it's somehow connected to Mtor.
It was intriguing because of the great results they got in improving ejection fraction.
Do you have any insight on this drug. Have heard great things about it for increased performance and life longevity. I know it's not approved yet for someone like myself but I'd love to know your thoughts on it.
Thanks.
 
@Michael Scally MD
I recently came across a study on dogs using Rapamycin. I know it's somehow connected to Mtor.
It was intriguing because of the great results they got in improving ejection fraction.
Do you have any insight on this drug. Have heard great things about it for increased performance and life longevity. I know it's not approved yet for someone like myself but I'd love to know your thoughts on it.
Thanks.

There are dog clinical trials with rapamycin.

The Dog Aging Project has made national headlines in scientific and popular media for its innovative approach to understanding human aging by studying canine longevity.

Led by Matt Kaeberlein, Ph.D., Co-director, University of Washington Medicine Nathan Shock Center of Excellence in the Basic Biology of Aging, The Dog Aging Project aims to identify the genetic and environmental factors that underlie healthy aging to develop therapies--such as the use of the FDA-approved drug Rapamycin-- that extend healthy lifespan.

In this webinar geared for both the general public and research community, Dr. Kaeberlein will share updates on the Dog Aging Project’s key research:
[Watch a recording of the webinar here. ]

  • A Longitudinal study, where individual animals will be followed throughout life to understand the biological and environmental factors that determine why some dogs die early or succumb to diseases such as cancer, kidney failure, and dementia, while others live to a relatively old age free from these problems;
  • Trial One Study with Rapamycin, which expanded on studies in older mice and looked for improvements in heart function in the dogs that received rapamycin relative to those that received a placebo;
  • Trial Two Study with Rapamycin, which is currently enrolling a second cohort of middle-aged dogs into a longer-term, low-dose rapamycin regimen designed to maximize lifespan and healthspan extension. Several age-related parameters will be assessed before, during, and after the treatment period, including cognitive function, heart function, and activity.


U.S. Doc Prescribing Anti-Aging Cocktail To Seniors
http://longevityfacts.com/u-s-doc-prescribing-anti-aging-cocktail-rapamycin-metformin/

Summary: Could an experimental anti-aging cocktail of rapamycin and metformin and other drugs extend life? New York physician is treating patients with an anti-aging drug regimen. This article details which medications the doctor prescribes and why he prescribes them.
 
There are dog clinical trials with rapamycin.

The Dog Aging Project has made national headlines in scientific and popular media for its innovative approach to understanding human aging by studying canine longevity.

Led by Matt Kaeberlein, Ph.D., Co-director, University of Washington Medicine Nathan Shock Center of Excellence in the Basic Biology of Aging, The Dog Aging Project aims to identify the genetic and environmental factors that underlie healthy aging to develop therapies--such as the use of the FDA-approved drug Rapamycin-- that extend healthy lifespan.

In this webinar geared for both the general public and research community, Dr. Kaeberlein will share updates on the Dog Aging Project’s key research:
[Watch a recording of the webinar here. ]

  • A Longitudinal study, where individual animals will be followed throughout life to understand the biological and environmental factors that determine why some dogs die early or succumb to diseases such as cancer, kidney failure, and dementia, while others live to a relatively old age free from these problems;
  • Trial One Study with Rapamycin, which expanded on studies in older mice and looked for improvements in heart function in the dogs that received rapamycin relative to those that received a placebo;
  • Trial Two Study with Rapamycin, which is currently enrolling a second cohort of middle-aged dogs into a longer-term, low-dose rapamycin regimen designed to maximize lifespan and healthspan extension. Several age-related parameters will be assessed before, during, and after the treatment period, including cognitive function, heart function, and activity.


U.S. Doc Prescribing Anti-Aging Cocktail To Seniors
http://longevityfacts.com/u-s-doc-prescribing-anti-aging-cocktail-rapamycin-metformin/

Summary: Could an experimental anti-aging cocktail of rapamycin and metformin and other drugs extend life? New York physician is treating patients with an anti-aging drug regimen. This article details which medications the doctor prescribes and why he prescribes them.
Amazing!! Cant believe the benefits this may offer not only to those sick like myself but also to the general public.
Blown away by the strides the medical community have made in regards to prolonging are longevity.
I'm going to talk with my Docs about the possibility of seeing that Dr. in NY.
I really appreciate the great info Doc.
Hope everything is well.
Thank you.
 
Association of Extremely High Levels of High-Density Lipoprotein Cholesterol with Cardiovascular Mortality

Highlights
· There are insufficient studies to examine the effect of high levels of high-density lipoprotein cholesterol (HDL-C).
· Extremely high levels of HDL-C had adverse effects on atherosclerotic cardiovascular disease mortality.
· The risk for extremely high HDL-C was more evident among current drinkers.

Background - The effect of very high or extremely high levels of high-density lipoprotein cholesterol (HDL-C) on cardiovascular disease (CVD) is not well described. Although a few recent studies have reported the adverse effects of extremely high levels of HDL-C on CVD events, these did not show a statistically significant association between extremely high levels of HDL-C and cause-specific CVD mortality. In addition, Asian populations have not been studied.

Objective - We examine the impact of extremely high levels of HDL-C on cause-specific CVD mortality using pooled data of Japanese cohort studies.

Methods - We performed a large-scale pooled analysis of 9 Japanese cohorts including 43,407 participants aged 40–89 years, dividing the participants into 5 groups by HDL-C levels, including extremely high levels of HDL-C ≥2.33 mmol/L (≥90 mg/dL). We estimated the adjusted hazard ratio of each HDL-C category for all-cause death and cause-specific deaths compared with HDL-C 1.04–1.55 mmol/L (40–59 mg/dL) using a cohort-stratified Cox proportional hazards model.

Results - During a 12.1-year follow-up, 4995 all-cause deaths and 1280 deaths due to overall CVD were identified. Extremely high levels of HDL-C were significantly associated with increased risk of atherosclerotic CVD mortality (hazard ratio = 2.37, 95% confidence interval: 1.37–4.09 for total) and increased risk for coronary heart disease and ischemic stroke. In addition, the risk for extremely high HDL-C was more evident among current drinkers.

Conclusion - We showed extremely high levels of HDL-C had an adverse effect on atherosclerotic CVD mortality in a pooled analysis of Japanese cohorts.

Hirata A, Sugiyama D, Watanabe M, et al. Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: The EPOCH–JAPAN study. Journal of clinical lipidology 2018;12:674-84.e5. Redirecting
 
Testosterone Reduces Circulating PCSK9 But Does Not Influence Cholesterol or Bile Acid Synthesis

Objective: Human cholesterol metabolism is influenced by age and gender. LDL cholesterol increases with age, and is lower in premenopausal females than in males, while HDL cholesterol is increased by estrogen.

The synthesis of cholesterol is higher in males, as are bile acid synthesis and pool size. Estrogen stimulates hepatic LDL receptors, and appears to lower circulating PCSK9. The role of testosterone for these gender differences is less clear.

We tested the hypothesis that increased levels of testosterone will increase bile acid and cholesterol syntheses and PCSK9 levels in normal males.

Methods: Serum lipoproteins, PCSK9, lathosterol (marker of cholesterol synthesis), 7α-hydroxy-4-cholesten-3-one (C4; marker of bile acid synthesis), fibroblast growth factor 19 (FGF19) and individual serum bile acids were measured in 25 male volunteers before and after treatment with 250 and 500 mg of testosterone.

Results: Testosterone treatment resulted in a dose-related reduction in circulating PCSK9, but had no effects on lathosterol, C4 or FGF19 levels. Increased VLDL and lowered LDL and HDL cholesterol levels were seen 14 days after treatment.

Conclusions: Our results indicate that testosterone reduces PCSK9 levels, further supporting that this modulator of LDL receptors is under hormonal control. However, differences in testosterone are unlikely to explain known gender differences in bile acid and cholesterol synthesis.

Laskar MG, Beckman L, Laskar A, et al. Testosterone Reduces Circulating PCSK9 But Does Not Influence Cholesterol or Bile Acid Synthesis in Healthy Males. Atherosclerosis Supplements 2018;32:63. https://www.sciencedirect.com/science/article/pii/S1567568818301909
 
Testosterone Reduces Circulating PCSK9 But Does Not Influence Cholesterol or Bile Acid Synthesis

Objective: Human cholesterol metabolism is influenced by age and gender. LDL cholesterol increases with age, and is lower in premenopausal females than in males, while HDL cholesterol is increased by estrogen.

The synthesis of cholesterol is higher in males, as are bile acid synthesis and pool size. Estrogen stimulates hepatic LDL receptors, and appears to lower circulating PCSK9. The role of testosterone for these gender differences is less clear.

We tested the hypothesis that increased levels of testosterone will increase bile acid and cholesterol syntheses and PCSK9 levels in normal males.

Methods: Serum lipoproteins, PCSK9, lathosterol (marker of cholesterol synthesis), 7α-hydroxy-4-cholesten-3-one (C4; marker of bile acid synthesis), fibroblast growth factor 19 (FGF19) and individual serum bile acids were measured in 25 male volunteers before and after treatment with 250 and 500 mg of testosterone.

Results: Testosterone treatment resulted in a dose-related reduction in circulating PCSK9, but had no effects on lathosterol, C4 or FGF19 levels. Increased VLDL and lowered LDL and HDL cholesterol levels were seen 14 days after treatment.

Conclusions: Our results indicate that testosterone reduces PCSK9 levels, further supporting that this modulator of LDL receptors is under hormonal control. However, differences in testosterone are unlikely to explain known gender differences in bile acid and cholesterol synthesis.

Laskar MG, Beckman L, Laskar A, et al. Testosterone Reduces Circulating PCSK9 But Does Not Influence Cholesterol or Bile Acid Synthesis in Healthy Males. Atherosclerosis Supplements 2018;32:63. Testosterone Reduces Circulating PCSK9 But Does Not Influence Cholesterol or Bile Acid Synthesis in Healthy Males
So should I assume higher test levels are good? Or even more beneficial to healthy males?
At 41 years old my last bloodwork had a TT of 593. I wonder if higher test would help.
Although I'm not a healthy male.
 
Vani A, Underberg James A. Lowering LDL‐cholesterol and CV benefits: Is there a limit to how low LDL‐C needs to be for optimal health benefits? Clinical Pharmacology & Therapeutics 2018. https://doi.org/10.1002/cpt.1133

Atherosclerotic cardiovascular disease (ASCVD) is the number one cause of morbidity and mortality worldwide. Low‐density lipoprotein cholesterol (LDL‐C) has been implicated as one of the major risk factors causing ASCVD based on multiple hierarchical levels of evidence.

The advent of powerful LDL‐C lowering therapies, such as the proprotein convertase subtilisin/kexin type 9 inhibitor, have raised the question of how low to target LDL‐C and whether there are any adverse safety events associated with a very low LDL‐C level.

The present review summarizes the available evidence and concludes that even a very low LDL‐C is associated with cardiovascular benefit, although the magnitude of benefit depends on baseline ASCVD risk and the absolute change in LDL‐C with pharmacologic therapy.

The safety data in patients treated to very low LDL‐C is reassuring, although it is inconsistent and requires longer‐term follow‐up.
 
[OA] Mechanisms of Testosterone Deficiency-Related Endothelial Dysfunction

Evidence from clinical studies suggests that patients with low testosterone levels are at increased cardiovascular disease risk. Even though the exact mechanisms remain poorly understood, low plasma testosterone is associated with a pro-atherogenic lipid profile, insulin resistance and increased levels of pro-inflammatory mediators, and vascular dysfunction which is typically observed in patients with hypogonadism. Furthermore, recent evidence suggests that testosterone deficiency has also direct adverse effects on endothelium and nitric oxide bioavailability.

Observations from studies in patients with hypogonadal hypogonadism imply that the mechanisms of endothelial dysfunction related with testosterone-deficiency may involve changes in asymmetric dimethylarginine (ADMA) levels, a known endogenous inhibitor of nitric oxide synthase.

Evidence suggests that testosterone replacement therapy is not only a safe, but also an effective means to reduce atherosclerotic risk and reverse endothelial dysfunction in patients with hypogonadal hypogonadism. Further research in the field is expected to clarify whether changes in ADMA metabolism constitute the central mechanism via which low testosterone leads to endothelial dysfunction.

Antonopoulos AS, Antoniades C. Mechanisms of testosterone deficiency-related endothelial dysfunction. Hellenic journal of cardiology: HJC = Hellenike kardiologike epitheorese 2018. Mechanisms of testosterone deficiency-related endothelial dysfunction - ScienceDirect
 
[OA] Flo FJ, Kanu O, Teleb M, Chen Y, Siddiqui T. Anabolic androgenic steroid–induced acute myocardial infarction with multiorgan failure. Proceedings (Baylor University Medical Center). 2018;31(3):334-336. Anabolic androgenic steroid–induced acute myocardial infarction with multiorgan failure

The abuse of anabolic androgenic steroids (AAS) has remained on the rise despite their well-known deleterious effects. We describe a case of AAS-induced multisystem failure following an extensive history of abuse in a 41-year-old bodybuilder. Furthermore, we review pertinent literature and discuss the different pathophysiologic mechanisms through which AAS affect the heart and other organs. This case points to the possibility of multiorgan involvement and severe cardiac effects of AAS abuse in young individuals who may not have any past medical history.
 
[OA] Flo FJ, Kanu O, Teleb M, Chen Y, Siddiqui T. Anabolic androgenic steroid–induced acute myocardial infarction with multiorgan failure. Proceedings (Baylor University Medical Center). 2018;31(3):334-336. Anabolic androgenic steroid–induced acute myocardial infarction with multiorgan failure

The abuse of anabolic androgenic steroids (AAS) has remained on the rise despite their well-known deleterious effects. We describe a case of AAS-induced multisystem failure following an extensive history of abuse in a 41-year-old bodybuilder. Furthermore, we review pertinent literature and discuss the different pathophysiologic mechanisms through which AAS affect the heart and other organs. This case points to the possibility of multiorgan involvement and severe cardiac effects of AAS abuse in young individuals who may not have any past medical history.
Great read Doc. Except he's 41 just like me!! Was schocked that his ejection fraction improved so quickly.
Took me 2 weeks in the hospital to go from 20% to 30%. I wish they would of stated what medications he was taking besides the diuretic.
Also what AAS he had used.
I'm not trying to be a dick but you abuse AAS for 20 years you're a ticking time bomb IMO.
Have a great weekend Doc. They just added Renaxa to my ever growing med list. 500mg 2x day.
 
Zeller T, Schnabel RB, Appelbaum S, et al. Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women – results from the FINRISK study. European journal of preventive cardiology 2018:2047487318778346. SAGE Journals: Your gateway to world-class journal research

Background - Atrial fibrillation is the most common serious abnormal heart rhythm, and a frequent cause of ischaemic stroke. Recent experimental studies, mainly in orchiectomised rats, report a relationship between sex hormones and atrial electrophysiology and electroanatomy. We aimed to evaluate whether low testosterone levels are predictive for atrial fibrillation and/or ischaemic stroke in men and women.

Design and methods - The serum total testosterone levels were measured at baseline in a population cohort of 7892 subjects (3876 male, 4016 female), aged 25–74 years, using a commercially available immunoassay. The main outcome measure was atrial fibrillation or ischaemic stroke, whichever came first.

Results - During a median follow-up of 13.8 years, a total of 629 subjects (8.0%) suffered from incident atrial fibrillation (n = 426) and/or ischemic stroke (n = 276). Cox regression analyses, adjusted for age (used as time-scale), geographical region, total cholesterol (log), high-density lipoprotein-cholesterol (log), hypertension medication, known diabetes, smoking status, waist-hip-ratio, and time of blood drawn, documented differential predictive value of low sex-specific testosterone levels for atrial fibrillation and/or ischaemic stroke, in men and in women: Increasing levels were associated with lower risk in men (hazard ratio per one nmol/l increase 0.98 (95% confidence interval 0.93–1.00); p = 0.049). On the other hand, increasing testosterone levels were associated with higher risk in women (hazard ratio per one nmol/l increase 1.17 (95% confidence interval 1.02–1.36); p = 0.031).

Conclusion - Our study indicates that low testosterone levels are associated with increased risk of future atrial fibrillation and/or ischaemic stroke in men, while they are protective in women.


Guerra F, Ciliberti G, Capucci A. Sex differences in atrial fibrillation: The case of testosterone. European journal of preventive cardiology 2018:2047487318784741. SAGE Journals: Your gateway to world-class journal research

In this issue of the European Journal of Preventive Cardiology, Zeller et al.1 delve into the FINRISK97 study to deliver impressive data over a 15-year follow-up period. Their take-home message is simple, yet intriguing: serum testosterone levels and the risk of atrial fibrillation and ischaemic stroke are positively associated in women, but negatively associated in men. More simply, an increase of 1 nmol/L is associated with a 2% reduction of risk in men and a 17% increase of risk in women after correction for the most important cardiovascular risk factors. This finding has a profound (and two-fold) clinical implication.

The paper adds evidence to the idea that low testosterone should be considered as a risk factor for atrial fibrillation and the most dreaded complication, ischaemic stroke. The role of testosterone deficiency was suggested in the milestone experimental work of Tsuneda et al.,2 which showed that the gonadectomy of male rats increased atrial vulnerability and arrhythmogenicity by inducing ryanodine receptor type 2-dependent intracellular calcium leaks from the sarcoplasmic reticulum.

...
 
Zeller T, Schnabel RB, Appelbaum S, et al. Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women – results from the FINRISK study. European journal of preventive cardiology 2018:2047487318778346. SAGE Journals: Your gateway to world-class journal research

Background - Atrial fibrillation is the most common serious abnormal heart rhythm, and a frequent cause of ischaemic stroke. Recent experimental studies, mainly in orchiectomised rats, report a relationship between sex hormones and atrial electrophysiology and electroanatomy. We aimed to evaluate whether low testosterone levels are predictive for atrial fibrillation and/or ischaemic stroke in men and women.

Design and methods - The serum total testosterone levels were measured at baseline in a population cohort of 7892 subjects (3876 male, 4016 female), aged 25–74 years, using a commercially available immunoassay. The main outcome measure was atrial fibrillation or ischaemic stroke, whichever came first.

Results - During a median follow-up of 13.8 years, a total of 629 subjects (8.0%) suffered from incident atrial fibrillation (n = 426) and/or ischemic stroke (n = 276). Cox regression analyses, adjusted for age (used as time-scale), geographical region, total cholesterol (log), high-density lipoprotein-cholesterol (log), hypertension medication, known diabetes, smoking status, waist-hip-ratio, and time of blood drawn, documented differential predictive value of low sex-specific testosterone levels for atrial fibrillation and/or ischaemic stroke, in men and in women: Increasing levels were associated with lower risk in men (hazard ratio per one nmol/l increase 0.98 (95% confidence interval 0.93–1.00); p = 0.049). On the other hand, increasing testosterone levels were associated with higher risk in women (hazard ratio per one nmol/l increase 1.17 (95% confidence interval 1.02–1.36); p = 0.031).

Conclusion - Our study indicates that low testosterone levels are associated with increased risk of future atrial fibrillation and/or ischaemic stroke in men, while they are protective in women.


Guerra F, Ciliberti G, Capucci A. Sex differences in atrial fibrillation: The case of testosterone. European journal of preventive cardiology 2018:2047487318784741. SAGE Journals: Your gateway to world-class journal research

In this issue of the European Journal of Preventive Cardiology, Zeller et al.1 delve into the FINRISK97 study to deliver impressive data over a 15-year follow-up period. Their take-home message is simple, yet intriguing: serum testosterone levels and the risk of atrial fibrillation and ischaemic stroke are positively associated in women, but negatively associated in men. More simply, an increase of 1 nmol/L is associated with a 2% reduction of risk in men and a 17% increase of risk in women after correction for the most important cardiovascular risk factors. This finding has a profound (and two-fold) clinical implication.

The paper adds evidence to the idea that low testosterone should be considered as a risk factor for atrial fibrillation and the most dreaded complication, ischaemic stroke. The role of testosterone deficiency was suggested in the milestone experimental work of Tsuneda et al.,2 which showed that the gonadectomy of male rats increased atrial vulnerability and arrhythmogenicity by inducing ryanodine receptor type 2-dependent intracellular calcium leaks from the sarcoplasmic reticulum.

...
 
Navarro-Peñalver M, Perez-Martinez MT, Gómez-Bueno M, et al. Testosterone Replacement Therapy in Deficient Patients With Chronic Heart Failure: A Randomized Double-Blind Controlled Pilot Study. Journal of Cardiovascular Pharmacology and Therapeutics 2018:1074248418784020. SAGE Journals: Your gateway to world-class journal research

Background: Testosterone deficiency is associated with heart failure (HF) progression and poor prognosis. Testosterone therapy has been shown to improve exercise capacity in patients with chronic HF, but no trial has evaluated the impact of replacement in patients with demonstrated testosterone deficiency.

Methods: Prospective, randomized, double-blind, placebo-controlled, and parallel-group trial comparing testosterone replacement with placebo in males with chronic HF with reduced ejection fraction (HFrEF) and testosterone deficiency (NCT01813201). Long-acting undecanoate testosterone at a fixed dose of 1000 mg was supplied by intramuscular injection at inclusion and then every 3 months. The placebo group received isotonic saline serum. Patients were randomly allocated 1:1 to testosterone or placebo while receiving optimal medical therapy, and the study was conducted for 12 months.

Results: The final sample comprised 29 patients, 15 in the placebo group and 14 in the testosterone group (aged 65 ± 8, 62% with an ischemic etiology, left ventricular ejection fraction [LVEF] 30% ± 6%, 69% New York Heart Association functional [NYHA II]). After 12 months, testosterone replacement increased testosterone levels (P = .002) but was not associated with benefit in terms of clinical symptoms and functional capacity including NYHA class, Framingham score, Minnesota Living Heart Failure Questionnaire, 6-minute walk test, or LVEF and N-terminal pro-B-type natriuretic peptide levels. No significant side effects associated with testosterone treatment were observed. No effects were found in other hormonal, metabolic, and bone turnover biomarkers.

Conclusion: In patients with HFrEF and testosterone deficiency, replacement therapy was not associated with any significant improvement.
 
Zeller T, Schnabel RB, Appelbaum S, et al. Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women – results from the FINRISK study. European journal of preventive cardiology 2018:2047487318778346. SAGE Journals: Your gateway to world-class journal research

Background - Atrial fibrillation is the most common serious abnormal heart rhythm, and a frequent cause of ischaemic stroke. Recent experimental studies, mainly in orchiectomised rats, report a relationship between sex hormones and atrial electrophysiology and electroanatomy. We aimed to evaluate whether low testosterone levels are predictive for atrial fibrillation and/or ischaemic stroke in men and women.

Design and methods - The serum total testosterone levels were measured at baseline in a population cohort of 7892 subjects (3876 male, 4016 female), aged 25–74 years, using a commercially available immunoassay. The main outcome measure was atrial fibrillation or ischaemic stroke, whichever came first.

Results - During a median follow-up of 13.8 years, a total of 629 subjects (8.0%) suffered from incident atrial fibrillation (n = 426) and/or ischemic stroke (n = 276). Cox regression analyses, adjusted for age (used as time-scale), geographical region, total cholesterol (log), high-density lipoprotein-cholesterol (log), hypertension medication, known diabetes, smoking status, waist-hip-ratio, and time of blood drawn, documented differential predictive value of low sex-specific testosterone levels for atrial fibrillation and/or ischaemic stroke, in men and in women: Increasing levels were associated with lower risk in men (hazard ratio per one nmol/l increase 0.98 (95% confidence interval 0.93–1.00); p = 0.049). On the other hand, increasing testosterone levels were associated with higher risk in women (hazard ratio per one nmol/l increase 1.17 (95% confidence interval 1.02–1.36); p = 0.031).

Conclusion - Our study indicates that low testosterone levels are associated with increased risk of future atrial fibrillation and/or ischaemic stroke in men, while they are protective in women.


Guerra F, Ciliberti G, Capucci A. Sex differences in atrial fibrillation: The case of testosterone. European journal of preventive cardiology 2018:2047487318784741. SAGE Journals: Your gateway to world-class journal research

In this issue of the European Journal of Preventive Cardiology, Zeller et al.1 delve into the FINRISK97 study to deliver impressive data over a 15-year follow-up period. Their take-home message is simple, yet intriguing: serum testosterone levels and the risk of atrial fibrillation and ischaemic stroke are positively associated in women, but negatively associated in men. More simply, an increase of 1 nmol/L is associated with a 2% reduction of risk in men and a 17% increase of risk in women after correction for the most important cardiovascular risk factors. This finding has a profound (and two-fold) clinical implication.

The paper adds evidence to the idea that low testosterone should be considered as a risk factor for atrial fibrillation and the most dreaded complication, ischaemic stroke. The role of testosterone deficiency was suggested in the milestone experimental work of Tsuneda et al.,2 which showed that the gonadectomy of male rats increased atrial vulnerability and arrhythmogenicity by inducing ryanodine receptor type 2-dependent intracellular calcium leaks from the sarcoplasmic reticulum.

...
 
Analysis of Cardiovascular Risk Factors Associated with Serum Testosterone Levels According to The US 2011–2012 National Health and Nutrition Examination Survey

Objective: To investigate associations between cardiovascular disease risk factors, including fasting glucose, cholesterol, high density lipoprotein cholesterol (HDL-c), LDL-c, blood pressure, body mass index (BMI), C-peptide, creatinine kinase, smoking, alcohol use, physical activity, C-reactive protein as well as homocysteine levels and cardiovascular events.

Methods: Data from 1545 men aged ≥40 years, with testosterone deficiency (TD) (<300 ng/dL) and non-TD (≥300 ng/dL) which were extracted from the National Health and Nutrition Examination Survey database 2011–2012 and analyzed.

Results: Multivariate logistic regression analysis showed positive associations between TD and BMI (≥35 vs. < 18.5: OR = 2.51, 95% CI: 1.19–5.32, p = .016), HDL-c (<0.91 vs. ≥0.91: OR = 1.60, 95% CI: 1.14–2.24, p = .006) and diabetes (diabetes vs. non-diabetes: OR = 1.48, 95% CI: 1.14–1.92, p = .004) as well as negative associations between TD and metabolic equivalent scores (≥12 vs. <12: OR = 0.69, 95% CI: 0.52–0.91, p = .009) and smoking (Ever vs. never: OR = 0.69, 95% CI: 0.51–0.94, p = .018).

Furthermore, total serum testosterone levels were lower in patients with heart failure (p = .04) and angina/angina pectoris (p = .001) compared with subjects without these cardiac problems.

Conclusion: Low serum testosterone was associated with multiple risk factors for CHD.

Deng C, Zhang Z, Li H, Bai P, Cao X, Dobs AS. Analysis of cardiovascular risk factors associated with serum testosterone levels according to the US 2011–2012 National Health and Nutrition Examination Survey. The Aging Male 2018:1-8. https://doi.org/10.1080/13685538.2018.1479387
 
Cardiac Systolic Dysfunction in Past Illicit Users of Anabolic Androgenic Steroids

Background - Illicit use of anabolic androgenic steroids (AAS) is associated with left ventricle (LV) systolic dysfunction and increased LV mass (LVM), but whether these findings persist in former AAS users has yet to be elucidated. The objective was to assess LV systolic function, LVM and myocardial fibrosis in current and former illicit AAS users compared with non-users.

Methods - Community-based cross-sectional study among men, aged 18–50 years, involved in recreational resistance training. We included 37 current and 33 former illicit AAS users, geometric mean (95%CI), 30 (21; 44) months since AAS cessation, and 30 non-users as controls. We assessed myocardial function and structure using advanced echocardiography and cardiac MRI with late-gadolinium enhancement.

Results - Mean (SE) LV global longitudinal strain (GLS) was impaired in former AAS users compared with non-users, −16.7 (0.5) versus −18.2 (0.4) %, P < .05.

Mean (SE) LV ejection fraction (EF) was decreased, 51 (1) versus 58 (1) %, P < .001 and LV GLS impaired, −14.5 (0.4)%, P < .001, in current AAS users compared with non-users.

Measures of LVM were increased in current AAS users compared with the other two groups, P < .001.

Plasma total testosterone was independently associated with reduced LVEF (P = .049) and increased LVM/body surface area (P = .005) in multivariate linear regressions.

Focal myocardial fibrosis was not detected in any participants and diffuse myocardial fibrosis, assessed using post-contrast T1-mapping time, did not differ among the three groups.

Conclusions - Past illicit AAS use is associated with impaired LV GLS, suggesting subclinical cardiac systolic dysfunction years after AAS cessation.

Rasmussen JJ, Schou M, Madsen PL, et al. Cardiac systolic dysfunction in past illicit users of anabolic androgenic steroids. American Heart Journal. http://dx.doi.org/10.1016/j.ahj.2018.06.010
 
Burgess S, Ference BA, Staley JR, et al. Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies - A Mendelian Randomization Analysis. JAMA Cardiol. Published online June 20, 2018. LPA Variants, Risk of Coronary Disease, and Estimated Clinical Benefit of Lipoprotein(a)-Lowering Therapies

Key Points

Question How much does plasma lipoprotein(a) need to be lowered to produce a clinically meaningful reduction in the risk of coronary heart disease?

Findings In a mendelian randomization analysis involving more than 80 000 patients and more than 150 000 controls, coronary heart disease risk was proportionally associated with the absolute change in plasma lipoprotein(a) mass concentration; a 101.5-mg/dL change in lipoprotein(a) concentration was associated with the same coronary heart disease risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol level.

Meaning Lipoprotein(a) concentration must be lowered by approximately 100 mg/dL to achieve the same reduction in coronary heart disease risk as can be achieved by lowering low-density lipoprotein cholesterol level by 38.67 mg/dL.

Abstract

Importance Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.

Objective To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.

Design, Setting, and Participants A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.

Exposures Genetic LPA score and plasma Lp(a) mass concentration.

Main Outcomes and Measures Coronary heart disease.

Results Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10−37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10−12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.

Conclusions and Relevance The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).
 
Athlete’s Heart: Is the Morganroth Hypothesis Obsolete?

In 1975, Morganroth and colleagues reported that the increased left ventricular (LV) mass in highly trained endurance athletes versus nonathletes was primarily due to increased end-diastolic volume while the increased LV mass in resistance trained athletes was solely due to an increased LV wall thickness.

Based on the divergent remodelling patterns observed, Morganroth and colleagues hypothesised that the increased “volume” load during endurance exercise may be similar to that which occurs in patients with mitral or aortic regurgitation while the “pressure” load associated with performing a Valsalva manoeuvre (VM) during resistance exercise may mimic the stress imposed on the heart by systemic hypertension or aortic stenosis.

Despite widespread acceptance of the four-decade old Morganroth hypothesis in sports cardiology, some investigators have questioned whether such a divergent “athlete’s heart” phenotype exists.

Given this uncertainty, the purpose of this brief review is to re-evaluate the Morganroth hypothesis regarding:

i) the acute effects of resistance exercise performed with a brief VM on LV wall stress, and the patterns of LV remodelling in resistance-trained athletes;

ii) the acute effects of endurance exercise on biventricular wall stress, and the time course and pattern of LV and right ventricular (RV) remodelling with endurance training; and

iii) the value of comparing “loading” conditions between athletes and patients with cardiac pathology.

Haykowsky MJ, Samuel TJ, Nelson MD, La Gerche A. Athlete’s Heart: Is the Morganroth Hypothesis Obsolete? Heart, Lung and Circulation 2018. Athlete’s Heart: Is the Morganroth Hypothesis Obsolete? - ScienceDirect
 

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