Rishi Sharma

Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men

AIMS There is a significant uncertainty regarding the effect of testosterone replacement therapy (TRT) on cardiovascular (CV) outcomes including myocardial infarction (MI) and stroke. The aim of this study was to examine the relationship between normalization of total testosterone (TT) after TRT and CV events as well as all-cause mortality in patients without previous history of MI and stroke. METHODS AND RESULTS We retrospectively examined 83 010 male veterans with documented low TT levels. The subjects were categorized into (Gp1: TRT with resulting normalization of TT levels), (Gp2: TRT without normalization of TT levels) and (Gp3: Did not receive TRT). By utilizing propensity score-weighted Cox proportional hazard models, the association of TRT with all-cause mortality, MI, stroke, and a composite endpoint was compared between these groups. The all-cause mortality [hazard ratio (HR): 0.44, confidence interval (CI) 0.42-0.46], risk of MI (HR: 0.76, CI 0.63-0.93), and stroke (HR: 0.64, CI 0.43-0.96) were significantly lower in Gp1 (n = 43 931, median age = 66 years, mean follow-up = 6.2 years) vs. Gp3 (n = 13 378, median age = 66 years, mean follow-up = 4.7 years) in propensity-matched cohort. Similarly, the all-cause mortality (HR: 0.53, CI 0.50-0.55), risk of MI (HR: 0.82, CI 0.71-0.95), and stroke (HR: 0.70, CI 0.51-0.96) were significantly lower in Gp1 vs. Gp2 (n = 25 701, median age = 66 years, mean follow-up = 4.6 years). There was no difference in MI or stroke risk between Gp2 and Gp3. CONCLUSION In this large observational cohort with extended follow-up, normalization of TT levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.

Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation

Background Atrial fibrillation (AF) is the most common cardiac dysrhythmia associated with significant morbidity and mortality. Several small studies have reported that low serum total testosterone (TT) levels were associated with a higher incidence of AF. In contrast, it is also reported that anabolic steroid use is associated with an increase in the risk of AF. To date, no study has explored the effect of testosterone normalization on new incidence of AF after testosterone replacement therapy (TRT) in patients with low testosterone. Methods and Results Using data from the Veterans Administrations Corporate Data Warehouse, we identified a national cohort of 76 639 veterans with low TT levels and divided them into 3 groups. Group 1 had TRT resulting in normalization of TT levels (normalized TRT), group 2 had TRT without normalization of TT levels (nonnormalized TRT), and group 3 did not receive TRT (no TRT). Propensity score–weighted stabilized inverse probability of treatment weighting Cox proportional hazard methods were used for analysis of the data from these groups to determine the association between post‐TRT levels of TT and the incidence of AF. Group 1 (40 856 patients, median age 66 years) had significantly lower risk of AF than group 2 (23 939 patients, median age 65 years; hazard ratio 0.90, 95% CI 0.81–0.99, P=0.0255) and group 3 (11 853 patients, median age 67 years; hazard ratio 0.79, 95% CI 0.70–0.89, P=0.0001). There was no statistical difference between groups 2 and 3 (hazard ratio 0.89, 95% CI 0.78– 1.0009, P=0.0675) in incidence of AF. Conclusions These novel results suggest that normalization of TT levels after TRT is associated with a significant decrease in the incidence of AF.

Ethanol at low concentrations protects glomerular podocytes through alcohol dehydrogenase and 20-HETE

Clinical studies suggest cardiovascular and renal benefits of ingesting small amounts of ethanol. Effects of ethanol, role of alcohol dehydrogenase (ADH) or of 20-hydroxyeicosatetraenoic acid (20-HETE) in podocytes of the glomerular filtration barrier have not been reported. We found that mouse podocytes at baseline generate 20-HETE and express ADH but not CYP2e1. Ethanol at high concentrations altered the actin cytoskeleton, induced CYP2e1, increased superoxide production and inhibited ADH gene expression. Ethanol at low concentrations upregulated the expression of ADH and CYP4a12a. 20-HETE, an arachidonic acid metabolite generated by CYP4a12a, blocked the ethanol-induced cytoskeletal derangement and superoxide generation. Ethanol at high concentration or ADH inhibitor increased glomerular albumin permeability in vitro. 20-HETE and its metabolite produced by ADH activity, 20-carboxy-arachidonic acid, protected the glomerular permeability barrier against an ADH inhibitor, puromycin or FSGS permeability factor. We conclude that ADH activity is required for glomerular function, 20-HETE is a physiological substrate of ADH in podocytes and that podocytes are useful biosensors to understand glomeruloprotective effects of ethanol.

Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Not Associated With Reduced Myocardial Infarction in Smokers

Objective To examine the effect of cigarette smoking (CS) status and total testosterone (TT) levels after testosterone replacement therapy (TRT) on all-cause mortality, myocardial infarction (MI), and stroke in male smokers and nonsmokers without history of MI and stroke. Participants and Methods Data from 18,055 males with known CS status and low TT levels who received TRT at the Veterans Health Administration between December 1, 1999, and May 31, 2014, were grouped into (1) current smokers with normalized TT, (2) current smokers with nonnormalized TT, (3) nonsmokers with normalized TT, and (4) nonsmokers with nonnormalized TT. Combined effect of CS status and TT level normalization after TRT on all-cause mortality, MI, and stroke was compared using propensity score–weighted Cox proportional hazard models. Results Normalization of serum TT levels in nonsmokers was associated with a significant decrease in all-cause mortality (hazard ratio [HR]=0.526; 95% CI, 0.477-0.581; P<.001) and MI (HR=0.717; 95% CI, 0.522-0.986; P<.001). Among current smokers, normalization of serum TT levels was associated with a significant decrease in only all-cause mortality (HR=0.563; 95% CI, 0.488-0.649; P<.001) without benefit in MI (HR=1.096; 95% CI, 0.698-1.720; P=.69). Importantly, compared with nonsmokers with normalized TT, all-cause mortality (HR=1.242; 95% CI, 1.104-1.396; P<.001), MI (HR=1.706; 95% CI, 1.242-2.342; P=.001), and stroke (HR=1.590; 95% CI, 1.013-2.495; P=.04) were significantly higher in current smokers with normalized TT. Conclusion We conclude that active CS may negate the protective effect of testosterone level normalization on all-cause mortality and MI after TRT.

Treatment of Angio-Seal® Vascular Closure Device-Induced Acute Femoral Artery Occlusion with SilverHawk® Directional Atherectomy

Vascular closure devices provide a safe and cost-effective method to achieve rapid hemostasis and early ambulation after angiographic procedures. Rarely, they can result in arterial injury with resultant stenosis or acute arterial closure requiring open surgical intervention. We report an Angio-Seal® vascular closure device-induced acute arterial closure successfully treated percutaneously with the SilverHawk® plaque excision system. This report discusses the possible mechanisms of Angio-Seal® induced arterial occlusion and various percutaneous options for treatment.

EFFECT OF TESTOSTERONE REPLACEMENT THERAPY ON INCIDENCE OF DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM

Testosterone Replacement Therapy (TRT) prescriptions have increased 400% in the last decade. Concern over the risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) with TRT has led the FDA to issue an alert. The association of TRT with DVT/PE is not clearly understood. The aim of this