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CARDIOVASCULAR DISEASE

CARDIOVASCULAR DISEASE

Atherosclerosis/Antioxidant Status

Aviram et al, 2004. A small open label, parallel group clinical trial was conducted with 19 patients (5 women and 14 men, aged 65-75 years) with severe carotid artery stenosis (CAS, 70-90% occlusion of the internal carotid arteries as confirmed by Doppler ultrasound) who were recruited from the Vascular Surgery Clinic at the Rambam Medical Center in Haifa, Israel.9 Patients were randomized to receive 50 ml POM Wonderful PJ concentrate per day (treatment group; n = 10) or no POM Wonderful PJ (control group; n = 9). A subgroup of the POM Wonderful PJ subjects (n = 2) along with 7 additional matched control subjects underwent carotid endartherectomy. Subjects received 50 ml of POM Wonderful PJ per day. The concentrated POM Wonderful PJ was diluted 1:5 (v:v) with water to obtain a single strength juice equivalent to 8 ounces per day. The study period lasted for one year and 5 patients consuming POM Wonderful PJ continued for another 2 years.

The primary outcome was the change in intima-media thickness (IMT) over time measured at the distal common carotid artery by Doppler ultrasound. Additional outcomes included peak systolic velocity (PSV); end diastolic velocity (EDV); total cholesterol; high density lipoprotein cholesterol; triglycerides; apolipoproteins A-1 and B-100; serum paraoxonase 1 (PON 1) arylesterase activity (a high density lipoprotein associated enzyme that can reduce lipid peroxides, thereby decreasing oxidative stress); total antioxidant status; serum antioxidized LDL antibodies; LDL oxidation; and chemical analyses of atherosclerotic plaques obtained by endartherectomy for cholesterol, lipid peroxides, and reduced glutathione concentrations.

Compared to pretreatment values, mean IMT decreased significantly in the treatment group after 3, 6, 9 and 12 months (–13%, –22%, –26% and –35%, respectively; p < 0.01). After 12 months of treatment the mean IMT had decreased from 1.5 ± 0.2 mm at baseline to 1.1 ± 0.1 mm (p < 0.01) and remained at that approximate mean thickness for the duration of the study. In contrast, the mean IMT in the control group significantly increased from baseline to 12 months from 1.52 ± 0.03 to 1.65 ± 0.04 mm, (p < 0.01). Comparisons between groups were not provided. Significant decreases after 1 year of treatment were noted for mean PSV (cm/s), which decreased from 135 ± 6 to 103 ± 10 (p < 0.01), and for mean EDV, which decreased from 38 ±1 to 30 ± 12 (p < 0.01), with no additional significant reductions for the remainder of the trial. The large standard deviation calculated for EDV after one year of supplementation (30 ± 12) narrowed during the rest of the trial. The mean EDV at 22 months was 27 ± 5, 29 ± 2 at 28 months and 29 ± 2 at 36 months.

Systolic, but not diastolic, blood pressure (mmHg) was significantly reduced after 1 month of treatment from 174 ± 8 to 162 ± 9 (p < 0.05), and, compared to baseline, was further significantly reduced after 12 months to 153 ± 7 (p < 0.01). Blood pressure was not significantly changed in the control group at any time period compared to baseline. Compared to baseline, antioxidized LDL antibodies (EU/ml) decreased by 24% after 1 month of treatment, from 2070 ± 61 to 1563 ± 69 and by 19% after 3 months, to 1670 ± 52 (p < 0.01). Mean total antioxidant status (nmol/L) increased after 12 months of PJ consumption from 0.95 ± 0.12 at baseline to 2.20 ± 0.25; however, 1 month after stopping treatment, mean total antioxidant status decreased to 1.4 ± 0.1. Mean serum lipid oxidation (nmol lipid peroxides/ml) significantly decreased after 12 months of treatment from 1670 ± 66 to 691 ± 43 (p < 0.01). Mean serum lipid oxidation was further significantly decreased to 690 ± 40 after 28 months and 660 ± 30 after 36 months compared to baseline (p < 0.01). PON 1 (U/ml) significantly increased in the treatment group after 1 year from baseline to 56 ± 5 to 97 ±10 (p < 0.01) and continued to significantly increase throughout the duration of the study to 107 ± 10 (p < 0.01) at 3 years; however, one month after stopping treatment, PON 1 activity decreased to 88 ± 18 U/mL.

Carotid endartherectomy was performed in 2 patients, one after 3 months and one after 12 months of consuming PJ, due to clinical deterioration during the trial. Compared to 7 controls, their carotid lesions had significantly lower mean concentrations of cholesterol (58% and 20% lower, respectively; p < 0.01), lipid peroxides (61% and 44%, respectively; p < 0.01), and lesion-induced LDL oxidation (43% and 32%, respectively; p < 0.01), and they had significantly greater reduction of glutathione (2.5 times greater in both samples; p < 0.01). Exact values for samples obtained by endartherectomy were not reported. No adverse events were reported.

The main limitation of this study is that both groups were not treated equally. While there was a control group, there was no placebo, and the PJ group received many more interventions than the control group, including blood draws and carotid ultrasounds at 1, 3, 6, 9, and 12 months, whereas the control group only received these interventions at 1 year. The carotid lesion analysis introduced a new group of controls who appear not to have been part of the original study. Finally, analysis between groups was not performed for any of the outcomes, only analysis within group.

Rosenblat et al, 2006. An open label, control group comparison was conducted with 10 non-insulin dependent diabetic (NIDDM) males (ages 35–71 years old; mean 50 ± 10 years) and 10 healthy age-matched controls (non-smokers).10 The NIDDM subjects were non-smokers, did not have ischemic heart disease, had been diabetic for at least 4 years (up to 10 years), had a fasting serum glucose above 160 mg%, and a hemoglobin A1c ranging from 7.5 to 11.3%. Half had hypertriglyceridemia. All NIDDM subjects were treated with oral hypoglycemic drugs and 2 were treated with angiotensin II converting enzyme (ACE) inhibitors for hypertension. All subjects received 50 ml of POM Wonderful PJ concentrate per day for 3 months. The concentrated PJ was diluted 1:5 (v:v) with water to obtain a single strength juice equivalent to 8 ounces per day. The PJ was noted to contain 10% sugar and have a glycemic index “similar to that of other fruit juices.”

Pre- and post-PJ blood samples from the NIDDM subjects were analyzed for several parameters including glucose, HbA1c, cholesterol, triglycerides, antioxidant measures including lipid peroxides, cellular peroxides, glutathione levels, thiobarbituric acid reactive substances (TBARS), PON1 activity, and serum total sulfhydryl groups (SH groups in serum). Cellular uptake of oxidized LDL was also measured ex vivo.

PJ consumption did not affect serum glucose, cholesterol, and triglyceride levels. At baseline, serum lipid peroxides and TBARS levels were increased by 350% and 51%, respectively, in diabetic subjects compared to controls, whereas serum SH groups content and PON1 activity were both decreased by 23% compared to controls. After PJ consumption, lipid peroxides and TBARS levels were decreased by 56% and 28%, respectively, as compared to baseline in diabetic subjects. Total SH groups and PON1 activity were significantly increased by 12% and 24%, respectively. At baseline, patient versus control measures of HMDM found increased levels of cellular peroxides (by 36%) and decreased glutathione content (by 64%). After PJ consumption, there was a 71% decrease in cellular peroxides and a 141% increase in glutathione in the diabetic patients compared to baseline. Compared to controls at baseline, diabetic patients had a cellular uptake of oxidized LDL at an enhanced rate of 37%. After 3 months of PJ consumption, this was decreased by 39%.

Ischemic Coronary Heart Disease

Sumner et al, 2005. A randomized, placebo-controlled, double-blind study was conducted by researchers at the Preventive Medicine Research Institute, Sausalito, CA, and the California Pacific Medical Center and the School of Medicine, University of California, San Francisco.11 Forty-five patients (mean age 69 years) with stable coronary heart disease were recruited for the trial. Patients were confirmed to have stress-induced ischemia that was documented by ≥ 1 reversible myocardial perfusion defect on single-photon emission computed tomographic technetium-99m tetrofosmin scintigraphy. Patients were randomized to receive either 240 ml (8 ounces) per day of POM Wonderful PJ or a placebo drink (“modified sports beverage of similar caloric content, flavor, and color”) for 3 months.

At baseline and at 3 months, patients underwent radionucleotide exercise treadmill or pharmacologic (adenosine or dipyridamole) stress testing by gated, single-isotope myocardial perfusion with single-photon-emission computed tomography using a radiotracer. Beta blockers, ACE-inhibitors, calcium antagonists, and nitrates were withheld for 24 hours before stress testing. A semiquatitiative scoring method analyzed radiotracer uptake in 17 myocardial segments. Using a 5-point scoring system for each segment (ranging from 0 = normal uptake to 4 = absent uptake), a summed stress score and a summed rest score were calculated. A summed difference score (SDS) was calculated using the difference between summed stress and summed rest scores. The SDS is a measurement of inducible myocardial infarction and has been found to be predictive of myocardial infarction.

Three month testing data was available for 39 of the original 45 patients (2 dropouts in each group and 1 in each group who had unreadable perfusion tests). After 3 months of treatment, the extent of stress-induced ischemia decreased in the PJ group compared to baseline (SDS: – 0.8 ± 2.7) and increased in the placebo group (SDS: 1.2 ± 3.1); the difference between the 2 groups was significant (p < 0.05). There were no significant changes in summed stress or summed rest scores in the PJ group, while the placebo group had a significant increase in summed stress score (p < 0.05). The change in SDS in the PJ group was not accompanied by any changes in plasma lipids, blood glucose, hemoglobin A1c, body weight, or blood pressure. Angina episodes decreased by 50% in the PJ group (from 0.26 to 0.13) as compared to a 38% increase in the placebo group (0.53 to 0.75); this difference was not statistically significant. There were several reported cardiac adverse events during the study, but the authors did not attribute any of these events to the intervention, nor was an analysis done demonstrating whether the rate of events was different in the 2 groups.

Hypertension

Aviram and Dornfeld, 2001. A small open-label study was conducted with 10 hypertensive (mean blood pressure levels of 155 ± 7/83 ± 7 mm Hg) patients (7 males and 3 females, aged 62–77 years old).12 All patients were nonsmokers, 2 were diabetic, and 2 were hyperlipidemic. Eight patients were on ACE inhibitors (enalapril or ramipril) and 2 were on calcium channel blockers. It was not made clear whether or not the subjects continued their antihypertensive regiments during the study. Patients received 50 ml of POM Wonderful PJ concentrate per day for 2 weeks. The concentrated PJ was diluted 1:5 (v:v) with water to obtain a single strength juice equivalent to 8 ounces per day. Serum ACE was determined at baseline and after 2 weeks of PJ ingestion. Blood pressure was also measured at the end of 2 weeks.

After 2 weeks of PJ ingestion, 7 out of 10 patients had a mean decrease in serum ACE activity of 36% (significance is claimed but no statistical analysis is reported). Mean blood pressure levels were 147 ± 10/82 ± 5 mmHg—a small (5%) but significant (p < 0.05) decrease in systolic blood pressure. Adverse events were not reported.

Two significant factors confound the results of this trial: (1) 3 of the 10 subjects are not included in the analysis nor are they accounted for, and (2) it is unclear whether 8 patients continued their use of ACE inhibitor medication (the change in serum ACE levels was one of the primary endpoints).

Discussion

In summary, these 4 pilot studies show that PJ can demonstrate statistically significant improvements in intima-media thickness (IMT), end-diastolic volume, peak systolic velocity (PSV), systolic blood pressure, TBARS, lipid peroxides, serum ACE activity, summed stress and rest scores, and the number of angina episodes. No improvements were seen in lipids, glucose, or HbA1c. The clinical relevance of these improvements varies, but in general they can be taken to represent positive trends in overall improvement of cardiovascular risk.

ERECTILE DYSFUNCTION

Forest et al, 2007. A randomized, double-blind, placebo controlled crossover study of 61 subjects (21–70 years old) was performed at an erectile dysfunction (ED) clinic in Beverly Hills, CA.13 The rationale for the study was that the antioxidant properties of PJ would increase nitric oxide production, improve smooth muscle relaxation, and reduce atherosclerotic plaque, all of which can contribute to ED.

Seventy-four subjects with a history of ED for at least 3 months and who were in a monogamous heterosexual relationship were screened. Of those, 61 qualified and were enrolled. Subjects were excluded if they had a documented secondary cause of ED. The primary outcome was Global Assessment Questionnaire (GAQ), which represents the subject self-evaluation of the study beverage effect on erectile activity. The secondary outcome was the International Index of Erectile Function (IIEF) questionnaire, which evaluates intercourse satisfaction, overall satisfaction, orgasm, and desire. The study design incorporated a screening period during which any prescription, nonprescription (over-the-counter), or dietary supplement ED therapies were discontinued. The first arm of the crossover was 28 days, followed by a 2-week washout, and then the second 28-day arm. The group was split into 2 cohorts whose baseline characteristics were similar. Subjects consumed 8 ounces of POM Wonderful PJ with their evening meal.

Fifty-three of the 61 subjects completed the study. Seven were lost to follow-up and one subject was discontinued “for reasons not related to the study.” No serious adverse events were noted and no subjects discontinued due to adverse events. The results of the GAQ showed that a total of 42 subjects attributed an improvement in erectile activity to drinking the beverage, and of those 25 were attributed to the PJ beverage. Subjects were more likely to report an improvement in GAQ score while drinking the PJ beverage, and the difference between beverages approached statistical significance (p = 0.058). There was a sizable difference between cohorts in their response rates. There was no difference in the secondary endpoint within any domains on the IIEF.

While generally well designed, the authors admit that a sexual encounter diary would have been helpful since the GAQ and IIEF were administered only at the end of each crossover arm (28 days), which may limit the interpretation of the efficacy (or lack thereof) of the study product. In addition, the significant between-cohort differences may point to a sequence effect indicating that the washout period between arms may not have been long enough.