Literature Review and Commentary

By Alan R. Gaby, MD

Does Skipping Breakfast Promote Heart Disease?

The association between skipping breakfast and cardiovascular and all-cause mortality was examined in a prospective cohort study of a nationally representative sample of 6,550 US adults (mean age 53 years) participating in the National Health and Nutrition Examination Survey III (1988 to 1994). During 112,148 person-years of follow-up, 2,318 deaths occurred, including 619 from cardiovascular disease. After adjustment for age, sex, race/ethnicity, socioeconomic status, dietary and lifestyle factors, body mass index, and cardiovascular risk factors, participants who never consumed breakfast, as compared with those who consumed breakfast every day, had hazard ratios of 1.87 (95% confidence interval [CI], 1.14 -3.04) for cardiovascular mortality and 1.19 (95% CI, 0.99-1.42) for all-cause mortality.

Comment: In this study, skipping breakfast was associated with a significantly increased risk of mortality from cardiovascular disease and from all causes. Although observational studies cannot prove causation, the possibility that skipping breakfast promotes the development of cardiovascular disease is biologically plausible. Skipping breakfast would presumably put downward pressure on morning blood glucose levels, forcing the body to secrete more epinephrine and cortisol in order to prevent hypoglycemia. Both of these hormones appear to have adverse effects on the cardiovascular system. In addition, breakfast skippers may eat relatively large meals later in the day, potentially resulting in periods of hyperinsulinemia, which itself may be atherogenic. In a previous randomized controlled trial, skipping breakfast was found to increase insulin resistance,¹ which is another risk factor for heart disease.

Rong S, et al. Association of skipping breakfast with cardiovascular and all-cause mortality. J Am Coll Cardiol. 2019;73:2025-2032.

Plant-Based, Raw-Food Diet Improves Heart Failure

Three patients with heart failure received conventional therapy and also consumed a plant-based diet, consisting of raw fruits, vegetables, avocado, seeds, and small amounts of raw oats and buckwheat. Patients were advised to eliminate all animal products, cooked foods, free oils, soft drinks, alcohol, and coffee. The diet was followed for 53 to 95 days (mean, 79 days). Mean left ventricular ejection fraction increased from 22% at baseline to 42.2% at follow-up. Mean left ventricular mass decreased by 21%, mean stroke volume increased by 62%, and mean cardiac output increased by 17%. One of the patients had had a 90-95% ostial stenosis of the left anterior descending artery, which almost completely regressed. All patients reported subjective improvements, including a reduction in angina, less shortness of breath, and less fatigue. The authors stated that such dramatic and rapid improvements in heart morphology and function would be highly improbable with conventional treatment alone.

Comment: Plant-based diets are known to improve serum lipid concentrations, reduce blood pressure, decrease inflammation and, as part of a lifestyle intervention, lead to the regression of atherosclerotic lesions. However, there has been little research on the use of plant-based diets in patients with heart failure. These case reports are encouraging and warrant larger, controlled trials. If plant-based, raw-food diets are beneficial for patients with heart failure, they may work by decreasing inflammation (heart failure has a significant inflammatory component) and by providing abundant amounts of cardioprotective nutrients such as magnesium, potassium, flavonoids, vitamin C, and essential fatty acids.

Najjar RS, Montgomery BD. A defined, plant-based diet as a potential therapeutic approach in the treatment of heart failure: A clinical case series. Complement Ther Med. 2019;45:211-214.

Vitamin K and Arterial Calcification

Sixty-eight patients (mean age, 69 years) with type 2 diabetes and cardiovascular disease were randomly assigned to receive, in double-blind fashion, 360 µg per day of menaquinone-7 (MK-7; a form of vitamin K₂) or placebo for six months. Calcification of the femoral artery was assessed at baseline and after six months by two different methods: ¹⁸sodium fluoride positron emission tomography (¹⁸F-NaF PET) and computed tomography (CT). After six months, compared with placebo, MK-7 nonsignificantly increased arterial calcification by both assessment methods (p = 0.06 with ¹⁸F-NaF PET and p = 0.18 with CT).

Comment: Arterial calcification is an independent risk factor for myocardial infarction and stroke. Matrix Gla protein (MGP) is a vitamin K-dependent protein that inhibits vascular calcification. Some studies have suggested that vitamin K is a cardioprotective nutrient, but the research is conflicting. In a previous trial, supplementation with 500 µg per day of vitamin K₁ (the form of vitamin K found in plants) slowed the progression of coronary artery calcification in elderly volunteers.² In contrast, the present study found that MK-7 (which is found in cheese, butter, egg yolks, meats, and natto [fermented soybeans]) did not prevent arterial calcification, and may even have made it worse. The findings from these two trials conflict with those of an observational study, in which higher vitamin K₂ intake was associated with a lower risk of cardiovascular mortality, whereas no association was found between vitamin K₁ intake and cardiovascular mortality.³ Thus, the effect of vitamin K on cardiovascular disease risk remains unclear.

In recent years, many practitioners have been recommending large doses of vitamin D (such as 5,000 IU per day or more) for various purposes. I have pointed out in the Townsend Letter and elsewhere that high-dose vitamin D has not been shown to be more effective than moderate doses. Furthermore, large doses of vitamin D caused atherosclerosis in experimental animals. Proponents of high-dose vitamin D argue that vitamin K can prevent the potential adverse effects of vitamin D on the cardiovascular system. As far as I am aware, there is no clinical evidence to support that argument. Moreover, atherosclerosis and arterial calcification are separate (though possibly related) pathological processes. The present study underscores the point that vitamin K may not be effective for preventing the side effects of high-dose vitamin D.

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 Aug 6 [Epub ahead of print].

Serenoa repens (Saw Palmetto) for Benign Prostate Hyperplasia

A meta-analysis was conducted on 15 randomized controlled trials and 12 observational studies (including a total of 5,800 patients) that examined the effect of an extract of saw palmetto berries (Serenoa repens) (Permixon; Pierre Fabre Medicament, Castres, France) at a dose of 320 mg per day on lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). Articles studying Serenoa repens extracts other than Permixon were excluded. Compared with placebo, Permixon was associated with a mean of 0.64 fewer voids at night (p < 0.001) and a mean increase in maximum urinary flow rate (Qmax) of 2.75 ml per second (p = 0.01). When compared with alpha-blockers, Permixon showed similar improvements in the International Prostate Symptom Score (IPSS) and in Qmax. After six months of treatment, efficacy (as determined by IPSS) was similar between Permixon and 5-alpha-reductase inhibitors. Prostate volume decreased slightly with Permixon. The treatment did not adversely affect sexual function and was generally well tolerated, with gastrointestinal symptoms being the most frequent adverse effect (mean incidence, 3.8%).

Comment: Extracts of Serenoa repens inhibit the enzyme 5-alpha-reductase and also have anti-androgenic and anti-inflammatory effects. Each of these actions would be expected to be beneficial in the treatment of LUTS/BPH. The results of the present meta-analysis provide strong evidence that at least one of the many commercially available Serenoa repens products is effective. Current American Urological Association practice guidelines state that there is not sufficient evidence to recommend Serenoa repens as a treatment for BPH. This conclusion may have resulted in part from the negative results in some studies. For example, a 2011 study published in the Journal of the American Medical Association found that an extract of Serenoa repens (Prosta-Urgenin Uno; Rottapharm/Madaus, Cologne, Germany) did not improve symptoms of BPH.⁴ In other research, different Serenoa repens products were found to differ in their physiological effects. Therefore, some Serenoa repens products may be more effective than others.

Vela-Navarrete R, et al. Efficacy and safety of a hexanic extract of Serenoa repens (Permixon®) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies. BJU Int. 2018;122:1049-1065.

Sambucus nigra (Black Elderberry) for Influenza and Colds

A meta-analysis was conducted on four randomized controlled trials (including a total of 180 participants) that examined the effect of Sambucus nigra (black elderberry) on cold or flu symptoms. In the pooled analysis, Sambucus nigra significantly reduced upper respiratory symptoms (p < 0.001), with a large effect size.

Comment: Sambucus nigra has been used traditionally to treat cold and flu symptoms, but there have been no large-scale studies examining its effectiveness. The results of this meta-analysis indicate that Sambucus nigra is indeed an effective treatment for colds and influenza. It may work in part by exerting a direct antiviral effect. In test-tube studies, extracts of Sambucus nigra inhibited the replication of influenza virus types A and B and decreased the infectivity of human influenza virus H1N1.⁵

Hawkins J, et al. Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials. Complement Ther Med. 2019;42:361-365.

Selenium for Cancer-Related Lymphedema

Twenty-six women who had undergone surgery for breast cancer up to three years previously, most of whom had received chemotherapy, radiation therapy, or both, were randomly assigned to receive, in double-blind fashion, five intravenous infusions of selenium (500 µg in each infusion, as sodium selenite) or placebo (0.9% saline) over a two-week period. All patients were taught manual lymphatic drainage. The severity of lymphedema was assessed before and at the end of selenium treatment, and one month after the end of treatment. At the end of treatment, as compared with before selenium treatment, 75% of women receiving selenium were improved, whereas there was no change in the placebo group. At follow-up one month later, the proportion of women who had improved from stage III to stage II was 83.3% in the selenium group and 10% in the placebo group (p = 0.002).

Comment: In this study, short-term intravenous administration of selenium decreased the severity of breast cancer-related lymphedema, and the benefit persisted for at least 1 month after the treatment was discontinued. Previous studies found that selenium, given orally or intravenously, decreased the severity of chronic lymphedema resulting from radiation therapy, and accelerated the improvement of acute lymphedema following surgery and lymph node removal for cancer of the oral cavity.⁶ The mechanism of action of selenium is not known.

Han HW, et al. Sodium selenite alleviates breast cancer-related lymphedema independent of antioxidant defense system. Nutrients. 2019;11:E1021.

Curcumin Enhances the Effect of Chemotherapy in Patients with Colorectal Cancer

In a phase IIa trial, 28 patients (mean age, 68 years) with metastatic colorectal cancer were treated with folinic acid/5-fluorouracil/oxaliplatin chemotherapy (FOLFOX) and were randomly assigned in a 2:1 ratio to receive or not to receive (control group) 2 g per day of curcumin. Curcumin was found to be safe and tolerable (the primary outcome), with similar adverse events occurring in both groups. Median progression-free survival time was 291 days in the curcumin group and 171 days in the control group (hazard ratio for progression-free survival = 0.57; p = 0.2). Median overall survival time was 596 days (range, 323 days to still alive [13 of 18 still alive]) in the curcumin group and 200 days (range, 9-563 days; 9 of 9 dead) in the control group (hazard ratio for overall survival = 0.27; p = 0.004). Note: The numbers for overall survival were taken from the text, which differed from the numbers in the abstract.

Comment: Curcumin is a compound found in the spice, turmeric. Curcumin has demonstrated anticancer effects in vitro and in animal studies; and preliminary evidence suggests that it may be useful for preventing or treating certain types of cancer in humans. In the present study, curcumin was safe when used in combination with chemotherapy in patients with metastatic colorectal cancer, and it appeared to increase survival times.

Howells LM, et al. Curcumin combined with FOLFOX chemotherapy Is safe and tolerable in patients with metastatic colorectal cancer in a randomized phase IIa trial. J Nutr. 2019;149:1133-1139.

Eggs and Cardiovascular Disease

The association between dietary cholesterol or egg consumption and cardiovascular disease (CVD) and all-cause mortality was examined by pooling individual participant data from six prospective US cohorts. These cohorts included a total of 29,615 participants whose mean age at baseline was 51.6 years. During a median follow-up period of 17.5 years, there were 5,400 CVD events (a composite of fatal and nonfatal coronary heart disease, stroke, heart failure, and other CVD deaths) and 6,132 all-cause deaths. Each additional 300 mg of dietary cholesterol consumed per day was significantly associated with a higher risk of incident CVD (adjusted hazard ratio [HR] = 1.17) and all-cause mortality (adjusted HR = 1.18). Each additional half an egg consumed per day was significantly associated with a higher risk of incident CVD (adjusted HR = 1.06) and all-cause mortality (adjusted HR = 1.08).

Comment: In this study, higher consumption of cholesterol or eggs was associated with a higher risk of CVD and all-cause mortality in a dose-dependent manner. However, the study did not consider the possibility that the effect of dietary cholesterol and eggs on CVD risk depends on the way in which these foods are cooked. Research in animals has shown that feeding pure cholesterol does not cause atherosclerosis, whereas oxidized cholesterol in food is highly atherogenic.⁷ Cholesterol is an unstable molecule, and the cholesterol in food is susceptible to spontaneous oxidation, even in room air. The extent to which cholesterol in food becomes oxidized (and, by implication, the atherogenicity of the food) presumably varies with different cooking and storage methods. For example, 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 shielded from room air and might therefore be less susceptible to oxidation and less atherogenic. Similarly, butter left exposed to room air might be more atherogenic than butter kept covered and refrigerated.

Zhong VW, et al. Associations of dietary cholesterol or egg consumption with incident cardiovascular disease and mortality. JAMA. 2019;321:1081-1095.