PrimeCuts: This Week in the Journals

January 26, 2010

Jon-Emile Kenny MD

Faculty peer reviewed

As the leading cause of death in the United States (1), cardiovascular disease enjoys much basic and clinical research. This week’s PrimeCuts will focus on recent inquiry and review pertaining to this vital system.

JAMA reported that researchers have highlighted a putative link between omega-3 fatty acids and molecular aging in patients with baseline coronary heart disease (2). Telomeres are important lengths of DNA at the ends of chromosomes. Due to the mechanics of replication, small pieces of telomeres are lost with each successive copy. Indeed critical shortening of telomeres are thought to be an important cause of molecular aging and death. The authors found an inverse association between baseline omega-3 fatty acid levels and subsequent rate of telomere shortening over time. Mechanisms are many and unclear but may relate to decreased oxidative stress and increased telomerase activity.

Radiation from occupational, medical, and environmental exposures has been associated with risk of vascular disease. This was further studied among survivors of the Hiroshima atomic bomb, and presented in the BMJ (3). As reported, doses above 0.5 Gray are associated with an elevated risk of both stroke and heart disease and that this accounted for about one third as many radiation-associated excess deaths as did cancers among atomic bomb survivors. The mechanisms are unclear, but are potentially related to pro-inflammatory states and endothelial changes that result in microvascular disease.

Airflow obstruction and ventricular mechanics were studied and reported in this week’s New England Journal of Medicine (4). Their results showed that in a population-based study of subjects without very severe COPD, the degree of airflow obstruction was associated with significant decrements in left ventricular filling and cardiac output. Interestingly, in mild COPD the mechanism of impaired LV filling is likely not secondary to elevated juxtacardiac pressure or pulmonary venous compression but more due to loss of pulmonary artery cross-sectional area observed in early disease.

COPD also made news in Chest this month as investigators provided evidence that anticholinergic medicines such as ipratropium may increase cardiovascular morbidity (10). COPD patients within the Seattle VA Hospital system were analyzed and it was found that 44 percent were exposed to anticholinergics (mainly ipratropium) at some time during the study. Further, any exposure to anticholinergics within the past 6 months was associated with an increased risk of a cardiovascular event. These results are not new and have been previously discussed in Dr. Jani’s Clinical Correlations entry (11).

Also in the New England Journal of Medicine, a computer-based model was analyzed for the effect of salt reduction on cardiovascular health (5). This model found that reducing dietary salt by three grams per day (about 1200 mg of sodium) would result in 11 percent fewer cases of new heart disease, 13 percent fewer heart attacks, 8 percent fewer strokes, and 4 percent fewer deaths. The authors note that the effect of decreased adverse cardiovascular outcomes with lower salt intake may be greater in African Americans and therefore narrow health disparities. Regardless, this article may provide fuel to the fire in New York City over the proposed municipal salt restriction (6).

What about gender differences in cardiovascular risk? It has long been known that estrogen can stimulate vascular repair (e.g. in the uterus) but also in cardiac tissue. Little has been known about the effect of androgens on angiogenesis. However, researchers have published data in the Journal of Experimental Medicine showing the importance of androgens in neovascularization (7). Interestingly, castration of male mice impaired vessel growth and androgen replacement reversed this effect. This may have implications for androgen replacement in men.

Red wine may exert its beneficial effects via the estrogen receptor (8). Investigators published results in PloS One showing the effects of red wine polyphenols on vascular physiology. Importantly the beneficial effects of polyphenols act through the estrogen receptor in a nitric oxide dependent pathway. Not only does this provide a potential mechanism for the vascular effects of red wine, but may partially explain the epidemiological data that has showed lower cardiovascular risk in women than men; and why this protection progressively disappears after menopause.

In a similar, but seemingly paradoxical, vein investigators have replicated earlier findings that Bisphenol A (BPA) is associated with adverse cardiovascular outcomes (9). Oddly, BPA imparts some of its biochemical effects via the estrogen receptor, but also through the PPAR gamma receptor. The latter may also explain the association of elevated urinary BPA and insulin resistance. Regardless, the replication of these results in an independent population provides mounting evidence that environmental exposure to BPA may lead to adverse cardiovascular events.

Lastly, Tomlinson and Detsky from the University of Toronto, afforded a great commentary on composite end-points in randomized trials (12). These are frequently used in cardiovascular research and often frustrating when trying to interpret results. Frequently composite end-points are used for efficiency, but the trade-off is that less-severe surrogates of death and disease (e.g. hospitalization) may drive statistical significance. The authors recommend that readers and authors of randomized trials weight each of the outcomes by an importance factor (e.g. as quality of life is measured) and/or note that although a randomized trial was designed to detect a difference in a composite outcome, the trial may have mainly demonstrated an effect on surrogate outcomes and not definitive ones.

Dr. Kenny is a 3rd year resident in internal medicine at NYU Medical Center.

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