Pomegranate Juice May Not Affect the Carotid Artery, with Caveats

Abstract & Commentary

By David Kiefer, MD. Dr. Kiefer is Clinical Instructor, Family Medicine, University of Washington, Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson; and Adjunct Faculty, Bastyr University, Seattle; he reports no financial relationship to this field of medicine.

Synopsis: Addressing the accumulating evidence for pomegranate's effects on various cardiovascular parameters, this study explored the impact of 240 mL of pomegranate juice daily for 18 months on carotid intima-media thickness (CIMT), a known risk factor for stroke and myocardial infarction. The results failed to show a difference in CIMT or antioxidant parameters (the proposed mechanism), except for subgroup analyses on people at particularly high risk for cardiovascular disease.

Source: Davidson MH, et al. Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease. Am J Cardiol 2009;104:936-942.

This double-blind, placebo-controlled study with an intention-to-treat analysis was designed to examine the cardiovascular actions of pomegranate juice, following up on some in vitro and in vivo research showing relevant effects, such as inhibition of LDL oxidation, lowered blood pressure, and decreased angina frequency. The primary outcome was the effect on carotid intima-media thickness (CIMT), known to be a risk factor for coronary artery disease, stroke, and myocardial infarction. Subjects of this trial had to have at least one major risk factor for coronary heart disease, with a CIMT within very specific parameters, and no obvious carotid stenosis. People with known coronary heart disease, HIV, liver disease, hypothyroidism, uncontrolled hypertension, diabetes, or who were obese, were excluded from this trial.

The study randomized 383 people to either 240 mL of pomegranate juice (n = 192) or similar-appearing placebo drink (n = 191) daily for up to 18 months. These two groups were similar in all parameters except that the pomegranate group was more likely to use angiotensin II receptor blocker medications. For the research protocol, a carotid ultrasound was done at baseline, 12 months, and 18 months, focusing on the CIMT of the posterior wall of the right and left common and carotid arteries. Research subjects had the option of an intravenous injection of dye that would allow visualization of the anterior wall; 52% of people agreed to this. In addition, the research protocol included checking fasting lipids, blood chemistries, hematology, urinalyses, apoprotein-B100, high-sensitivity C-reactive protein, and two specialized tests to measure serum susceptibility to oxidation. Of the original randomized group, 149 (76%) and 143 (75%) people in the pomegranate and placebo groups, respectively, finished the trial.

Of the many parameters tested, only a couple of differences between the pomegranate and placebo groups were noted. The pomegranate group had a significant decrease in one of the tests for oxidative stress at 12 months (P < 0.01), and a lower apoprotein-B100 (P value not given). Of all the measurements of CIMT, only the composite value at 12 months was significantly less in the pomegranate group (P = 0.022), a difference that disappeared by the end of 18 months.

Although it was not part of the original study design, and therefore difficult to comment on statistically, various subgroup analyses were done. For people in the top tertiles for baseline serum triglycerides, total/HDL cholesterol, triglycerides/HDL cholesterol, and apoprotein-B100, and the lowest tertile for HDL cholesterol, significantly lower CIMT for the anterior wall and composite values were noted in the active group (varied P values). There were still no differences in posterior wall CIMT. In the top tertiles for triglycerides, total/HDL cholesterol, and apoprotein-B100, the C-reactive protein was significantly lower in the pomegranate group. In addition, the pomegranate group showed less progression of CIMT in these same subgroups, the ones that typically have faster CIMT progression.

Commentary

Of all dietary supplements, the juices have shown the greatest increase in sales over the past couple of years.1 Pomegranate, açaÍ, noni, and mangosteen are all being marketed and used to prevent and treat a wide range of medical conditions, from cancer, heart disease, and cholesterol, to diabetes and aging. For pomegranate, its postulated effects can dovetail somewhat with other plants that have been researched significantly. For example, pomegranate contains catechins and epicatechins, as in dark chocolate and green tea, both cardioprotective foods. Also, the dark red color of pomegranate comes from its anthocyanins and proanthocyanidins, antioxidant flavonoids present in some form in many fruits and vegetables.2 Finally, the quercetin in pomegranate is being examined for its anti-inflammatory activity, relevant to many diseases.

This study did not have the results expected from a plant with such presumed cardiovascular potential. The dose used (240 mL) is in line with other studies that showed effects of pomegranate on blood pressure, lipid profiles, and myocardial ischemia,3 so it does not seem to be an underdosing issue, relatively common in negative herbal trials. There were a significant number of study dropouts, but the authors used an intention-to-treat analysis that should have adequately addressed that issue from a statistical standpoint. Furthermore, the authors seemed to have the correct mechanism in mind, utilizing what we know about oxidation's role in the development of atherosclerotic plaques, and chose a well-known antioxidant source in pomegranate.

The results in the higher tertiles of some of the baseline parameters provide preliminary hints about pomegranate's possible effects. Caution is necessary in drawing too many conclusions from these subgroup analyses because it wasn't a part of the main study design; further, studies using these subgroups as the main focus are necessary to avoid statistical biases. Nonetheless, despite no difference in most serum anti-inflammatory markers for the treatment group as compared to the placebo group, some of the higher tertile subgroup analyses did show some differences in antioxidant effects, leading the authors to cling to an antioxidant mechanism for pomegranate's role in the inhibition of CIMT progression, if any.

People with more and more severe risk factors, thought to be the groups that progress faster in CIMT changes, showed trends toward CIMT improvements, but, again, this would need to be clarified in a different research study. Also, additional research is necessary to definitively say that this is where pomegranate has its most important role, in people with more significant oxidative stress and disease pathology, as opposed to general benefit for all people. Furthermore, the authors are right to comment on the complexity of the underlying changes associated with CIMT progression, many of which were not measured in this trial and should be the focus of future investigations. For example, effects of pomegranate on platelet activity, endothelial function, and prostacyclin were mentioned as possible contributing factors not addressed by this study.

In summary, there does not seem to be a benefit with pomegranate juice on one cardiovascular parameter, CIMT, and some associated laboratory tests, in people with mild-to-moderate cardiovascular risks. This study does not allow any conclusions to be drawn about other demographics, though some beneficial preliminary trends appeared for people at more serious cardiovascular risk. More data are needed for this safe, but expensive, treatment before it can seriously be considered as an adjunctive therapy in cardiovascular disease.

References

1. Cavaliere C, et al. Herbal supplement sales experience slight increase in 2008. HerbalGram 2009;82:58-61.

2. Guo C, et al. Pomegranate juice is potentially better than apple juice in improving antioxidant function in elderly subjects. Nutr Res 2008;28:72-77.

3. Kiefer D. Imported fruits: Drink their juices? Altern Med Alert 2009;12:89-94.