Does hormone replacement therapy influence retinal microvascular caliber?

Previous population-based data suggest that retinal arteriolar diameter is wider in women than in men. Estrogen exposures could account for this difference. To evaluate the effects of HRT on small blood vessels, we assessed the relationship between use of hormone replacement therapy (HRT) and retinal microvascular diameter in older women in the Blue Mountains Eye Study baseline population (n = 1993, age >/= 49 years). Information on HRT use was recorded by trained interviewers. A computer-assisted program measured retinal vessel diameters from digitized photographs. Average arteriolar diameter was calculated as the central retinal arteriolar equivalent (CRAE); the lowest quintile of CRAE was considered generalized arteriolar narrowing. Of the 1897 women with complete data, 79 (4%) were premenopausal and 315 (17%), 224 (12%), and 1279 (67%) were current, past, and never HRT users, respectively. Among women aged < 65 years, multivariate-adjusted mean CRAE for the four groups was 196, 198, 201, and 200 microm (P < 0.0001), respectively. Among postmenopausal women >/= 65 years, multivariate-adjusted mean CRAE was 187, 188, 191 microm (P < 0.0001), respectively, for current, past, and never users. Current HRT users were 40% more likely than never users to have generalized arteriolar narrowing (95% confidence interval 1.0-2.1). It appears that the use of HRT in older women may not have any long-term vasodilatory effects on retinal arterioles. These data do not support our hypothesis that exogenous estrogen exposures account for observed wider retinal arteriolar diameters in women.     

Does aggressive statin therapy offer improved cholesterol-independent benefits compared to conventional statin treatment?

There is currently intense research interest in the properties of HMG-CoA reductase inhibitors (statins) beyond their well-documented lipid-lowering action. Studies have consistently demonstrated that administration of statin therapy decreases levels of the inflammatory marker C-reactive protein (CRP), a marker associated with an increased risk of cardiovascular events. This effect appears to be independent of the extent of reduction in total or LDL-cholesterol. Statins also appear to improve endothelial dysfunction by increasing endothelium-dependent vasodilatation. There is also evidence that statins inhibit fibrin formation and thrombus development, an effect that which would be clinically beneficial following plaque fissure or rupture. Early preclinical and clinical evidence suggests that there are quantitative differences between statin regimens in terms of their cholesterol-independent properties. Trials comparing equipotent doses of different statins, based on lipid-lowering efficacy, have not reported any differences in cholesterol-independent properties. However, the current evidence base indicates that more aggressive statin regimens are associated with an enhanced anti-inflammatory effect. Intensive lipid-lowering using statin therapy generates a greater reduction in mortality than standard lipid management, and it is possible that enhanced cholesterol-independent effects may account for some of this excess benefit.     

Extrathyroidal thyroid hormone synthesis?

A paper published in this issue of the Journal of Endocrinology has revisited the hypothesis that thyroid hormones may be generated by tissues outside the thyroid gland in higher organisms including mammals. This commentary appraises the strengths and weaknesses of the study, the alternative explanations for the findings and possible future measures to investigate further. The concept of extrathyroidal thyroxine and triiodothyronine synthesis has previously been proposed; by assuming that Nagao et al. and earlier authors are correct, the plausibility and possible mechanisms underlying the hypothesis are discussed.     

How safe is aggressive statin therapy?

The most recent guidelines of the National Cholesterol Education Program recommend more aggressive low-density lipoprotein cholesterol goals: <100 mg/dL for patients at moderate or high risk of cardiovascular disease, and <70 mg/dL for patients at very high risk. These lower goals are more likely to be achieved using the more powerful statins--atorvastatin, rosuvastatin, and simvastatin. Although statins are widely used, extensively studied, and known to have an excellent safety profile, the perception of many health care providers and patients is that safety concerns about the more efficacious statins, especially at high doses, limit their use. However, clinical data consistently support the view that adverse events are uncommon even when intensive therapy is used to reach aggressive low-density lipoprotein cholesterol goals. Overall, the more potent statins have similar safety profiles. The benefits of aggressive statin treatment in reducing the risk of cardiovascular events appear to far outweigh any potential risks of adverse events.     

Can a healthy endothelium influence the cardiovascular effects of hormone replacement therapy?

Emerging clinical and observational evidences suggest that estrogen confers physiologic benefits that are receptor mediated and depend on the integrity and functional status of the endothelium within the coronary vasculature. In postmenopausal women, estrogen replacement therapy (ERT) and hormone replacement therapy (HRT) regimens can enhance the lipoprotein panel; blunt the expression of numerous cytokines, chemokines, and other proinflammatory mediators of endothelial injury and vascular smooth muscle cell proliferation; up-regulate endothelial nitric oxide synthase activity and nitric oxide production; and augment fibrinolysis potential and vasodilator capacity (diminish arterial resistance). Advancing age and atherosclerotic injury to the vessel wall tend to deplete estrogen receptors, compromise endothelial function, promote thrombus formation, and thus potentially diminish the efficacy of ERT and HRT. Therefore, optimizing the clinical benefits of these regimens in postmenopausal women depends largely on promoting a healthy endothelium through life-style modifications that diminish coronary risk.     

Does intensive medical therapy influence the outcome in unstable angina?

Three hundred and forty-six patients of all ages and both sexes were admitted to coronary care with documented unstable angina. Management was conservative, without the routine use of beta-blockers or calcium antagonists. Mortality was 3.2%, and the nonfatal myocardial infarction rate was 10.1% during the first 28 days. After one year, coronary mortality was 10.5% with a nonfatal infarction rate of 13.1%. Twenty-six patients were subjected to coronary artery bypass surgery, eleven during the first 28 days and fifteen subsequently. No patient underwent coronary angioplasty. The factors influencing immediate and long-term prognosis in these patients were studied. Persistence of pain in hospital, previous chronic angina, and age had an adverse effect on outcome. A total of 143 patients complained of persistent pain lasting for 24 hours or more. The use of beta blockers or calcium antagonists in patients with persistent pain exceeding five days did not appear to influence outcome. The current widespread adherence to "intensive medical treatment," including the routine use of beta blockers and calcium antagonists, is questioned.     

Does antioxidant therapy influence every aspect of quality of life?

To present problems that might severely impact the conclusions drawn by the authors of an article on antioxidant treatment in chronic pancreatitis (World J Gastroenterol 2010; 16: 4066-4071). We analyzed and discussed this paper by Shah et al, and found that promising as it is, this study has some methodological shortcomings, such as: cross-sectional nature of the study, lack of initial evaluations of quality of life and regular follow-ups to determine the dynamics and real directions of changes in quality of life. We therefore concluded that the results of the study by Shah et al are biased and, although very promising, should not be considered as scientifically relevant.     

Does preoperative statin therapy improve outcomes in patients undergoing isolated cardiac valve surgery?

Preoperative statins have been associated with decreased mortality after coronary artery bypass grafting. Data are limited on whether these benefits extend to patients undergoing cardiac valve surgery. We examined whether preoperative statins decrease morbidity and mortality in patients undergoing isolated cardiac valve surgery. In a retrospective cohort analysis of consecutive patients who underwent surgical valve repair or replacement (excluding concomitant coronary artery bypass grafting, aortic root replacement, or ventricular assist device placement) at St. Luke's Episcopal Hospital, the primary outcome was 30-day mortality. Secondary outcomes included 30-day major adverse events (composite of early mortality, postoperative myocardial infarction, or stroke). Of 825 patients, 31% received preoperative statins (n = 255). Logistic regression analysis revealed that age >65 years (p = 0.02), history of congestive heart failure (p = 0.001), and total bypass time >80 minutes (p = 0.01) were independent predictors of increased 30-day mortality. Preoperative statin therapy was not associated with decreased 30-day mortality (odds ratio 0.89, 95% confidence interval 0.38 to 2.03), major adverse events (odds ratio 1.09, 95% confidence interval 0.61 to 1.96), postoperative myocardial infarction (p = 0.70), or stroke (p = 0.57). At a mean follow-up of 1.57 years, preoperative statin therapy was not associated with decreased mortality (p = 0.81). In the analysis using propensity score matching (354 propensity-matched patients, 177 in each group), preoperative statin was not associated with improved primary or secondary outcomes. In conclusion, preoperative statin therapy was not associated with a decrease in morbidity or mortality in patients undergoing isolated cardiac valve surgery.     

Does statin therapy decrease the risk for bleeding in patients who are receiving warfarin?

Purpose

Recent observations in patients with atrial fibrillation who are receiving warfarin suggest that concomitant treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) decreases the risk for bleeding.

Methods

We conducted a population-based, nested case-control study using the linked administrative databases of Ontario, Canada, to assess whether statin use decreases the risk of bleeding in warfarin users. Eligible patients were Ontario residents, age 66 years or more, with atrial fibrillation who were prescribed warfarin between April 1, 1994, and December 31, 2001. Patients were followed until hospitalization for upper gastrointestinal or intracranial bleeding, study end (March 31, 2002), discontinuation of warfarin, or death. Cases were matched to controls by age and sex. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between bleeding and statin use.

Results

We identified 79,207 warfarin users with atrial fibrillation. There were 1518 cases with an upper gastrointestinal or intracranial bleed and 15,100 matched controls without bleeding. Long-term (≥1 year) statin use was associated with a lower risk for any bleeding (OR = 0.80; 95% CI, 0.66-0.97). However, there was no association between bleeding and recent (<6 months) statin use (OR = 1.04; 95% CI, 0.74-1.48) or statin use of any duration (OR: 0.91; 95% CI, 0.77-1.07), suggesting potential confounding of the association between statin use and bleeding by a health-user effect.

Conclusion

Long-term statin use may be associated with a decreased risk for bleeding in warfarin users with atrial fibrillation. Additional research is needed to further explore this putative association.     

Does growth hormone cause cancer?

The ability of GH, via its mediator peptide IGF-1, to influence regulation of cellular growth has been the focus of much interest in recent years. In this review, we will explore the association between GH and cancer. Available experimental data support the suggestion that GH/IGF-1 status may influence neoplastic tissue growth. Extensive epidemiological data exist that also support a link between GH/IGF-1 status and cancer risk. Epidemiological studies of patients with acromegaly indicate an increased risk of colorectal cancer, although risk of other cancers is unproven, and a long-term follow-up study of children deficient in GH treated with pituitary-derived GH has indicated an increased risk of colorectal cancer. Conversely, extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. However, given the experimental evidence that indicates GH/IGF-1 provides an anti-apoptotic environment that may favour survival of genetically damaged cells, longer-term surveillance is necessary; over many years, even a subtle alteration in the environmental milieu in this direction, although not inducing cancer, could result in acceleration of carcinogenesis. Finally, even if GH/IGF-1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population. Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency.