Impact of incomplete revascularization in patients undergoing PCI for unprotected left main stem stenosis.

INTRODUCTION: Percutaneous revascularization of patients with multivessel and left main stem (LMS) disease may be incomplete and the impact of this is not well reported and may influence outcome. In this study we assessed the role of completeness of revascularization upon outcome after PCI for unprotected left main stem (uLMS) PCI in the "real world." MATERIALS AND METHOD: Consecutive patients (n = 353) with uLMS disease were treated by PCI by a single operator with a policy of maximal feasible revascularization between 2000 and 2011. The SYNTAX score was calculated before and after PCI (residual SYNTAX score) to gauge the completeness of revascularization. The endpoints were mortality and repeat revascularization. RESULTS: Mean age was 69 ± 11 years, baseline SYNTAX score was 33.4 ± 15, 53% were nonelective, 10% were in cardiogenic shock, and 45% were not surgical candidates. LMS bifurcation was involved in 74% and 2.0 ± 0.9 other vessels were diseased. Complete revascularization was achieved in 49% and was associated with reduced mortality compared with incomplete, at 30 days [5(2.9%) v 23(13%)], 1 year [9(5%) v 34(19%)], and 3 years [14(8%) v 46(26%)]; all P < 0.0001). Median rSYNTAX score was 1(0-11), 1-year survival for the lowest, middle and highest tertiles of rSYNTAX were 1.7%, 3.1% and 7.3% (P < 0.0001), respectively. In multivariate analysis postprocedure rSYNTAX score independently predicted outcome but preprocedural SYNTAX score did not. CONCLUSIONS: For unselected patients with uLMS treated by PCI, completeness of revascularization is associated with superior survival. The rSYNTAX score, a novel index of completeness of revascularization, independently predicts survival. Baseline SYNTAX score does not.

Low serum testosterone and increased mortality in men with coronary heart disease.

BACKGROUND: To examine the effect of serum testosterone levels on survival in a consecutive series of men with confirmed coronary disease and calculate the prevalence of testosterone deficiency. DESIGN: Longitudinal follow-up study. SETTING: Tertiary referral cardiothoracic centre. Patients 930 consecutive men with coronary disease referred for diagnostic angiography recruited between June 2000 and June 2002 and followed up for a mean of 6.9±2.1 years. OUTCOME: All-cause mortality and vascular mortality. Prevalence of testosterone deficiency. RESULTS: The overall prevalence of biochemical testosterone deficiency in the coronary disease cohort using bio-available testosterone (bio-T) <2.6 nmol/l was 20.9%, using total testosterone <8.1 nmol/l was 16.9% and using either was 24%. Excess mortality was noted in the androgen-deficient group compared with normal (41 (21%) vs 88 (12%), p=0.002). The only parameters found to influence time to all-cause and vascular mortality (HR ± 95% CI) in multivariate analyses were the presence of left ventricular dysfunction (3.85; 1.72 to 8.33), aspirin therapy (0.63; 0.38 to 1.0), ß-blocker therapy (0.45; 0.31 to 0.67) and low serum bio-T (2.27; 1.45 to 3.6). CONCLUSIONS: In patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival. Prospective trials of testosterone replacement are needed to assess the effect of treatment on survival.

Testosterone and heart failure.

PURPOSE OF REVIEW: Chronic heart failure (CHF) is a common condition with significant morbidity despite optimal medical therapy. Standard therapy involves inhibiting the maladaptive changes of metabolism and neuro-hormones that characterize the syndrome of CHF. Anabolic deficiency is a major component of the CHF syndrome and testosterone replacement therapy has been subject to recent trials. RECENT FINDINGS: The recent literature shows that physiological testosterone replacement therapy leads to modest improvements in voluntary muscle strength, lean muscle mass, endurance and positive effects on neuro-muscular and baro-receptor reflexes. Long-term efficacy and safety remain unstudied at present. SUMMARY: Testosterone replacement therapy appears to improve metabolism and endurance in patients with CHF; further trials will be necessary before widespread use. Physicians who regularly treat patients with CHF may consider testosterone therapy but it is likely that they will require the advice and support from endocrine specialists.

Neuroendocrine effects on the heart and targets for therapeutic manipulation in heart failure.

Chronic heart failure (CHF) involves derangements in multiple neurohormonal axes leading to a procatabolic state and wasting syndrome associated with significant mortality. Catabolic abnormalities include excess catecholamines and glucocorticoids. Anabolic defects include deficiencies of sex steroids, insulin resistance, and growth hormone (GH) resistance. These abnormalities are also correlated with increased morbidity and mortality in CHF. Anabolic axes have been augmented in pilot studies in CHF with testosterone, GH, insulin-like growth factor-1, and GH secretagogues. Results have been varied although some treatments have been associated with improved surrogate endpoints. This review article explores the current understanding of metabolic derangements in CHF and highlights potential neuroendocrine treatment strategies.

The effect of testosterone on insulin sensitivity in men with heart failure.

Resistance to insulin occurs in chronic heart failure (CHF) and is related to prognosis. Studies of testosterone in non-(CHF) males suggest that physiological testosterone therapy improves insulin sensitivity. This was a single-blind placebo controlled crossover trial to determine the effect of testosterone replacement on insulin sensitivity in 13 men with moderate to severe CHF (ejection fraction 30.5+/-1.3). The primary outcome was the homeostatic model index (HOMA-IR) of fasting insulin sensitivity and secondary outcomes were body composition as measured by bioelectrical impedance and glucose tolerance to a standard 75 g oral glucose load. Analysis was performed on the delta values with the treatment effect of placebo compared with that of testosterone. At baseline HOMA-IR correlated with measures of body fat [% fat mass (rP=0.84, p=0.0001) and body mass index (rP=0.79, p=0.01)] but not with CHF severity. Testosterone reduced HOMA-IR (-1.9+/-0.8, p=0.03) indicating improved fasting insulin sensitivity. Testosterone also increased total mass (+1.5+/-0.5 kg, p=0.008) and decreased body fat (-0.8+/-0.3%, p=0.02). Testosterone improves fasting insulin sensitivity in men with CHF and may also increase lean body mass, these data suggest a favourable effect of testosterone on an important metabolic component of CHF.

Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial.

AIMS: Chronic heart failure is associated with maladaptive and prolonged neurohormonal and pro-inflammatory cytokine activation causing a metabolic shift favouring catabolism, vasodilator incapacity, and loss of skeletal muscle bulk and function. In men, androgens are important determinants of anabolic function and physical strength and also possess anti-inflammatory and vasodilatory properties. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled parallel trial of testosterone replacement therapy (5 mg Androderm) at physiological doses in 76 men (mean+/-SD, age 64+/-9.9) with heart failure (ejection fraction 32.5+/-11%) over a maximum follow-up period of 12 months. The primary endpoint was functional capacity as assessed by the incremental shuttle walk test (ISWT). At baseline, 18 (24%) had serum testosterone below the normal range and bioavailable testosterone correlated with distance walked on the initial ISWT (r=0.3, P=0.01). Exercise capacity significantly improved with testosterone therapy compared with placebo over the full study period (mean change +25+/-15 m) corresponding to a 15+/-11% improvement from baseline (P=0.006 ANOVA). Symptoms improved by at least one functional class on testosterone in 13 (35%) vs. 3 (8%) on placebo (P=0.01). No significant changes were found in handgrip strength, skeletal muscle bulk by cross-sectional computed tomography, or in tumour necrosis factor levels. Testosterone therapy was safe with no excess of adverse events although the patch preparation was not well tolerated by the study patients. CONCLUSION: Testosterone replacement therapy improves functional capacity and symptoms in men with moderately severe heart failure.

Physiologic testosterone therapy has no effect on serum levels of tumour necrosis factor-alpha in men with chronic heart failure.

Physiological testosterone therapy increases exercise capacity and reduces symptom scores in men with chronic heart failure (CHF). Tumour necrosis factor-alpha (TNF-alpha) exerts a significant pathologic activity in CHF, and physiologic testosterone replacement therapy is associated with reduced serum levels of TNF-alpha in hypogonadal men with concomitant coronary artery disease. It is unknown whether testosterone exerts a similar immunomodulatory action in men with CHF. Testosterone therapy administered in three placebo-controlled studies, for either 6 hours (two 30-mg buccal tablets, n=12) or 3 months (fortnightly 100 mg intra muscular injection, n=20; or daily 5 mg transdermally, n=62). The effects of testosterone were also assessed on lipopolysaccharide (LPS)-induced TNF- production in whole blood obtained from 27 men with CHF. Incubation with testosterone (10 nM, 1 M, and 100 M) resulted in a reduction in LPS-induced TNF- production from 12.6 +/- 1.3 to 11.2 +/- 1.1 (P = 0.053), 10.3 +/- 1.1 (P = 0.0046), and 9.2 +/- 1.1 (P = 0.000066) ng/ml, respectively. However in men with CHF, serum levels of TNF- were similar before and after treatment with testosterone or placebo, irrespective of the length of study or route of administration. The clinically beneficial actions of testosterone in men with CHF are unlikely to be mediated by reducing TNF-alpha.

A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men.

OBJECTIVE: In the absence of widely available measures of determining free and/or bioavailable testosterone (BioT) physicians may use formulae such as the free androgen index (FAI) to estimate free testosterone. We compared the efficacy of calculated markers of androgen status in predicting serum BioT and hypogonadism. DESIGN: Total testosterone (TT), sex hormone binding globulin (SHBG) and BioT were determined in a large cohort of men. Comparison of calculated androgen levels was performed following endocrine assessment. METHODS: TT and SHBG were determined by ELISA, and BioT was determined by ammonium sulphate precipitation. From these data we calculated FAI and free testosterone using two other published formulae - FTnw (free testosterone as calculated by the method of Nanjeee and Wheeler) and FTv (free testosterone as calculated by the method of Vermeulen). A novel formula was derived to calculate BioT from given levels of TT and SHBG (BTcalculated). The ability of the methods (FAI, FTnw, FTv, BTcalc) to predict BioT were compared using regression analysis. The ability of these markers of androgen status to predict biochemical hypogonadism was compared using area under receiver operator curve (auROC). RESULTS: The equation derived from our data was the best predictor of BioT (R(2)=0.73, P<0.0001) although TT was also a good marker (R(2)=0.68, P=0.0001). In the determination of hypogonadism, of all currently available formulae none were better that the TT (auROC: TT=0.93, FAI=0.72, FTnw=0.91, FTv=0.88) although when TT is borderline (7.5

The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men.

Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha, IL-1beta, and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10. We report a randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 +/- 9 yr) with symptomatic androgen deficiency (total testosterone, 4.4 +/- 1.2 nmol/liter; bioavailable testosterone, 2.4 +/- 1.1 nmol/liter). Compared with placebo, testosterone induced reductions in TNFalpha (-3.1 +/- 8.3 vs. 1.3 +/- 5.2 pg/ml; P = 0.01) and IL-1beta (-0.14 +/- 0.32 vs. 0.18 +/- 0.55 pg/ml; P = 0.08) and an increase in IL-10 (0.33 +/- 1.8 vs. -1.1 +/- 3.0 pg/ml; P = 0.01); the reductions of TNFalpha and IL-1beta were positively correlated (r(S) = 0.588; P = 0.003). In addition, a significant reduction in total cholesterol was recorded with testosterone therapy (-0.25 +/- 0.4 vs. -0.004 +/- 0.4 mmol/liter; P = 0.04). In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.

Effect of testosterone therapy on QT dispersion in men with heart failure.

The effects of testosterone on cardiac electrophysiology are poorly described. In this study we report the effect of physiologic testosterone therapy in 2 cohorts of men, the first with stable coronary disease and the second with congestive heart failure. Testosterone reduced QT dispersion in the heart failure cohort; no other effects were observed.