Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis.
Recent developments into anthero-thrombosis, the leading cause of morbidity and mortality in Western Society, may help to change our treatment strategy to a more casual approach. The composition of the atherosclerotic plaque, rather than the percent stenosis, appears to be a critical predictor for both risk of plaque rupture and subsequent thrombogenicity. A large lipid core, rich in tissue factor (TF) and inflammatory cells including macrophages, and a thin fibrous cap with compromise of its structural integrity by matrix degrading enzymes, such as metalloproteinases (MMPs), render a lesion susceptible to rupture and subsequent acute thrombosis. Thrombosis may lead to a complete occlusion or, in the case of mural thrombus or intraplaque hemorrhage, to plaque progression. Disruption of a vulnerable or unstable plaque (type IV and Va lesions of the AHA classification) with a subsequent change in plaque geometry and thrombosis may result in an acute coronary syndrome. The high-risk plaque tend to be relatively small, but soft or vulnerable to “passive” disruption because of high lipid content. Inflammatory processes are important components of all stages of atherosclerotic development, including plaque initiation and disruption. As such the early steps in atherosclerotic lesion formation are the over expression of endothelial adhesive protein (i.e. selectins, VCAM and ICAM), chemotactic factors (MCP-1), growth factors (M-CSF), and cytokines (IL-2) that will facilitate the recruitment, internalization and survival of blood-borne inflammatory cells into the vascular wall. Macrophages, following what appears to be a defense mission by protecting the vessel wall from excess lipid accumulation, may eventually undergo apoptosis with release of MMPs and TF. Specific cell recruitment in the vessel wall and build-up of the extracellular matrix are coordinated by a wide variety of stimulators and inhibitors. Active interaction of immune competent cells within the atherosclerotic lesions appears to play a pivotal role in the control of atherosclerotic plaque evolution and, therefore, deserves particular attention from the research community with the ultimate goal of improving preventive and therapeutic medical approaches. Inflam-mation, throm-bosis and atherosclerosis are interdependent and define a triad within the complex pathogenic process of athero-thrombosis.
J Thromb Thrombolysis. 2004 Feb;17(1):35-44
High-sensitivity C-reactive protein, inflammation, and cardiovascular risk: from concept to clinical practice to clinical benefit.
Advances in vascular biology have shown that inflammation plays an integral role in the development of cardiovascular disease. Extensive study of high-sensitivity C-reactive protein (hs-CRP) has demonstrated that this measure of inflammation predicts cardiovascular risk not reflected by traditional risk factors, adds prognostic information to traditional risk assessment, and predicts long-term cardiovascular risk in individuals with no prior evidence of cardiovascular disease. Patients with elevated hs-CRP levels in the absence of elevated cholesterol appear to derive preventive benefit from statin therapy that is similar in magnitude to that in patients with elevated cholesterol. The large-scale Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosvastatin (JUPITER) trial represents a critical study to determine the utility of a strategy for targeting statin therapy to prevent incident cardiovascular disease in patients at increased cardiovascular risk on the basis of elevated hs-CRP who would not be considered candidates for therapy on the basis of hypercholesterolemia or traditional risk assessment. Inclusion of hs-CRP measurement in risk screening and use of this information to guide preventive therapy could result in a marked improvement in prevention of cardiovascular morbidity and mortality.
Am Heart J. 2004 Jul;148(1 Suppl):S19-26
Blocking carbohydrate absorption and weight loss: a clinical trial using Phase 2 brand proprietary fractionated white bean extract.
Background: Phase 2’ starch neutralizer brand bean extract product (“Phase 2”) is a water-extract of a common white bean (Phaseolus vulgaris) that has been shown in vitro to inhibit the digestive enzyme alpha-amylase. Inhibiting this enzyme may prevent the digestion of complex carbohydrates, thus decreasing the number of carbohydrate calories absorbed and potentially promoting weight loss. Methods: Fifty obese adults were screened to participate in a randomized, double-blind, placebo-controlled study evaluating the effects of treatment with Phase 2 versus placebo on weight loss. Participants were randomized to receive either 1500 mg Phase 2 or an identical placebo twice daily with meals. The active study period was eight weeks. Thirty-nine subjects completed the initial screening process and 27 subjects completed the study. Results: The results after eight weeks demonstrated the Phase 2 group lost an average of 3.79 lbs (average of 0.47 lb per week) compared with the placebo group, which lost an average of 1.65 lbs (average of 0.21 lb per week), representing a difference of 129% (p=0.35). Triglyceride levels in the Phase 2 group were reduced an average of 26.3 mg/dL, more than three times greater a reduction than observed in the placebo group (8.2 mg/dL) (p=0.07). No adverse events during the study were attributed to the study medication. Conclusion: Clinical trends were identified for weight loss and a decrease in triglycerides, although statistical significance was not reached. Phase 2 shows potential promise as an adjunct therapy in the treatment of obesity and hypertriglyceridemia and further studies with larger numbers of subjects are warranted to conclusively demonstrate effectiveness.
Altern Med Rev. 2004 Mar;9(1):63-9
Depression in aging men: the role of testosterone.
Age-related decline in testosterone levels is associated with a number of mild, nonspecific symptoms, including depressive symptoms. The relationship between depressive symptoms and testosterone levels is confounded by numerous factors, including medical illness, obesity, smoking, alcohol use, diet, and stress, and is thus complex. Studies have not consistently supported an integral role of reduced testosterone levels in major depressive disorder, although levels may often be reduced in men with treatment-refractory depression and older men with dysthymia. Low testosterone levels may also increase the risk of incident depression in older males, although this may depend upon androgen receptor genetic polymorphisms. Testosterone replacement has demonstrated short-term tolerability and efficacy in augmenting antidepressants to alleviate treatment-refractory depression in adult males. Case studies support the potential need for maintenance therapy to maintain response. In a placebo-controlled trial, testosterone monotherapy was not effective in treating major depressive disorder in men with hypogonadism. However, in an open-label, noncomparative study, testosterone monotherapy appeared effective in treating late-onset but not early-onset major depressive disorder in older males. Test-osterone therapy is not without potential for adverse effects, the most worrisome of which is the worsening of pre-existing prostate carcinoma. Oral, short- and long-acting parenteral, and transdermal patch and gel formulations are available. Testosterone has demonstrated usefulness in the treatment of a number of depressed populations, but further studies are needed to fully elucidate its role in the treatment of depressive syndromes in the aging male.
Drugs Aging. 2004;21(6):361-76
Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome.
BACKGROUND: Mild hypoandrogenism in men, usually defined by low levels of testosterone, is a peculiar feature of abdominal obesity that independently predicts the development of insulin resistance and diabetes mellitus. Little is known about the short- and long-term effects of weight loss on sex steroids in abdominally obese men, however. OBJECTIVES: We assessed the effect of rapid weight loss and sustained weight maintenance on the plasma concentrations of testosterone and other sex hormones in 58 abdominally obese men (age, 46.3 +/- 7.5 years; body mass index, 36.1 +/- 3.8 kg/m(2); waist girth, 121 +/- 10 cm) with the metabolic syndrome. RESULTS: The men lost on average 16.3 +/- 4.5 kg during a 9-week very low-calorie diet (VLCD) and maintained 14.3 +/- 9.1 kg weight loss after a 12-month maintenance period (vs. baseline, p < 0.001). Sex hormone-binding globulin (SHBG) increased from 27.6 +/- 11.9 to 48.1 +/- 23.5 nmol/l during the VLCD but decreased to 32.6 +/- 12.9 nmol/l during weight maintenance, which was still higher than at baseline (p < 0.001). Free testosterone (fT) increased from 185 +/- 66 to 208 +/- 70 pmol/l (p = 0.002) during the VLCD and remained high after 1 year of weight maintenance (212 +/- 84 pmol/l, p = 0.002). Total testosterone levels followed a pattern intermediate between fT and SHBG. Plasma estradiol and dehydroepiandrosterone sulphate concentrations changed only transiently or not at all. CONCLUSIONS: Rapid weight loss with successful weight maintenance in abdominally obese men with the metabolic syndrome brings about a sustained increase in fT levels. The dramatic increase in SHBG attenuated initially during weight maintenance but remained elevated. These findings may be important with regard to prevention of progressive metabolic decompensation and cardiovascular disease associated with obesity and the metabolic syndrome.
Diabetes Obes Metab. 2004 May;6(3):208-15
Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging.
OBJECTIVES: To To compare testosterone undecanoate versus propionyl-L-carnitine plus acetyl-L-carnitine and placebo in the treatment of male aging symptoms. METHODS: A total of 120 patients were randomized into three groups. The mean patient age was 66 years (range 60 to 74). Group 1 was given testosterone undecanoate 160 mg/day, the second group was given propionyl-L-carnitine 2 g/day plus acetyl-L-carnitine 2 g/day. The third group was given a placebo (starch). Drugs and placebo were given for 6 months. The assessed variables were total prostate-specific antigen, prostate volume, peak systolic velocity, end-diastolic velocity, resistive index of cavernosal penile arteries, nocturnal penile tumescence, total and free testosterone, prolactin, luteinizing hormone, International Index of Erectile Function score, Depression Melancholia Scale score, fatigue scale score, and incidence of side effects. The assessment was performed at intervals before, during, and after therapy. RESULTS: Testosterone and carnitines significantly improved the peak systolic velocity, end-diastolic velocity, resistive index, nocturnal penile tumescence, International Index of Erectile Function score, Depression Melancholia Scale score, and fatigue scale score. Carnitines proved significantly more active than testosterone in improving nocturnal penile tumescence and International Index of Erectile Function score. Testosterone significantly increas-ed the prostate volume and free and total testosterone levels and significantly lowered serum luteinizing hormone; carnitines did not. No drug significantly modified prostate-specific antigen or prolactin. Carnitines and testosterone proved effective for as long as they were administered, with suspension provoking a reversal to baseline values. Only the group 1 prostate volume proved significantly greater than baseline 6 months after testosterone suspension. Placebo administration proved ineffective. Negligible side effects emerged. CONCLUSIONS: Testosterone and, especially, carnitines proved to be active drugs for the therapy of symptoms associated with male aging.
Urology. 2004 Apr;63(4):641-6
Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment.
OBJECTIVE: The present paper reviews the evidence that depression is a risk factor for the development and progression of coronary artery disease (CAD). METHODS: MEDLINE searches and reviews of bibliographies were used to identify relevant articles. Articles were clustered by theme: depression as a risk factor, biobehavioral mechanisms, and treatment outcome studies. RESULTS: Depression confers a relative risk between 1.5 and 2.0 for the onset of CAD in healthy individuals, whereas depression in patients with existing CAD confers a relative risk between 1.5 and 2.5 for cardiac morbidity and mortality. A number of plausible biobehavioral mechanisms linking depression and CAD have been identified, including treatment adherence, lifestyle factors, traditional risk factors, alterations in autonomic nervous system (ANS) and hypothalamic pituitary adrenal (HPA) axis functioning, platelet activation, and inflammation. CONCLUSION: There is substantial evidence for a relationship between depression and adverse clinical outcomes. However, despite the availability of effective therapies for depression, there is a paucity of data to support the efficacy of these interventions to improve clinical outcomes for depressed CAD patients. Randomized clinical trials are needed to further evaluate the value of treating depression in CAD patients to improve survival and reduce morbidity.
Psychosom Med. 2004 May-Jun;66(3):305-15