Lipids, Inflammation, and CAD: The View from JUPITER
Lipids, Inflammation, and CAD: The View from JUPITER
Abstract & Commentary
By Susan T. Marcolina, MD, FACP. Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; she reports no financial relationship to this field of study.
Synopsis: Healthy middle-aged men and women with normal LDL-cholesterol levels and elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) show significant decreases in clinical cardiovascular events when treated with rosuvastatin vs placebo. The identification and management of chronic systemic inflammation has a significant impact on the treatment of cardiovascular diseases particularly for persons who don't have other risk factors that would target them for primary prevention.
Source: Ridker PM, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207.
In the justification for the use of statins in prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, a large multicenter randomized, double-blind, placebo-controlled trial of 17,802 healthy middle-aged subjects, Ridker et al have definitively shown that an intervention to decrease levels of the inflammatory biomarker hsCRP resulted in decreased incidence of the clinical endpoints of myocardial infarction, stroke, and combined cardiovascular (CV) death.1 This study is particularly noteworthy because the patients had median levels of LDL-cholesterol of 108 mg/dL, which is below the currently established threshold of treatment recommended by the National Cholesterol Education Project Adult Treatment Panel III 2004 guidelines.2 This is also the first large-scale primary prevention trial that included a substantial proportion of female and minority subjects (approximately 38% and 19%, respectively, for both placebo and rosuvastatin-treated groups).
The study was terminated after a median follow-up of only 1.9 years, at which time the data safety and monitoring board found statistically significant improvements in clinical outcomes for patients treated with the statin drug, rosuvastatin. At the time of the study termination, the median LDL-cholesterol level was 55 mg/dL (down from a baseline median level of 108 mg/dL) and the median hsCRP level was 2.2 mg/L (down from a baseline median hsCRP of 4.2 mg/L) with a hazard ratio of 0.53 for rosuvastatin for the clinical endpoints of myocardial infarction, stroke, or confirmed CV cause of death. The clinical benefits were observed in every subgroup. Interestingly, subjects whose only risk factors were age and hsCRP elevation benefited from rosuvastatin as much as higher-risk subjects.
Commentary
Since 20% of all coronary events occur in individuals without any of the major Framingham risk factors and sudden cardiac death accounts for 50% of all CHD deaths,3,4 this study is pivotal in that it provides a way for primary care physicians to correctly identify these individuals for preventive treatment. Given that CV disease and atherothrombosis have inflammation as a root causative factor, the JUPITER trial raises another formidable question: Can inhibition of inflammation by agents other than statins reduce the rates of cardiovascular events? As a matter of fact, there is evidence from several clinical studies that two interventions can reduce inflammatory markers as well as clinical CV endpoints.
The first intervention is a dietary modification to increase intake of the omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as fish meals or supplements and the second is a lifestyle intervention to treat periodontal disease with professional dental care and prevent it by proactive early attention to the daily oral hygiene practices of tooth brushing and flossing.
An important implication of these interventions is that, although they will never make huge profits for large pharmaceuticals, they have the potential to improve the overall health and quality of life of individual patients in that each has ancillary benefits such as decreased tooth and alveolar bone loss (periodontitis treatment and prevention), increased fertility (omega-3 fatty acids),5 lowered blood triglyceride concentrations (omega-3 fatty acids),6 and improved glycemic control (periodontal disease treatment).7
Omega-3 Polyunsaturated Fatty Acids
The necessity of the dietary intervention comes as no surprise because the dietary ratio of omega-6 PUFAs to omega-3 PUFAs in the typical Western diet has dramatically increased from 4:1 to 25:1 over the past 50 years due to changes in agricultural practices that emphasized production. Domestic cattle have been largely grain-fed (a rich source of omega-6 fatty acids), which promotes greater and faster weight gain than cattle allowed to pasture. Additionally, post-World War I industrial innovations streamlined the production of vegetable oils for cooking and these oils were predominately composed of omega-6 fatty acids. This, coupled with studies demonstrating the hypolipidemic effects of corn oil (primarily omega-6 PUFAs) in the 1950s, resulted in displacement of other fats such as lard and butter in the U.S. diet.8 Although it is now recognized that dietary omega-6 fatty acids (primarily linoleic acid) favor oxidative modification of LDL-cholesterol and increase platelet response to aggregation, there remains a dietary preponderance relative to omega-3 PUFAs.9
Since omega-6 fatty acids are subunits of arachidonic acid, a primary inflammatory precursor, an increase in dietary concentration favors formation of a group of eicosanoids with proinflammatory, prothrombic, and vasoconstricting effects such as tumor necrosis factor alpha (TNF alpha), thromboxane A2, prostaglandin E2, and leukotriene B4.10
Conversely, the omega-3 fatty acids EPA and DHA are precursors to a group of eicosanoids that have anti-inflammatory, antithrombotic, and vasodilatory effects. Such omega-3-derived eicosanoids include leukotriene B5, thromboxane A3, and prostaglandin E3. When dietary ingestion of fatty fish and fish oil is increased, the EPA component competitively inhibits arachidonic acid metabolism, which results in the synthesis of less thrombogenic and less inflammatory eicosanoids. This change in the milieu of inflammatory mediators can decrease the risk of pathologic events in vascular beds throughout the body.11 Clinical studies, both epidemiological12 and prospective randomized trials, particularly secondary prevention trials, have shown a decrease in clinical CV events after increased fish oil supplementation or fish consumption equivalent to 1 g/d of EPA + DHA.13,14 A primary intervention trial showed a significant decrease in inflammatory markers hsCRP, TNF alpha, interleukin-6, and leukotriene B4 for the group of patients treated with 1.4 g/d of fish oil capsules compared to placebo.15
Additionally, omega-3 fatty acids and their derived eicosanoids appear to bind to and regulate a group of transcription factors, the peroxisome proliferator-activated receptors (PPAR) alpha and gamma, both of which have been shown to inhibit the activation of inflammatory genes responsible for the formation of TNF alpha, IL-1beta, IL-6, inducible NO synthase, matrix metalloproteinases, and acute-phase proteins such as CRP. Thus, these PPAR receptors link dietary fat concentrations to glucose, lipid, endothelial, and immune homeostasis, which have important ramifications for clinical CV events.16
Cholesterol and Depression
The use of rosuvastatin in the JUPITER study significantly reduced levels of CRP, as well as lowering cholesterol levels already considered by primary prevention standards to be low. Such low cholesterol levels raise the concern as to whether there will be an increase in depression and suicide for such populations. This concern stems from analyses of mortality rates in primary prevention trials, which revealed an association between low cholesterol levels and suicide rates.17,18 However, the exact association is not clear and there is no consensus from clinical trial results: While some studies support this finding,19 other studies have shown no association between low cholesterol levels and suicide rates20 and some, like Tanskanen et al,21 demonstrated a relationship between elevated cholesterol levels and increased rate of violent suicide.
Lower serotonergic function may account for the link between diminished cholesterol levels and depression. Scanlon et al have shown in in vitro studies that a depletion of neural membrane cholesterol modulates serotonin transporter activity.22 There may be some evidence for this in an autopsy study by Lalovic et al, which demonstrated decreased brain grey matter cholesterol in violent suicide victims.23
Given the complex relationship between suicidal risk, attempts, and suicidal death, and the multiple factors that influence cholesterol levels, it has been suggested that perhaps cholesterol is a surrogate marker of dietary PUFAs changes that have been linked to depression, one of the strongest risks for suicide.24 This is why it may be important to consider modifying dietary PUFA composition, particularly to decrease the omega-6:omega-3 ratio as initial treatment of elevated inflammatory biomarkers vs initial use of statins for primary prevention. Statins are expensive medications that may have significant side effects such as muscle pains and liver enzyme abnormalities and may increase the risk for diabetes, a small but significant adverse effect noted in the statin treatment group of the JUPITER trial. Interestingly, Weidner et al found that patients on a low-cholesterol diet had reductions in depression if they increased fish consumption.25 This suggests that differences in the dietary composition of PUFAs might explain the conflicting findings in the studies examining low cholesterol and rates of depression and suicide.
Omega-3 Fatty Acid Intake Recommendations
The American Heart Association recommendations for persons with known CHD are to eat one fatty fish meal at least twice a week or take 1 g/d of omega-3 PUFAs (EPA + DHA).26 There is a standardized prescription formulation of omega-3 fatty acid ethyl esters called Lovaza® available in 1 g liquid-filled gel capsules, each of which contains 465 mg of EPA and 375 mg DHA.27 It is currently, however, only FDA approved for treatment of significant hypertriglyceridemia, but as a result of JUPITER findings it may be a recommendation for persons with elevated levels of hsCRP. Indeed, instead of putting everyone on statins, it may be of greater benefit to increase dietary intakes of omega-3 PUFAs.
The Role of Periodontitis
Periodontitis is a local inflammatory process that causes destruction of the supporting gum and ligamentous tissue that anchors the teeth in alveolar bone. Although once thought to be a local process that was wholly the concern of dentists and other oral health practitioners, it is now clear that periodontal diseases play an important role in numerous conditions that impact CV health. The local oral mucosal response to the elaboration of lipopolysaccharides by the periodontopathic anaerobes in the gingival pockets causes infiltration of the periodontal tissues with inflammatory cells including polymorphonuclear neutrophils, macrophages, and lymphocytes. Such activated macrophages release cytokines, which destroy oral connective tissue and alveolar bone and activate a systemic acute-phase response with an increase in inflammatory biomarkers such as CRP. The vascularity of the oral cavity ensures systemic dissemination of periodontopathic bacteria such as Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, which have been found in atherosclerotic plaques.28,29
Elevated CRP serum levels in patients with periodontal disease (PD) have been demonstrated in several studies.30,31 A meta-analysis of several cross-sectional, prospective cohort and case-control studies found that after adjustment for smoking, diabetes, alcohol use, obesity, and blood pressure, subjects with PD had a 1.1-1.6 greater risk for developing CHD compared to those without PD.32 Treatment of periodontitis results in a significant decrease in serum CRP levels33 and an improvement in endothelial function.34 The fact that PD is treatable and preventable through a regular regimen of brushing, flossing, and professional dental care suggests that to modify this risk factor for inflammation and CVD there is a need to get back to basics and educate patients about the importance of a daily routine of oral hygiene to general health.
Conclusion
Primary care physicians who see patients daily in the office for routine and urgent care are uniquely positioned to identify persons who are at risk for cardiovascular disease. Although dental and dietary assessments may not have been part of a physician's medical school training, they are now part of the on-the-job continuous learning process that is necessary to promote cost-effective dietary and lifestyle interventions that will not only modify a patient's cardiovascular risk factors by decreasing systemic inflammation, but also will improve their overall general medical health.
References
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Healthy middle-aged men and women with normal LDL-cholesterol levels and elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) show significant decreases in clinical cardiovascular events when treated with rosuvastatin vs placebo.Subscribe Now for Access
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