Vishal Bhatia

Hypogonadotrophic Hypogonadism in Type 2 Diabetes, Obesity and the Metabolic Syndrome

Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.

Drug-eluting stents: new era and new concerns

At present there is much excitement about drug-eluting stents, which hold promise for the treatment of coronary artery disease. This ingenious therapy involves coating the outside of a standard coronary stent with a thin polymer containing medication that can prevent scarring at the site of coronary intervention. Early trials with sirolimus coated stents showed that they might prevent coronary artery restenosis, but later studies, involving more complex coronary lesions, did not show a complete absence of restenosis. Recent studies have demonstrated the long term cost effectiveness of drug-eluting stents as they have reduced the need for revascularisation procedures. At present there are few data on the safety and effectiveness of stents over follow up periods exceeding two years, and data obtained from animal models of stenting might not be completely applicable to humans. There are concerns that drug-eluting stents might delay, rather than inhibit, restenosis. Also there is concern regarding the inflammation caused by the polymer substrate. This article reviews the present data on drug-eluting stents and their benefits, shortcomings, and concerns.

Imaging of the vulnerable plaque: new modalities.

Atherosclerosis is currently considered to be an inflammatory and thus a systemic disease affecting multiple arterial beds. Recent advances in intravascular imaging have shown multiple sites of atherosclerotic changes in coronary arterial wall. Traditionally, angiography has been used to detect and characterize atherosclerotic plaque in coronary arteries, but recently it has been found that plaques that are not significantly stenotic on angiography cause acute myocardial infarction. As a result, newer imaging and diagnostic modalities are required to predict which of the atherosclerotic plaque are prone to rupture and hence distinguish “stable” and “vulnerable”plaques. Intravascular ultrasound can identify multiple plaques that are not seen on coronary angiography. Thermography has shown much promise and is based on the concept that the inflammatory plaques are associated with increased temperature and can also identify “vulnerable patients.” Of all these newer modalities, magnetic resonance imaging has shown the most promise in identification and characterization of vulnerable plaques. In this article, we review the newer coronary artery imaging modalities and discuss the limitations of traditional coronary angiography.

Hypogonadotrophic hypogonadism in type 2 diabetes

Recent work shows a high prevalence of low testosterone and inappropriately low luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity in patients with type 2 diabetes. However, the duration of diabetes or HbA1c are not related to HH. Furthermore, recent data show that HH is not associated with type 1 diabetes. C-reactive protein concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and C- reactive protein concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is also relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations are also related to an increase in total and regional adiposity. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates insulin resistance and inflammation. In addition, low testosterone levels are associated with an increase in cardiovascular events. Testosterone therapy may therefore, reduce cardiovascular risk. This important aspect requires further investigation.

Insulin resistance in polycystic ovarian disease

The classic polycystic ovarian syndrome (PCOS) was originally described by Stein and Leventhal as the association of amenorrhea with polycystic ovaries and, variably, hirsutism and/or obesity. It is estimated that 5 to 10% of women of reproductive age have PCOS. Although insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance, independent of total or fat-free body mass. Postreceptor defects in the action of insulin have been described in PCOS that are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin, and thiazolidinediones (TZDs) improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that women who have PCOS have higher circulating levels of inflammatory mediators such as C-reactive protein, tumor necrosis factor, tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1). It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

Elevation of the tumor marker CA125 in right heart failure.

Carbohydrate antigen 125, known as a marker for ovarian cancer, has been reported to be elevated in heart failure caused by left ventricular dysfunction. A case of elevated carbohydrate antigen 125 in isolated right heart failure due to atrial septal defect with preserved left ventricular function is reported.

Angiotensin Receptor Blockers in Congestive Heart Failure Evidence, Concerns, and Controversies

Heart failure results in neurohormonal activation of which the renin–angiotensin–aldosterone system (RAS) is the main mediator. Activation of this system leads to the production of angiotensin II (ATII), which leads to multiple adverse short-term and long-term effects, including hemodynamic dysfunction, renal dysfunction, inflammation, and cardiac remodeling. Angiotensin-converting enzyme inhibitors (ACEIs) exert favorable effects in congestive heart failure (CHF) by inhibiting the production of ATII. It has been shown that ACEIs may not be able to suppress the production of ATII completely because there are RAS-independent mechanisms of ATII production. Hence, it was thought that angiotensin receptor blockers (ARBs) might be more useful in CHF because they directly block the ATII receptors. Many studies have been done to evaluate the role of ARBs in CHF. We reviewed these studies and have attempted to define the place and ARBs in the therapy for CHF.

Nonsurgical Carotid Revascularization

Carotid endarterectomy is a well-established treatment of improving the carotid luminal diameter and preventing strokes, and the indications and complications are well-defined. Carotid angioplasty and stent placements are relatively newer ways of treating carotid artery stenosis. In certain contexts, they may have some advantages over carotid endarterectomy. However, the success rates, morbidity, and mortality associated with these procedures are less well characterized. In earlier comparative studies, the incidence of ipsilateral stroke rate was higher with angioplasty, but in later studies, this trend is reversing. Angioplasty may also have an edge in specific situations like patients with coexisting significant coronary arterial disease, contralateral carotid artery occlusion, and in instances when the narrowing is long and at multiple sites. Protective devices like distal occlusion balloon and filter protection devices may reduce the incidence of stroke. We are still awaiting the results of some major randomized head-to-head trials comparing carotid endarterectomy and stenting.

Stroke in atrial fibrillation: a need for effective anticoagulation.

Atrial fibrillation (AF) occurs in 2 to 4% of the population aged 60 years and older and in up to 10% of the population above the age of 80 years. In the Framingham study, AF was found to be responsible for approximately one-sixth of all ischemic strokes in people older than 60 years of age. In addition to causing clinical stroke with major deficits, AF is also associated with silent cerebral infarctions. Paroxysmal AF, which usually lasts less than 7 days and is usually asymptomatic, can also cause embolization with almost the same risk as persistent AF. Furthermore embolic events can even occur in patients with acute AF for as little as 72 hours. The AFFIRM and RACE trials have demonstrated that embolic events occur with equal frequency regardless of whether a rate control or rhythm control strategy is pursued in the management of AF. Hence most patients with AF, regardless of whether a rate control or rhythm control strategy is chosen, should be on long-term anticoagulants with an international normalized ratio (INR) in the therapeutic range.