Clinical Briefs

With Comments from Russell H. Greenfield, MD. Dr. Greenfield is Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC; and Visiting Assistant Professor, University of Arizona, College of Medicine, Tucson, AZ.

Slow is Good? Tai Chi and CAD

Source: Lan C, et al. Effect of T'ai Chi Chuan training on cardiovascular risk factors in dyslipidemic patients. J Altern Complement Med 2008;14:813-819.

Goal: To assess the effect of Tai Chi Chuan (TCC) training on risk factors for coronary artery disease (CAD) in people with dyslipidemia.

Study design: One-year, case-controlled trial in a community setting (Taiwan).

Subjects: People < 65 years old (n = 70, data evaluable on 53 subjects, including 29 women) referred from a tertiary hospital center's dyslipidemia clinic who were sedentary and who had been treated for at least 6 months (medication and diet therapy).

Methods: When, at study entry, participants were asked about their interest in engaging in a regular program of exercise, 34 replied "no" and were placed into a "usual care" group that did not participate in any structured exercise over the ensuing year. The remaining 36 subjects received TCC training three times a week that included 24 minutes of TCC (108 postures) sandwiched between 20 minutes of stretching and range of motion exercise, and a 10-minute cool-down period. It was estimated that exercise intensity during TCC training was at 70-80% of peak heart rate. Exercise testing was completed at baseline and at the end of one year's time, and blood tests were obtained at the same time periods for markers of inflammation, fasting glucose and insulin levels, and lipids. Subjects were asked not to change their dietary patterns during the study.

Results: Members of the usual care group showed no significant improvement in markers for cardiovascular risk, in fact exhibiting a diminution in aerobic capacity. Those in the TCC group experienced a slight reduction in blood pressure, and blood tests revealed lower levels of LDL-C (11.9%), total cholesterol (7.3%), triglycerides (26.3%), fasting insulin, and high-sensitivity C-reactive protein. The TCC group also showed improved aerobic capacity by trial's end.

Conclusion: One year of TCC may improve overall cardiovascular risk profile in people with dyslipidemia.

Study strengths: Monthly follow-up; number of parameters examined.

Study weaknesses: Non-randomized protocol; 24% dropout rate; no mention of how exercise intensity was assessed; no monitoring of subjects' diet.

Of note: TCC is sometimes called "moving meditation," reflecting the graceful, slow movements that characterize this traditional martial art; to some eyes TCC would not be classified as exercise, but prior data suggest TCC can improve aerobic capacity as well as balance, perhaps lessening the risk of falls; early research also suggests a beneficial effect on blood pressure and cholesterol levels from regular TCC practice; compliance with TCC attendance in this trial was 77%; reasons for dropping out of the study included lack of time and loss of interest.

We knew that: Economic growth in Asia has spurred dramatic lifestyle changes, and adjusted mortality rates from cardiovascular disease have increased markedly; data suggest that mean cholesterol levels of people living in Beijing increased by > 45 mg/dL over a 15-year period that ended at the turn of the century; physical activity appears to have a beneficial effect on lipid profiles.

Comments: A number of trials have examined the effects of TCC on physical fitness, the majority suggesting both physical and emotional benefits. The authors of the current trial attempted to build upon earlier data to look at potential reductions in CAD with regular TCC practice, but the flaws of the trial are so significant as to minimize the authors' findings. Thankfully, few practitioners would consider the treatment of a sedentary, dyslipidemic individual solely with medications and diet "usual care." Exercise is a core constituent of any CAD risk-reduction program, and making no intervention in this regard for at-risk patients would be imprudent at best. Another problem is the lack of randomization. Study groups were developed based on subject interest, introducing a major confounding factor. Taken together with the lack of dietary monitoring and a significant dropout rate, reflecting some of the challenges associated with any exercise recommendations, and it appears the authors have undue confidence in their conclusions.

Prior data suggest that TCC may offer aerobic benefits to those unable to participate in more active forms of physical activity, as well as to those who simply enjoy this calming art form. It is reasonable to recommend TCC training to patients at risk for CAD as a gentle form of exercise; however, the current study does little to further our understanding of TCC's impact on CAD risk, and clinical recommendations should not be made based on this study's conclusions.

What to do with this article: Remember that you read the abstract.

No C for the 'Big C'? Vitamin C and Chemotherapy

Source: Heaney ML, et al. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res 2008;68:8031-8038.

Goal: To determine the effect of vitamin C on the cytotoxicity of various antineoplastic agents.

Study design: Bench research and animal data.

Subjects: ICR SCID mice.

Methods: Using cell lines (myeloblastic chronic myeloid leukemia cell line K562 and the lymphoma cell line RL), dehydroscorbic acid (DHAA) was employed to increase intracellular vitamin C levels. The cells were then exposed to vincristine, doxorubicin, methotrexate, cisplatin, and imatinib (Gleevec®) in doses corresponding to an IC75, and cellular response was documented. In another part of the study, mice with RL cell xenografts were studied. The animals were divided into cohorts that received vehicle, DHAA, doxorubicin, or DHAA plus doxorubicin through the tail vein. Tumor growth was followed.

Results: Both cell lines accumulated substantial intracellular concentrations of vitamin C. Increased intracellular vitamin C levels not only generated resistance to the therapeutic effects of anticancer drugs that work at least in part through the generation of reactive oxygen species (ROS) within cancer cells, but also negatively impacted the efficacy of antineoplastic drugs that do not rely upon ROS generation for therapeutic effect. Cells with higher intracellular vitamin C levels were more resistant to cytotoxicity, suggesting a dose-dependent effect of vitamin C, but high intracellular vitamin C levels had no effect on cells not exposed to antineoplastics. Vitamin C pretreatment decreased apoptosis with all tested agents, and its effects did not appear to be related to its antioxidant capacity. In the mouse phase of the study, treatment with DHAA alone did not affect tumor growth; however, mice pretreated with DHAA that then received doxorubicin had markedly increased tumor growth compared to those mice receiving doxorubicin alone. Further studies showed that vitamin C did not affect tumor cell uptake of doxorubicin, suggesting that vitamin C might interfere with the intracellular working of the antineoplastic agents. Mitochondrial membrane potential was preserved with vitamin C pretreatment, suggesting a mitochondrial site of action.

Conclusion: Vitamin C may attenuate the cytotoxicity of antineoplastic agents, regardless of mechanism of action.

Study strengths: Use of multiple forms of chemotherapy with varied mechanisms of action; measurement of intracellular vitamin C levels; comparison with another potent antioxidant, N-acetyl cysteine.

Study weakness: Bench and animal data yet to be corroborated in humans.

Of note: Antineoplastic agents like cisplatin and doxorubicin create increases in intracellular ROS that may be important to therapeutic effect; some reports suggest a benefit of vitamin C when combined with chemotherapy, specifically in the setting of arsenic trioxide use, where vitamin C may modulate extracellular production of hydrogen peroxide.

We knew that: Vitamin C is a potent antioxidant that donates electrons to at least eight different important enzymes and helps mitigate the effects of ROS, especially in the mitochondria; ascorbic acid (AA) and DHAA are the main physiologic forms of vitamin C (DHAA has a much wider distribution via facilitated intracellular transport utilizing glucose transporters, after which it is converted into AA); the effects of vitamin C on cancer and its treatment are unclear and a source of significant controversy.

Comments: The results of this study are scary. True, there are reports of vitamin C being an effective aid in the treatment of some cancers, but the supportive data have not been as complete and did not drill down to potential intracellular effects as thoroughly as the authors of the current trial have done.

These results must give practitioners who care for people undergoing cancer treatment pause. In the past, many have left the decision regarding antioxidant supplementation to the oncologists, some of whom are well-versed in this arena but many of whom are not, and the result was often a blanket statement: "Don't use supplements during your treatment." Those days are long past, as it is clear that people are acting on their own to supplement their treatment regimens, and seeking out information from a range of sources that runs the gamut from the lay press to neighbors' folk remedies to the 17-year-old health food store clerk to reputable web sites. In this regard, one of our roles is to provide credible guidance, and caution where appropriate.

This article alone will not end the debate over antioxidant therapy during treatment for cancer. Existing data regarding other antioxidants, such as CoQ10, suggest promise in certain situations where chemotherapy is employed. Clearly the need for further study remains, especially human trials, but for now there is significant reason to consider foregoing the use of high-dose vitamin C supplementation during chemotherapy until greater clarity is achieved. This caution does not appear to apply to the eating of foods high in vitamin C, however.

What to do with this article: Make copies to hand out to your peers.