Alan R. Gaby, MD
Hesperidin for Hypertension?
One hundred fifty-nine Spanish adults (aged 18-65 years) with pre-hypertension or stage 1 hypertension were randomly assigned to receive, in double-blind fashion, 500 ml per day of orange juice (containing 345 mg of hesperidin), orange juice enriched with additional hesperidin (total, 600 mg per day), or a hesperidin-free control drink (contents not specified). At 2, 6, 10, and 12 weeks, compared with the control drink, mean systolic blood pressure was significantly lower with high-dose hesperidin and nonsignificantly lower with low-dose hesperidin. At all time-points, high-dose hesperidin was nonsignificantly more effective than low-dose hesperidin for decreasing systolic blood pressure.
Comment: Hesperidin is a flavonoid found mainly in oranges and other citrus fruits. In a previous double-blind trial, administration of 292 mg per day of hesperidin to overweight middle-aged and elderly men decreased mean diastolic blood pressure by 3.2 mm Hg compared with placebo (p < 0.05).[1] The results of the present study are also consistent with a modest antihypertensive effect of hesperidin, although the findings are not definitive. One possible interpretation of the results is that hesperidin has a dose-dependent blood pressure lowering effect, since the higher dose was more effective than the lower dose. However, another possible interpretation is that low-dose hesperidin was of little or no benefit (since the effect was not statistically significant), and that the greater effect with the higher dose was due at least in part to other components of orange juice (such as potassium and vitamin C).
Hesperidin is safe and inexpensive, so if a patient wishes to supplement with it as part of a comprehensive program to treat hypertension, I see no reason to discourage it. If hesperidin does not lower blood pressure, the patient will at least have stronger capillaries,[2] which may provide partial protection against some of the adverse effects of hypertension.
Valls RM, et al. Effects of hesperidin in orange juice on blood and pulse pressures in mildly hypertensive individuals: a randomized controlled trial (Citrus study). Eur J Nutr. 2021;60:1277-1288.
Do Omega-3 Fatty Acids Cause Atrial Fibrillation?
In this editorial, the author discussed four randomized trials conducted in the past four years that examined the effect of omega-3 fatty acids on risk of atrial fibrillation. The primary outcome in these trials was the incidence of a composite of cardiovascular endpoints or the incidence of cancer. The risk of atrial fibrillation was a secondary endpoint or the data were derived from an ancillary study of the original trial. Considered together, these trials suggest there may be a dose-related increase in risk of atrial fibrillation with omega-3 fatty acid intake.
At a dose of 4 g per day, there was a highly significant increase in risk (nearly double). With an intermediate dose (1.8 g per day), there was an 84% increase in risk, which was of borderline statistical significance (p = 0.06). With a standard dose (840 mg per day, equivalent to about 2.8 g per day of fish oil), there was a nonsignificant 9% increase in risk.
Comment: This review of the evidence suggests that treatment with large doses of omega-3 fatty acids can increase the risk of developing atrial fibrillation. However, there is no clear evidence that there is an increased risk from the moderate doses of fish oil that are used by many people for cardiovascular disease prevention. High doses of fish oil or of eicosapentaenoic acid (EPA) are used in some cases to treat conditions such as rheumatoid arthritis, bipolar disorder, and hypertriglyceridemia. For patients with these conditions, the potential risk of atrial fibrillation should be balanced against the potential benefit of the treatment. For example, it may not be a good idea to recommend high-dose omega-3 fatty acids for people with certain risk factors for atrial fibrillation, such as excessive alcohol consumption, sleep apnea, or diabetes.
The studies described above pertain to fish oil and to the fatty acids present in fish oil (EPA and docosahexaenoic acid [DHA]). These studies do not imply that consumption of large amounts of alpha-linolenic acid (the omega-3 fatty acid present in plant foods) would have the same adverse effect as EPA and DHA. That is because humans have a limited capacity to convert alpha-linolenic acid to EPA and DHA.
Curfman G. Omega-3 fatty acids and atrial fibrillation. JAMA. 2021;325:1073.
Can Diet Help Prevent Heart Failure?
The association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet pattern and risk of developing heart failure was examined in a prospective cohort study of 18,856 US adults (mean age, 64 years) participating in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who were free of suspected heart failure at baseline. The DASH diet score was calculated as the sum of eight component scores, as determined from a food-frequency questionnaire that assessed intakes of 1) fruits, 2) vegetables, 3) nuts and legumes, 4) low-fat dairy products, 5) whole grains, 6) sodium, 7) sweetened beverages, and 8) red and processed meats. For components 1 to 5, participants received a score of 5 if they were in the highest quintile and a score of 1 if they were in the lowest quintile. For components 6 to 8, participants received a score of 1 if they were in the highest quintile and a score of 5 if they were in the lowest quintile. The final DASH diet score ranged from 8 to 40, with 8 indicating the lowest adherence to the DASH diet and 40 indicating the highest adherence.
Each participant was categorized into a quartile based on their score. During a median follow-up period of 10.1 years, compared with the lowest quartile of DASH diet score, individuals in the second to fourth quartiles had a lower risk for incident heart failure after adjustment for sociodemographic and health characteristics: quartile 2: hazard ratio [HR] = 0.69 (95% confidence interval [CI], 0.56-0.85); quartile 3: HR = 0.71 (95% CI, 0.58-0.87); and quartile 4: HR = 0.73 (95% CI, 0.58-0.92). However, there was no association between DASH diet score and risk of heart failure among participants aged 75 years or older at baseline.
Comment: The DASH diet was designed to provide abundant amounts of nutrients that play a role in blood pressure regulation, such as potassium, calcium, magnesium, vitamin C, and essential fatty acids. The diet is rich in fruits, vegetables, and low-fat dairy products; contains moderate amounts of nuts, seeds, and legumes; and is relatively low in saturated fat, total fat, and refined sugar. Randomized trials have found that adherence to this diet can lower both systolic and diastolic blood pressure in people with hypertension. The original DASH diet did not restrict sodium intake, but later research found that a sodium-restricted DASH diet was more effective than the original DASH diet for lowering blood pressure.
The results of the present study found that adherence to the DASH diet was associated with a reduced risk of developing heart failure among individuals younger than 75. Some of this reduced risk may be attributable to better blood pressure control. In addition, nutrients such as magnesium, potassium, and vitamin C may have a positive effect on myocardial function, independent of any effect they have on blood pressure.
Goyal P, et al. The Dietary Approaches to Stop Hypertension (DASH) diet pattern and incident heart failure. J Card Fail. 2021;27:512-521.
Vitamin K and Arterial Calcification
Forty-eight patients with chronic renal failure who were receiving maintenance dialysis were randomly assigned to receive, in double-blind fashion, 360 µg per day of menaquinone-7 (a form of vitamin K2) or placebo for two years. Thirty-seven patients completed year 1, and 21 completed year 2. Vitamin K status improved in the group assigned to receive vitamin K. The mean degree of coronary artery calcification increased in both groups. There was a nonsignificant trend toward greater increases in calcification in the vitamin K group than in the placebo group.
Comment: Arterial calcification is associated with an increased risk of cardiovascular disease-related mortality both in people with and without renal failure. Vitamin K is a cofactor for matrix Gla protein, which is an inhibitor of arterial calcification. Dialysis patients have accelerated vascular calcification and also tend to have low vitamin K status. It has therefore been suggested that vitamin K supplementation could decrease arterial calcification in people with end-stage renal disease. However, in the present study, vitamin K was not effective for that purpose, and it may have even accelerated arterial calcification. Similar findings were reported in an earlier study of patients with type 2 diabetes and cardiovascular disease. In that study, supplementation with 360 µg per day of menaquinone-7 for six months nonsignificantly increased calcification of the femoral artery compared with placebo.[3]
It is not clear why vitamin K was not beneficial in these studies. However, the results should remind us that we cannot always make assumptions about clinical efficacy from what we know about biochemistry.
Levy-Schousboe K, et al. Vitamin K supplementation and arterial calcification in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial. Clin Kidney J. 2021;14:2114-2123.
Magnesium and Heart Failure
Mice were fed for six weeks a diet that contained a normal amount of magnesium (600 mg per kg of diet) or a low-magnesium diet (15-30 mg per kg). The low-magnesium diet resulted in diastolic dysfunction (impaired cardiac relaxation), decreased left ventricular ejection fraction, and decreased myocardial ATP concentrations. All of these changes were reversed when the mice were fed a normal-magnesium diet for six weeks.
Comment: In this study, magnesium deficiency caused a reversible cardiomyopathy in mice. Magnesium deficiency is common in patients with heart failure. Factors that predispose to magnesium deficiency in these patients include anorexia, malabsorption secondary to bowel wall edema, and the use of magnesium-depleting drugs such as furosemide. Even when serum magnesium concentrations are normal, some heart failure patients have low magnesium levels in their heart tissue,[4] apparently because the diseased myocardium has an impaired capacity to take up magnesium against a concentration gradient. In my experience and according to uncontrolled trials, intravenous or intramuscular administration of magnesium often produces substantial clinical improvement in patients with heart failure. Oral magnesium supplementation is much less effective, presumably because oral administration does not raise serum magnesium levels enough to allow the diseased myocardium to extract magnesium from the serum.
Liu M, et al. Magnesium deficiency causes a reversible metabolic, diastolic cardiomyopathy. J Am Heart Assoc. 2021;10:e020205.
Serious Side Effects from a Nutritional Supplement
An 81-year-old woman presented with pancytopenia (anemia, leukopenia/neutropenia, and thrombocytopenia). The serum zinc level was elevated (168 µg/dl; normal range, 60-130 µg/dl) and serum copper was very low (10 µ/L; normal range, 810-1,990 µ/L). The woman had been taking a multivitamin-multimineral (MVM) product for many years for the treatment of age-related macular degeneration. The product provided daily a relatively large amount of zinc (80 mg) and 2 mg of copper. The patient was advised to discontinue the MVM and she was started on 8 mg per day of copper. Within two weeks, white blood cell, neutrophil, and platelet counts became normal and the anemia improved markedly.
Comment: Zinc is known to inhibit copper absorption, and long-term use of large doses of zinc can cause copper deficiency. Reported manifestations of zinc-induced copper deficiency include anemia, neutropenia, and myelopathy (thrombocytopenia is uncommon). This case report did not mention the name of the MVM the patient was taking. One can assume it was PreserVision (marketed by Bausch and Lomb) or a similar product that contains the formula used in the Age-Related Eye Disease Study (i.e., the AREDS or AREDS 2 formula). PreserVision provides 80 mg per day of zinc and 2 mg of copper, which was the amount this patient was taking.
Unfortunately, the copper in PreserVision is in the form of cupric oxide. Animal studies have shown that the bioavailability of orally administered cupric oxide “is not significantly different from zero,”[5] and it has been argued that cupric oxide should not be used as a copper supplement for either animals or humans. Zinc-induced copper deficiency can be prevented by supplementing with an adequate amount of copper, but a copper supplement that cannot be absorbed is likely to be ineffective.
Wahab A, et al. Zinc-induced hypocupremia and pancytopenia, from zinc supplementation to its toxicity, a case report. J Community Hosp Intern Med Perspect. 2021;11:843-846.
Eggs and Cardiovascular Disease
A meta-analysis was conducted on 23 prospective studies, including a total of 1,415,839 participants, that examined the association between egg consumption and cardiovascular disease events. During a median follow-up period of 12.3 years, 157,324 cardiovascular disease events were documented. Compared with consumption of one egg per day or less, consumption of more than one per day was not associated with an increased risk of overall cardiovascular disease events (pooled hazard ratio = 0.99; 95% confidence interval [CI], 0.93-1.06). Higher egg consumption (more than 1 per day) was associated with a significantly decreased risk of coronary artery disease (pooled hazard ratio = 0.89; 95% CI, 0.86-0.93; p < 0.001), compared with consumption of one egg per day or less.
Comment: It has been suggested for many years that eating eggs can cause heart disease, because of the large amount of cholesterol present in egg yolks. In the present study, higher consumption of eggs was not associated with an increased risk of overall cardiovascular disease events, and was associated with a significant decrease in the incidence of coronary artery disease. These results conflict with a previous observational study, in which higher egg intake was associated with a modest but statistically significant increase in cardiovascular disease risk.[6]
It is difficult to draw conclusions from these conflicting studies, particularly since observational studies cannot prove causation. As I have noted before, the effect of egg consumption on cardiovascular disease risk might depend in large part on how the eggs are cooked. Cholesterol is an unstable molecule, and the cholesterol in food is susceptible to spontaneous oxidation, even in room air. Research in animals has shown that feeding pure cholesterol does not cause atherosclerosis, whereas oxidized cholesterol is highly atherogenic.
Breaking the yolk of an egg during cooking exposes the cholesterol to high temperatures and oxygen (room air), which might accelerate the formation of cholesterol oxides. In contrast, the cholesterol in boiled or poached eggs, or fried eggs with an intact yolk, would be largely shielded from room air and might therefore be less susceptible to oxidation and less atherogenic. Future studies should examine whether the association between egg consumption and cardiovascular disease differs according to how the eggs are cooked.
Krittanawong C, et al. Association between egg consumption and risk of cardiovascular outcomes: a systematic review and meta-analysis. Am J Med. 2021;134:76-83.e2.
Oxygen Therapy for Acute Myocardial Infarction
Patients (n = 6,629) with a suspected acute myocardial infarction (MI), with oxygen saturation of 90% or higher were randomly assigned to receive supplemental oxygen (6 liters per minute for 6 to 12 hours, delivered through an open face mask) or room air. If it was deemed clinically necessary, particularly in cases of hypoxemia (oxygen saturation < 90%) caused by circulatory or respiratory failure, supplemental oxygen outside the protocol was provided. The primary endpoint of death from any cause within one year after randomization occurred in 5.0% of patients assigned to oxygen therapy and 5.1% of patients assigned to room air (p = 0.80). Re-hospitalization within one year for MI occurred in 3.8% of patients assigned to oxygen and 3.3% of those assigned to room air (p = 0.33). In the subgroup of patients with a confirmed MI, oxygen therapy had no significant effect on the composite endpoint of all-cause mortality, re-hospitalization for MI, or heart failure during long-term follow-up.
Comment: For more than a century, supplemental oxygen was used routinely in the treatment of suspected acute MI, and this treatment has been recommended in clinical guidelines (based on expert opinion). The rationale for using supplemental oxygen was to increase the oxygen supply to the ischemic myocardium and thereby limit infarct size and subsequent complications. However, above-normal oxygen concentrations in the blood can cause coronary vasoconstriction and increase the production of oxygen-derived free radicals, potentially contributing to reperfusion injury. A Cochrane review from 2016 did not show any evidence supporting the routine use of oxygen in patients with acute MI. Based on the results of the present study, clinical guidelines no longer recommend routine oxygen therapy in patients with acute MI who have normal oxygen saturation.
This is one of many examples of treatments that were considered “standard of care” in mainstream medicine, but ultimately turned out to be ineffective. Because of its own weaknesses, mainstream medicine is not in a position to criticize “alternative” medicine as being non-evidence based.
Alfredsson J, et al. Randomized comparison of early supplemental oxygen versus ambient air in patients with confirmed myocardial infarction: outcomes from DETO2X-AMI Sex-related. Am Heart J. 2021;237:13–24.
Hofmann R, et al. Oxygen therapy in suspected acute myocardial infarction. N Engl J Med. 2017;377:1240-1249.
This column was first published in Townsend Letter (June 2022).
1. Morand C, et al. Hesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteers. Am J Clin Nutr. 2011;93:73-80.
2. Griffith JQ Jr, Lindauer MA. Increased capillary fragility in hypertension: incidence, complications, and treatment. Am Heart J. 1944;28:758-762.
3. Zwakenberg SR, et al. The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2019;110:883-890.
4. Frustaci A, et al. Myocardial magnesium content, histology, and antiarrhythmic response to magnesium infusion. Lancet 1987;2:1019.
5. Baker DH. Cupric oxide should not be used as a copper supplement for either animals or humans. J Nutr. 1999;129:2278-2279.
6. Zhong VW, et al. Associations of dietary cholesterol or egg consumption with incident cardiovascular disease and mortality. JAMA. 2019;321:1081-1095.
Published June 29, 2024
About the Author
Alan R. Gaby, MD, is the author of the textbook, Nutritional Medicine, which is now in its third edition (doctorgaby.com). He received his undergraduate degree from Yale University, his M.S. in biochemistry from Emory University, and his M.D. from the University of Maryland. He was in private practice for 19 years, specializing in nutritional medicine. Over the past 43 years, Dr. Gaby has developed a computerized database of more than 29,000 individually chosen medical journal articles related to the field of natural medicine. He was professor of nutrition and a member of the clinical faculty at Bastyr University in Kenmore, Washington, from 1995 to 2002.
He is past president of the American Holistic Medical Association and gave expert testimony to the White House Commission on Complementary and Alternative Medicine on the cost-effectiveness of nutritional supplements. He is the author of Preventing and Reversing Osteoporosis (Prima, 1994), The Doctor’s Guide to Vitamin B6 (Rodale Press, 1984), and co-author of The Patient’s Book of Natural Healing (Prima, 1999). He was Chief Science Editor for Aisle 7 (formerly Healthnotes, Inc.) and has appeared on the CBS Evening News and the Donahue Show.