AAS and Cardiovascular/Pulmonary Function

[Old]

ejection fraction (EF) of 15% (vs. 57% three years prior)
his testosterone level was 30160.0 ng/dL (normal 280-1100 ng/dL).
at 3 months and 6 months showed improvement of EF to 39% and 54%, respectively.

Just how much was he injecting !!!

More amazing as that number is, is the fact he made such recovery in EF. Would be interesting to know the details this and of his lifestyle changes to achieve it ... besides carvedilol and (no doubt) much less T.

 

[Michael Scally MD]

At some point, medical community will realize/accept that for last 40y, we likely were wrong about HDL being a protective causal factor.

If you have low HDL, you *ARE* at higher risk for heart attack but it is likely *NOT* because of HDL.


Helgadottir A, Sulem P, Thorgeirsson G, et al. Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease. European heart journal 2018:ehy169-ehy. Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease | European Heart Journal | Oxford Academic

Aims - Scavenger receptor Class B Type 1 (SR-BI) is a major receptor for high-density lipoprotein (HDL) that promotes hepatic uptake of cholesterol from HDL. A rare mutation p.P376L, in the gene encoding SR-BI, SCARB1, was recently reported to associate with elevated HDL cholesterol (HDL-C) and increased risk of coronary artery disease (CAD), suggesting that increased HDL-C caused by SR-BI impairment might be an independent marker of cardiovascular risk. We tested the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-C also associate with increased risk of CAD in the relatively homogeneous population of Iceland.

Methods and results - Using a large resource of whole-genome sequenced Icelanders, we identified thirteen SCARB1 coding mutations that we examined for association with HDL-C (n = 136 672). Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M (combined allelic frequency = 0.2%) associate with elevated levels of HDL-C (p.G319V: β = 11.1 mg/dL, P = 8.0 × 10−7; p.V111M: β = 8.3 mg/dL, P = 1.1 × 10−6; p.V32M: β = 10.2 mg/dL, P = 8.1 × 10−4). These mutations do not associate with CAD (36 886 cases/306 268 controls) (odds ratio = 0.90, 95% confidence interval 0.67–1.22, P = 0.49), despite effects on HDL-C comparable to that reported for p.P376L, both in terms of direction and magnitude. Furthermore, HDL-C raising alleles of three common SCARB1 non-coding variants, including one previously unreported (rs61941676-C: β = 1.25 mg/dL, P = 1.7 × 10−18), and of one low frequency coding variant (p.V135I) that independently associate with higher HDL-C, do not confer increased risk of CAD.

Conclusion - Elevated HDL-C due to genetically compromised SR-BI function is not a marker of CAD risk.

 

[Michael Scally MD]

Cardiovascular Disease: The Rise Of The Genetic Risk Score

Summary points
· Use of risk factors for decision-making in cardiovascular disease has a long history in medicine.
· Early attempts to augment traditional risk factors with genetic risk scores were hampered by too little understanding of the genetic basis of complex cardiovascular disease.
· Newer studies based on hundreds of thousands of people and millions of genetic variants indicate that genetic risk scores can now outperform traditional risk factors in risk prediction.
· We propose the time has come to incorporate genetic risk scores into clinical practice.
· Studies should focus on the most appropriate way to do this to maximize benefit for our patients.

Knowles JW, Ashley EA. Cardiovascular disease: The rise of the genetic risk score. PLOS Medicine 2018;15:e1002546. https://doi.org/10.1371/journal.pmed.1002546

 

[Michael Scally MD]

 

[Michael Scally MD]

[OA] Role Of Testosterone In The Treatment Of Cardiovascular Disease

Cardiovascular disease (CVD) is the most prevalent non-communicable cause of death worldwide. Testosterone is a sex hormone that is predominant in males but also occurs in lower concentrations in females. It has effects directly on the blood vessels of the cardiovascular system and on the heart, as well as effects on risk factors for CVD.

Serum testosterone concentrations are known to decrease with age and reduced testosterone levels are linked to premature coronary artery disease, unfavourable effects on CVD risk factors and increased risk of cardiovascular mortality independent of age.

A significant number of men with heart failure demonstrate reduced serum testosterone concentrations and there is early evidence suggesting that low testosterone levels affect cardiac repolarisation. Any association between endogenous testosterone concentrations and CVD in women has yet to be established. Testosterone replacement is used to treat men with hypogonadism but also has cardiovascular effects.

This review will present the current evidence, expert opinion and controversies around the role of testosterone in the pathophysiology of CVD and surrounding the use of testosterone treatment and its effects on the cardiovascular system and CVD.

Webb CM, Collins P. Role Of Testosterone In The Treatment Of Cardiovascular Disease. European Cardiology Review. 2017;12(2):83–7. https://www.ecrjournal.com/testosterone-treatment

 

[Michael Scally MD]

[OA] The State of Testosterone Therapy Since the FDA's 2015 Labelling Changes: Indications and Cardiovascular Risk

Objective - A label change in testosterone (T) products in March 2015 followed a highly publicized FDA advisory committee meeting in September 2014. Changes included a warning of possible increased cardiovascular (CV) risks and restriction of indicated populations to younger men with a limited set of known aetiologies of testosterone deficiency (TD). These changes greatly impacted clinical practice and public perception of T therapy (TTh). Our aim was to review these changes in the light of subsequently published studies.

Design - We identified 23 studies through June 2017, including 12 clinical trials and 11 observational studies. The Testosterone Trials included 790 men aged 65 years and older with TD without known aetiology, assigned to 1‐year T gel or placebo.

Results - Demonstrated benefits of T included sexual activity and desire, physical activity and mood. There were 9 major adverse CV events (MACE) in the T arm and 16 in the placebo arm. No study reported increased MACE with TTh. A 3‐year RCT showed no difference in carotid atherosclerosis. Several large observational studies reported reduced CV events with TTh, including one showing progressively reduced CV and mortality risk with greater duration of TTh. Men whose serum T normalized with TTh had reduced risk of MI and death compared with men whose T levels failed to normalize.

Conclusion - WE CONCLUDE THAT EXISTING EVIDENCE FAILS TO SUPPORT INCREASED CV RISK WITH TTH; ON THE CONTRARY, THERE IS EVIDENCE SUGGESTIVE OF REAL‐WORLD CV BENEFITS. Finally, existing evidence provides benefits of TTh in older men without known aetiology for T deficiency.

Miner M, Morgentaler A, Khera M, Traish AM. The state of testosterone therapy since the FDA's 2015 labelling changes: Indications and cardiovascular risk. Clinical Endocrinology 2018. https://doi.org/10.1111/cen.13589

 

[Michael Scally MD]

[OA] Distinguishing Genetic Correlation from Causation Across 52 Diseases and Complex Traits

Mendelian randomization (MR) is widely used to identify causal relationships among heritable traits, but can be confounded by genetic correlations reflecting shared etiology. We propose a model in which a latent causal variable mediates the genetic correlation between two traits.

Under the latent causal variable (LCV) model, trait 1 is fully genetically causal for trait 2 if it is perfectly genetically correlated with the latent variable, implying that the entire genetic component of trait 1 is causal for trait 2; it is partially genetically causal for trait 2 if the latent variable has a high genetic correlation with the latent variable, implying that part of the genetic component of trait 1 is causal for trait 2.

To quantify the degree of partial genetic causality, we define the genetic causality proportion (gcp). We fit this model using mixed fourth moments E(α21α1α2) and E(α22α1α2) of marginal effect sizes for each trait, exploiting the fact that if trait 1 is causal for trait 2 then SNPs with large effects on trait 1 (large E(α21)) will have correlated effects on trait 2 (large E(α1α2)), but not vice versa.

We performed simulations under a wide range of genetic architectures and determined that LCV, unlike state-of-the-art MR methods, produced well-calibrated false positive rates and reliable gcp estimates in the presence of genetic correlations and asymmetric genetic architectures; we also determined that LCV is well-powered to detect a causal effect.

We applied LCV to GWAS summary statistics for 52 traits (average N=331k), identifying partially or fully genetically causal effects (1% FDR) for 59 pairs of traits, including 30 pairs of traits with high gcp estimates (gcp>0.6).

Results consistent with the published literature included causal effects on myocardial infarction (MI) for LDL, triglycerides and BMI. Novel findings included an effect of LDL on bone mineral density, consistent with clinical trials of statins in osteoporosis.

These results demonstrate that it is possible to distinguish between correlation and causation using genetic data.

Connor LJ, Price AL. Distinguishing genetic correlation from causation across 52 diseases and complex traits. bioRxiv 2018. Distinguishing genetic correlation from causation across 52 diseases and complex traits

 

[Michael Scally MD]

JR, Ruilope LM, de la Sierra A, et al. Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality. New England Journal of Medicine 2018;378:1509-20. NEJM - Error

BACKGROUND - Evidence for the influence of ambulatory blood pressure on prognosis derives mainly from population-based studies and a few relatively small clinical investigations. This study examined the associations of blood pressure measured in the clinic (clinic blood pressure) and 24-hour ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of patients in primary care.

METHODS - We analyzed data from a registry-based, multicenter, national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. Clinic and 24-hour ambulatory blood-pressure data were examined in the following categories: sustained hypertension (elevated clinic and elevated 24-hour ambulatory blood pressure), “white-coat” hypertension (elevated clinic and normal 24-hour ambulatory blood pressure), masked hypertension (normal clinic and elevated 24-hour ambulatory blood pressure), and normotension (normal clinic and normal 24-hour ambulatory blood pressure). Analyses were conducted with Cox regression models, adjusted for clinic and 24-hour ambulatory blood pressures and for confounders.

RESULTS - During a median follow-up of 4.7 years, 3808 patients died from any cause, and 1295 of these patients died from cardiovascular causes. In a model that included both 24-hour and clinic measurements, 24-hour systolic pressure was more strongly associated with all-cause mortality (hazard ratio, 1.58 per 1-SD increase in pressure; 95% confidence interval [CI], 1.56 to 1.60, after adjustment for clinic blood pressure) than the clinic systolic pressure (hazard ratio, 1.02; 95% CI, 1.00 to 1.04, after adjustment for 24-hour blood pressure).

Corresponding hazard ratios per 1-SD increase in pressure were 1.55 (95% CI, 1.53 to 1.57, after adjustment for clinic and daytime blood pressures) for nighttime ambulatory systolic pressure and 1.54 (95% CI, 1.52 to 1.56, after adjustment for clinic and nighttime blood pressures) for daytime ambulatory systolic pressure.

These relationships were consistent across subgroups of age, sex, and status with respect to obesity, diabetes, cardiovascular disease, and antihypertensive treatment. Masked hypertension was more strongly associated with all-cause mortality (hazard ratio, 2.83; 95% CI, 2.12 to 3.79) than sustained hypertension (hazard ratio, 1.80; 95% CI, 1.41 to 2.31) or white-coat hypertension (hazard ratio, 1.79; 95% CI, 1.38 to 2.32). Results for cardiovascular mortality were similar to those for all-cause mortality.

CONCLUSIONS - Ambulatory blood-pressure measurements were a stronger predictor of all-cause and cardiovascular mortality than clinic blood-pressure measurements. White-coat hypertension was not benign, and masked hypertension was associated with a greater risk of death than sustained hypertension.

 

[Michael Scally MD]

Serum Androgens and Risk of Atrial Fibrillation

BACKGROUND: Decline in serum androgens is common among older men and has been associated with cardiovascular disease, although its role in risk of atrial fibrillation (AF) has not been well defined. HYPOTHESIS: Low serum androgens are associated with an increased risk of AF.

METHODS: We examined the prospective associations between testosterone, its more active metabolite dihydrotestosterone (DHT), and sex-hormone binding globulin (SHBG) with risk of AF among 1019 otherwise healthy men of average age 76.3+/-4.9 years in the Cardiovascular Health Study.

RESULTS: After median follow-up of 9.5 years, 304 (30%) men developed AF. We detected a nonlinear association with risk of incident AF in both free and total DHT, in which subjects with the lowest levels had a higher risk of incident AF.

After adjustment for demographics, clinical risk factors, left atrial diameter, and serum NT-proBNP levels, men with free DHT less than 0.16 ng/dL were at increased risk compared with men with higher levels (HR 1.48, CI 1.01-2.17, p<0.05).

Sensitivity analyses confirmed that the increased risk was not cutpoint-specific, with a significant association noted up to cutpoints less than ~0.2 ng/dL. We also detected a complex nonlinear association between SHBG and incident AF, in which subjects in the middle quintile (52.9 - 65.3 nmol/L) had increased risk.

CONCLUSION: Among older men, low free DHT is associated with an increased risk of incident atrial fibrillation. Further studies are needed to explore mechanisms for this association.

Rosenberg MA, Shores MM, Matsumoto AM, et al. Serum Androgens and Risk of Atrial Fibrillation in Older Men: The Cardiovascular Health Study. Clinical cardiology 2018. https://onlinelibrary.wiley.com/doi/abs/10.1002/clc.22965

 

[Michael Scally MD]

Endogenous Testosterone Does Not Improve Prediction Of Incident Cardiovascular Disease

INTRODUCTION: To explore the predictive value of testosterone added to the Framingham Risk Score (FRS) for cardiovascular disease (CVD).

METHODS: Among 816 men, 30-70 years/old, without prevalent CVD, from a community-based cohort (Tehran Lipid and Glucose Study), we assessed the predictive value of testosterone with incident CVD, using three multivariate Cox proportional-hazards models. Model I: FRS variables; model II: Model I plus total testosterone; model III: Model II plus Systolic blood pressure (SBP) * total testosterone (the best fit interaction-term between testosterone and FRS variables). Discriminations and goodness-of-fit were assessed by the C-statistic and the approach of Gronnesby, respectively. p Value <.05 was significant.

RESULTS: During 12 years of follow-up, 121 CVD events occurred. In all models, age, treated SBP, smoking, and diabetes were associated with increased CVD (p values <.05). Neither testosterone (models II and III), nor SBP * testosterone (model III) were associated with CVD (p values >.05). The C-statistics for models I, II, and III were 0.819, 0.820, and 0.821, respectively, indicating no significant improvement in the discrimination power. The models' goodness-of-fit did not improve compared with the FRS.

CONCLUSION: Testosterone could not add to the predictive value of FRS for CVD in men, either directly, or through interactions with FRS variables.

Hatami H, Parizadeh D, Bidhendi Yarandi R, Tohidi M, Ramezani Tehrani F. Endogenous testosterone does not improve prediction of incident cardiovascular disease in a community-based cohort of adult men: results from the Tehran Lipid and Glucose Study. The aging male: the official journal of the International Society for the Study of the Aging Male 2018:1-8. https://www.tandfonline.com/doi/abs/10.1080/13685538.2018.1466876?journalCode=itam20

 

[Michael Scally MD]

 

[Michael Scally MD]

Sadaie MR, Farhoudi M, Zamanlu M, et al. What does the research say about androgen use and cerebrovascular events? Therapeutic Advances in Drug Safety 2018:2042098618773318. SAGE Journals: Your gateway to world-class journal research

Many studies have investigated the benefits of androgen therapy and neurosteroids in aging men, while concerns remain about the potential associations of exogenous steroids and incidents of cerebrovascular events and ischemic stroke (IS). Testosterone is neuroprotective, neurotrophic and a potent stimulator of neuroplasticity. These benefits are mediated primarily through conversion of a small amount of testosterone to estradiol by the catalytic activity of estrogen synthetase (aromatase cytochrome P450 enzyme).

New studies suggest that abnormal serum levels of the nonaromatized potent metabolite of testosterone, either high or low dihydrotestosterone (DHT), is a risk factor for stroke. Associations between pharmacologic androgen use and the incidence of IS are questionable, because a significant portion of testosterone is converted to DHT. There is also insufficient evidence to reject a causal relationship between the pro-testosterone adrenal androgens and incidence of IS. Moreover, vascular intima-media thickness, which is a predictor of stroke and myocardial symptoms, has correlations with sex hormones.

Current diagnostic and treatment criteria for androgen therapy for cerebrovascular complications are unclear. Confounding variables, including genetic and metabolic alterations of the key enzymes of steroidogenesis, ought to be considered. Information extracted from pharmacogenetic testing may aid in expounding the protective–destructive properties of neurosteroids, as well as the prognosis of androgen therapy, in particular their cerebrovascular outcomes.

This investigative review article addresses relevant findings of the clinical and experimental investigations of androgen therapy, emphasizes the significance of genetic testing of androgen responsiveness towards individualized therapy in post-IS injuries as well as identifying pertinent questions.

 

[Michael Scally MD]

Increased Long QT and Torsade De Pointes Reporting on Tamoxifen Compared with Aromatase Inhibitors

OBJECTIVE: A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status.

METHODS: We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR chi(2)) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole).

When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed.

RESULTS: SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p<0.001). SERMs were also associated with higher proportion of TdP and ventricular arrhythmia reports versus AIs (6/8318 vs 2/14851, ROR: 5.4 (1.29-26.15), p:0.02; 16/8318 vs 12/14851, ROR: 2.38 (1.15-4.94), p:0.02, respectively). Mortality was 38% in patients presenting ventricular arrhythmias associated with SERMs.

CONCLUSIONS: SERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs.

Grouthier V, Lebrun-Vignes B, Glazer AM, et al. Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors. Heart (British Cardiac Society) 2018. http://heart.bmj.com/content/early/2018/05/02/heartjnl-2017-312934

 

[Michael Scally MD]

Just how much should statin prescribing be driven by LDL-C @JAMA rather than total CV risk?

LDL-C lowering meta-analyzed

Twenty years of embroilment in the (quite unnecessary) statin wars has left me with a number of basic convictions, three of which are:

– LDL-C is a risk factor, but you should use LDL-C lowering drugs according to total cardiovascular risk, not LDL-C alone

– statins are for practical purposes the only LDL-C lowering drugs worth using

– it is pointless remeasuring LDL-C once it has been lowered by a statin.

Here’s a meta-analysis which questions the usefulness of statins in people with low baseline levels of LDL-C, defined as below 100mg/dl in the curious units used by Americans, or 2.4 mmol/L in the rest of the world. It is a marvellously thorough and well-illustrated analysis of 32 RCTs, which can’t be summarised in a few words, though it is worth quoting this sentence:” This analysis further supports individualizing estimates of the potential for a cardiovascular risk reduction benefit from LDL-C–lowering therapy based on consideration of not only a patient’s absolute risk and current LDL-C level, but also an individualized estimate of the risk reduction based on current LDL-C level and the outcomes desired.” Maybe.


Navarese EP, Robinson JG, Kowalewski M, et al. Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering - A Systematic Review and Meta-analysis. JAMA. 2018;319(15):1566–1579. https://jamanetwork.com/journals/jama/article-abstract/2678614

Key Points

Question Does the magnitude of reductions in total and cardiovascular mortality after low-density lipoprotein cholesterol (LDL-C) lowering depend on the baseline LDL-C level?

Findings In this meta-analysis of 34 randomized clinical trials that included 270 288 participants, more intensive LDL-C–lowering therapy was associated with a progressive reduction in total mortality with higher baseline LDL-C levels (rate ratio, 0.91 for each 40-mg/dL increase in baseline level); however, this relationship was not present with baseline LDL-C levels less than 100 mg/dL. There was a similar relationship for cardiovascular mortality.

Meaning The greatest benefit from LDL-C–lowering therapy may occur for patients with baseline LDL-C levels of 100 mg/dL or greater.

Abstract

Importance Effects on specific fatal and nonfatal end points appear to vary for low-density lipoprotein cholesterol (LDL-C)–lowering drug trials.

Objective To evaluate whether baseline LDL-C level is associated with total and cardiovascular mortality risk reductions.

Data Sourcesand Study Selection Electronic databases (Cochrane, MEDLINE, EMBASE, TCTMD, ClinicalTrials.gov, major congress proceedings) were searched through February 2, 2018, to identify randomized clinical trials of statins, ezetimibe, and PCSK9-inhibiting monoclonal antibodies.

Data Extraction and Synthesis Two investigators abstracted data and appraised risks of bias. Intervention groups were categorized as “more intensive” (more potent pharmacologic intervention) or “less intensive” (less potent, placebo, or control group).

Main Outcomes and Measures The coprimary end points were total mortality and cardiovascular mortality. Random-effects meta-regression and meta-analyses evaluated associations between baseline LDL-C level and reductions in mortality end points and secondary end points including major adverse cardiac events (MACE).

Results In 34 trials, 136 299 patients received more intensive and 133 989 received less intensive LDL-C lowering. All-cause mortality was lower for more vs less intensive therapy (7.08% vs 7.70%; rate ratio [RR], 0.92 [95% CI, 0.88 to 0.96]), but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with greater reductions in all-cause mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.91 [95% CI, 0.86 to 0.96]; P = .001; absolute risk difference [ARD], −1.05 incident cases per 1000 person-years [95% CI, −1.59 to −0.51]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Cardiovascular mortality was lower for more vs less intensive therapy (3.48% vs 4.07%; RR, 0.84 [95% CI, 0.79 to 0.89]) but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with a greater reduction in cardiovascular mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.86 [95% CI, 0.80 to 0.94]; P < .001; ARD, −1.0 incident cases per 1000 person-years [95% CI, −1.51 to −0.45]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Trials with baseline LDL-C levels of 160 mg/dL or greater had the greatest reduction in all-cause mortality (RR, 0.72 [95% CI, 0.62 to 0.84]; P < .001; 4.3 fewer deaths per 1000 person-years) in a meta-analysis. More intensive LDL-C lowering was also associated with progressively greater risk reductions with higher baseline LDL-C level for myocardial infarction, revascularization, and MACE.

Conclusions and Relevance In these meta-analyses and meta-regressions, more intensive compared with less intensive LDL-C lowering was associated with a greater reduction in risk of total and cardiovascular mortality in trials of patients with higher baseline LDL-C levels. This association was not present when baseline LDL-C level was less than 100 mg/dL, suggesting that the greatest benefit from LDL-C–lowering therapy may occur for patients with higher baseline LDL-C levels.

Navar AM, Peterson ED. Challenges in Interpreting the Lipid-Lowering Trials - Biology vs Ecology. JAMA. 2018;319(15):1549–1551. https://jamanetwork.com/journals/jama/article-abstract/2678596?redirect=true

 

[Michael Scally MD]

Cardiovascular Inflammation Trial ended very early and not for safety concerns. Could this be a home run for patients? Inexpensive med to reduce inflammation? Primary endpoint is major cardiovascular events. Can’t wait to hear.


NIH Halts Large Cardiovascular Inflammation Reduction (CIRT) Trial
NIH Halts Large Cardiovascular Inflammation Reduction (CIRT) Trial

The NHLBI has put an early stop to the large Cardiovascular Inflammation Reduction (CIRT) Trial. The NHLBI action was based on a recommendation from the trial’s Data and Safety Monitoring Board. The action was not based on any substantive safety concerns.

“Sometime in late March or early April the NHLBI informed me that there were no substantive safety concerns but that the trial had accrued enough data to answer the main question of the study,” said Paul Ridker (Brigham & Women’s Hospital), the trial’s Principal Investigator.

CIRT was designed to test the inflammatory hypothesis by randomizing 7,000 patients with prior MI and either type 2 diabetes or metabolic syndrome to low dose methotrexate or placebo for 3-5 years. Low dose methotrexate is used to treat rheumatoid arthritis and is known to have antiatherothrombotic effects.

The primary endpoint of CIRT was the composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Interest in the inflammatory hypothesis was heightened last year with the publication of the CANTOS trial, also headed by Paul Ridker, which demonstrated the beneficial effects of a different anti-inflammatory agent, canakinumab.

Ridker said the trial was stopped after 4,786 patients of the planned 7,000 patients had been enrolled. He said the investigators are now working to close out the study as fast as possible. “If all goes well we will present the results at the AHA in November,” he said.

Ridker emphasized that patients who take low dose methotrexate for arthritis have no reason to be concerned.


[OA] Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. New England Journal of Medicine 2017;377:1119-31. NEJM - Error

CONCLUSIONS - Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering.

 

[Michael Scally MD]

[OA] Genetic Predictors of Testosterone and Their Associations with Cardiovascular Disease and Risk Factors

Highlights
· Genetic predictors of testosterone were associated with cardiovascular risk factors, such as lipids and blood pressure.
· However, associations were not consistent between the two gene regions considered in this analysis.
· There was some evidence that genetic predictors of testosterone were associated with coronary artery disease risk, as well as risk of ischaemic stroke in men.
· This suggests that sex hormone-related mechanisms have a role in cardiovascular disease, although the potential effect of testosterone supplementation on cardiovascular disease remains unclear.

Background - Testosterone supplementation has been linked to increased cardiovascular disease risk in some observational studies. The causal role of testosterone can be investigated using a Mendelian randomization approach.

Methods and results - We assessed genetic associations of variants in two gene regions (SHBG and JMJD1C) with several cardiovascular risk factors (lipids, adiponectin, blood pressure, anthropometric traits) plus male pattern baldness, including control outcomes and potential mediators.

We assessed genetic associations with coronary artery disease (CAD) risk in the CARDIoGRAMplusC4D consortium (171,191 individuals including 60,801 cases), and associations with CAD and ischaemic stroke risk in the UK Biobank (367,643 individuals including 25,352 CAD cases and 8415 ischaemic stroke cases).

Genetic predictors of increased serum testosterone were associated with lipids, blood pressure, and height. There was some evidence of an association with risk of CAD (SHBG gene region: odds ratio (OR) 0.95 per 1 unit increase in log-transformed testosterone [95% confidence interval: 0.81–1.12, p = 0.55]; JMJD1C gene region: OR 1.24 [1.01–1.51, p = 0.04]) and ischaemic stroke in men (SHBG: OR 1.67 [0.90, 3.11, p = 0.10]; JMJD1C: OR 3.18 [1.43, 7.05, p = 0.003]). However, associations with some control outcomes were in the opposite direction to that expected.

Conclusions - Sex hormone-related mechanisms appear to be relevant to cardiovascular risk factors and for stroke (particularly for men). However, the extent that these findings are specifically informative about endogenous testosterone or testosterone supplementation is unclear.

These findings underline a fundamental limitation for the use of Mendelian randomization where biological knowledge about the function of genetic variants is uncertain.

Schooling CM, Luo S, Yeung SLA, et al. Genetic predictors of testosterone and their associations with cardiovascular disease and risk factors: A Mendelian randomization investigation. International journal of cardiology. http://dx.doi.org/10.1016/j.ijcard.2018.05.051

 

[Michael Scally MD]

[OA] Would male hormonal contraceptives affect cardiovascular risk?

The aim of hormonal male contraception is to prevent unintended pregnancies by suppressing spermatogenesis. Hormonal male contraception is based on the principle that exogenous administration of androgens and other hormones such as progestins suppress circulating gonadotropin concentrations, decreasing testicular Leydig cell and Sertoli cell activity and spermatogenesis. In order to achieve more complete suppression of circulating gonadotropins and spermatogenesis, a progestin has been added testosterone to the most recent efficacy trials of hormonal male contraceptives.

This review focusses on the potential effects of male hormonal contraceptives on cardiovascular risk factors, lipids and body composition, mainly in the target group of younger to middle-aged men. Present data suggest that hormonal male contraception can be reasonably regarded as safe in terms of cardiovascular risk.

However, as all trials have been relatively short (< 3 years), a final statement regarding the cardiovascular safety of hormonal male contraception, especially in long-term use, cannot be made. Older men with at high risk of cardiovascular event might not be good candidates for hormonal male contraception.

The potential adverse effects of hormonal contraceptives on cardiovascular risk appear to depend greatly on the choice of the progestin in regimens for hormonal male contraceptives. In the development of prospective hormonal male contraception, data on longer-term cardiovascular safety will be essential.

Zitzmann M. Would male hormonal contraceptives affect cardiovascular risk? Asian Journal of Andrology. 2018;20(2):145-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858097/

 

[Michael Scally MD]

Testosterone and Cardiovascular Risk: Meta-Analysis of Interventional Studies

Background - The relationship between testosterone (T) and cardiovascular (CV) risk in men is conflicting.

Aim - To verify whether T therapy (TTh) represents a possible risk factor for CV morbidity and mortality.

Methods - We conducted a random effect meta-analysis considering all available data from pharmaco-epidemiological studies as well as randomized placebo-controlled trials (RCTs).

Outcomes - CV mortality and morbidity were investigated.

Results - After screening, 15 pharmaco-epidemiological and 93 RCT studies were considered. The analysis of pharmaco-epidemiological studies documented that TTh reduces overall mortality and CV morbidity.

Conversely, in RCTs, TTh had no clear effect, either beneficial or detrimental, on the incidence of CV events. However, a protective role of TTh on CV morbidity was observed when studies enrolling obese (body mass index >30 kg/m2) patients were scrutinized (Mantel-Haenszel odds ratio 0.51 [95% CI 0.27–0.96]; P = .04), although this association disappeared when only high-quality RCTs were considered (Mantel-Haenszel odds ratio 0.64 [95% CI 0.22–1.88]; P = .42).

Finally, an increased risk of CV diseases was observed in RCTs when T preparations were prescribed at dosages above those normally recommended, or when frail men were considered.

Clinical Implications - Pharmaco-epidemiological studies showed that TTh might reduce CV risk, but this effect was not confirmed when RCTs were considered.

Strengths & Limitations - Meta-analysis of pharmaco-epidemiological studies indicates that TTh reduces overall mortality and CV morbidity. In addition, even in RCTs, a protective role of TTh on CV morbidity was envisaged when studies enrolling obese (body mass index >30 kg/m2) patients were considered.

Pharmaco-epidemiological studies should be considered with caution due to the lack of completeness of follow-up and of the management of missing data. In addition, properly powered placebo-controlled RCTs with a primary CV end point, in men with late-onset hypo-gonadism, are not yet available.

Finally, the duration of all studies evaluated in the present meta-analysis is relatively short, reaching a maximum of 3 years.

Conclusions - Data from RCTs suggest that treatment with T is not effective in reducing CV risk, however, when TTh is correctly applied, it is not associated with an increase in CV risk and it may have a beneficial effect in some sub-populations.

Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Testosterone and Cardiovascular Risk: Meta-Analysis of Interventional Studies. The Journal of Sexual Medicine 2018;15:820-38. Redirecting

 

[Michael Scally MD]

Left Atrial Myocardial Dysfunction After Chronic Abuse of Anabolic Androgenic Steroids: A Speckle Tracking Echocardiography Analysis

Anabolic-androgenic steroids (AAS) are used by power athletes to improve performance. However, the real effects of the chronic consumption of AAS on cardiovascular structures are subjects of intense debate. To detect by speckle tracking echocardiography (STE) underlying left atrial (LA) dysfunction in athletes abusing AAS and assess possible correlation between LA myocardial function and exercise capacity during cardiopulmonary stress test.

65 top-level competitive bodybuilders were selected (45 males), including 35 athletes misusing AAS for at least 5 years (users), 30 anabolic-free bodybuilders (non-users), compared to 40 age- and sex-matched healthy sedentary controls. Standard Doppler echocardiography, STE analysis and bicycle ergometric test were performed to assess LA myocardial function and exercise capacity.

Athletes showed increased left ventricular (LV) mass index, wall thickness and stroke volume compared with controls, whereas LV ejection fraction, LV end-diastolic diameter and transmitral Doppler indexes were comparable between the three groups. Conversely, LA volume index, LV and LA strain and LV E/Em were significantly increased in AAS users.

By multivariate analyses, LV E/Em (beta = - 0.30, p < 0.01), LA volume index (- 0.42, p < 0.001) and number of weeks of AAS use per year (- 0.54, p < 0.001) emerged as the only independent determinants of LA lateral wall peak STE.

In addition, a close association between LA myocardial function and VO2 peak during cardiopulmonary exercise testing was evidenced (p < 0.001), showing a powerful incremental value with respect to clinical and standard echocardiographic data.

STE represents a promising technique to assess LA myocardial function in athletes abusing steroids. AAS users showed a more impaired LA deformation, associated with reduced functional capacity during physical effort.

D'Andrea A, Radmilovic J, Caselli S, et al. Left atrial myocardial dysfunction after chronic abuse of anabolic androgenic steroids: a speckle tracking echocardiography analysis. The international journal of cardiovascular imaging 2018. Left atrial myocardial dysfunction after chronic abuse of anabolic androgenic steroids: a speckle tracking echocardiography analysis

 

[Michael Scally MD]

[OA] Santos MRD, Sayegh ALC, Armani R, et al. Resting spontaneous baroreflex sensitivity and cardiac autonomic control in anabolic androgenic steroid users. Clinics (Sao Paulo, Brazil) 2018;73:e226. Resting spontaneous baroreflex sensitivity and cardiac autonomic control in anabolic androgenic steroid users

OBJECTIVES: Misuse of anabolic androgenic steroids in athletes is a strategy used to enhance strength and skeletal muscle hypertrophy. However, its abuse leads to an imbalance in muscle sympathetic nerve activity, increased vascular resistance, and increased blood pressure.

However, the mechanisms underlying these alterations are still unknown. Therefore, we tested whether anabolic androgenic steroids could impair resting baroreflex sensitivity and cardiac sympathovagal control. In addition, we evaluate pulse wave velocity to ascertain the arterial stiffness of large vessels.

METHODS: Fourteen male anabolic androgenic steroid users and 12 nonusers were studied. Heart rate, blood pressure, and respiratory rate were recorded. Baroreflex sensitivity was estimated by the sequence method, and cardiac autonomic control by analysis of the R-R interval. Pulse wave velocity was measured using a noninvasive automatic device.

RESULTS: Mean spontaneous baroreflex sensitivity, baroreflex sensitivity to activation of the baroreceptors, and baroreflex sensitivity to deactivation of the baroreceptors were significantly lower in users than in nonusers. In the spectral analysis of heart rate variability, high frequency activity was lower, while low frequency activity was higher in users than in nonusers.

Moreover, the sympathovagal balance was higher in users. Users showed higher pulse wave velocity than nonusers showing arterial stiffness of large vessels. Single linear regression analysis showed significant correlations between mean blood pressure and baroreflex sensitivity and pulse wave velocity.

CONCLUSIONS: Our results provide evidence for lower baroreflex sensitivity and sympathovagal imbalance in anabolic androgenic steroid users. Moreover, anabolic androgenic steroid users showed arterial stiffness. Together, these alterations might be the mechanisms triggering the increased blood pressure in this population.