Cardioprotective Effect of Nutraceuticals - Indian National Science ...

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Proc Indian Natn Sci Acad 79 No. 4 December 2013, Spl. Issue, Part B, pp. 985-996 Printed in India.

Review Article

Cardioprotective Effect of Nutraceuticals — The Emerging Evidences M CHOUDHARY* and V TOMER* *Department of Food and Nutrition, College of Home Science, Punjab Agricultural University, Ludhiana 141 004, India (Received 01 May 2013; Revised 03 October 2013; Accepted 17 October 2013) Nutraceuticals are medicinal foods that play a role in maintaining well being, enhancing health, modulating immunity and thereby preventing as well as treating specific diseases. Thus the field of nutraceuticals can be envisioned as one of the missing blocks in the health benefit of an individual. More than any other disease, the etiology of cardiovascular disease reveals many risk factors that are amenable to nutraceutical intervention. Nutraceuticals hold promise in clinical therapy as they have the potential to significantly reduce the risk of side effects associated with chemotherapy along with reducing the global health care cost. In whole, nutraceutical has led to the new era of medicine and health, in which the food industry has become a research oriented sector. In this review, an attempt has been made to summarize some of the recent research findings on nutraceuticals that have beneficial effects on the heart and have cardioprotective effects. Key Words: Cardiovascular Diseases; Plant Fibers; Omega-3 Fatty Acids; Soy Protein

1. Introduction Nutrition is a fundamental need. Various risk factors related to health result from an imbalance in nutrition (Kota et al. 2013). Together, these factors contribute to more than 40 percent of deaths and 30 percent of the overall disease burden in developing countries. The nature of India’s nutrition concerns are three folds — on one hand is the undernourished population (380 million) with majority having inadequate purchasing power to even consume a diet sufficient in calories, let alone take sufficient nutrients (Ramaraj and Chellappa 2008). On the other hand is the huge population (570 million) that is nourished in calorie intake but not in terms of nutrient intake. This segment would typically include lower middle to upper class population with sufficient purchasing power but probably low awareness about their nutrient requirements, leading to unmet condition specific needs in addition to foundation needs. In fact, there are 340 million in our population (30% in urban

and 34% in rural areas) who consume more than recommended number of calories with higher than recommended levels of dietary fats and could be the largest contributor in making India the future cardiovascular and diabetes capital of the world (Vaidya and Devasagayam 2007). The third population segment (80 million) is one which consumes nutrients and calories more than the norm due to their enhanced physical requirement because of their chosen lifestyles and interest areas (Misra and Khurana 2008, Van Gaal et al. 2006). Many of the factors affecting nutrition related concerns are irreversible that have led to natural sources of nutrients being consumed in insufficient quantities. Hence, the requirement of external intervention, that can supplement diet to help prevent nutrition-related disorders and promote wellness over treatment of illness, has become critical. Such products are collectively called as “nutraceuticals” (Rajasekaran et al. 2008). With the ever increasing

*Authors for Correspondence: E-mail: [email protected], [email protected]

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epidemic of obesity, diabetes and hypertension among young adults, the risk of mortality and morbidity due to cardiovascular disease is gradually increasing. Nutraceutical supplements can provide valid alternate to patients who are intolerant to statins or patients preferring alternative treatments (Ramaraj and Chellappa 2008, Misra and Khurana 2008). The combination of a lipid lowering diet and scientifically proven nutraceutical supplements can significantly reduce low density lipoprotein (LDL) cholesterol, increase LDL particle size, decreased LDL particle number decreased triglycerides and increased high density lipoprotein (HDL) particles. In addition, they address lipid induced vascular damage by suppressing inflammation, oxidative stress and immune response leading to additional anti-hypertension, anti-diabetic properties (Kota et al. 2013). So, the present article is an attempt to review the evidence in support of different nutraceuticals and their cardioprotective effects. 2. Current Scenario of Cardiovascular Diseases Cardiovascular disease (CVD) due to atherosclerosis is the leading cause of morbidity and mortality all over the world. According to World Health Organization, an estimated 17.3 million people died from CVDs in 2008, representing 30 percent of all global deaths. Of these deaths, an estimated 7.3 million were due to coronary heart disease and 6.2 million were due to stroke. Over 80 percent of CVD deaths take place in low- and middle-income countries. It is projected that almost 23.6 million people will die from CVDs by 2030 (WHO 2012). Cardiovascular diseases have assumed epidemic proportions in India as well. Rapid westernization in India has ignited a rapid escalation of lifestyle related diseases, making the country the global capital for diabetes and heart disease. The Global Burden of Diseases (GBD) study reported the estimated mortality from coronary heart disease (CHD) in India at 1.6 million in the year 2000. A total of nearly 64 million cases of CVD are likely in the year 2015, of which nearly 61 million would be CHD cases (the remaining would include stroke, rheumatic heart disease and congenital heart diseases). Deaths from

this group of diseases are likely to amount to be a staggering 3.4 million. Coronary heart disease is more prevalent in Indian urban populations and there is a clear declining gradient in its prevalence from semi-urban to rural populations. Epidemiological studies show a sizeable burden of CHD in adult rural (3-5%) and urban (7-10%) populations. Thus, of the 30 million patients with CHD in India, there would be 14 million of them are in urban and 16 million in rural areas. In India about 50 per cent of CHD-related deaths occur in people younger than 70 years compared with only 22 per cent in the West. Extrapolation of these numbers estimates the burden of CHD in India to be more than 32 million patients (Shah and Mathur 2010). 3. Nutraceuticals About 2000 years ago, Hippocrates correctly emphasized “Let food be your medicine and medicine be your food”. Currently there is an increased global interest due to the recognition that “nutraceuticals” play a major role in health enhancement. The term “Nutraceutical” was coined by combining the terms “Nutrition” and “Pharmaceutical” in 1989 by Dr Stephen DeFelice, Chairman of the Foundation for Innovation in Medicine (Ghodake et al. 2011) “Nutraceutical” is a marketing term developed for nutritional supplement that is sold with the intent to treat or prevent disease and thus has no regulatory definition (Brower 1998). Hence a “nutraceutical” is any substance that may be considered a food or part of a food and provides medical or health benefits, encompassing, prevention and treatment of diseases. Such products may range from isolated nutrients, dietary supplements and diets to genetically engineered “designer” foods, herbal products and processed foods such as cereals, soups and beverages. Presently over 470 nutraceutical and functional food products are available with documented health benefits (Zeisel 1999). 4. Current Status of Nutraceuticals in CVD Majority of the CVD are preventable and controllable. It was reported that low intake of fruits and vegetables is associated with a high mortality in

Cardioprotective Effect of Nutraceuticals — The Emerging Evidences cardiovascular disease (Moller and Kaufman 2005, Zimmet et al 2005). Many research studies have identified a protective role for a diet rich in fruits and vegetables against CVD (Ramaraj and Chellappa 2008). This apart, nutraceuticals in the form of antioxidants, dietary fibers, omega-3 polyunsaturated fatty acids (n-3 PUFAs), vitamins, and minerals are recommended together with physical exercise for prevention and treatment of CVD. The role of various nutraceuticals in preventing CVD has been discussed below: 4.1 Coenzyme Q10 (Ubiquinone) Coenzyme Q10 (CoQ10) is a potent lipid phase antioxidant, free radical scavenger, co-factor and coenzyme in mitochondrial energy production and oxidative phosphorylation that regenerates vitamins E, C, and A, inhibits oxidation of LDL, membrane phospholipids, DNA, mitochondrial proteins, lipids, reduces total cholesterol (TC), and triglycerides (TG), raises HDL-C, improves insulin sensitivity, reduces fasting, random and postprandial glucose, lowers BP and protects the myocardium from ischemic reperfusion injury (Digiesi et al. 1990, Digiesi et al. 1992, Morisco et al. 1993, Yokoyama et al. 1996, Kontush et al. 1997, Langsjoen and Langsjoen 1999, Singh et al. 1999). Serum levels of CoQ10 decrease with age and are lower in patients with diseases characterized by oxidative stress such as hypertension, CHD, hyperlipidemia, DM, atherosclerosis, and in those who are involved in aerobic training, patients on total parenteral nutrition (TPN), those with hyperthyroidism and patients who take statin drugs (Digiesi et al. 1990, Kontush et al. 1997). There is a high correlation of CoQ10 deficiency and hypertension. Enzymatic assays showed a deficiency of CoQ10 in 39 percent of 59 patients with essential hypertension versus only 6 percent deficiency in controls (p < 0.01). Most foods contain minimal CoQ10, which is primarily found in meat and seafood. Supplements are needed to maintain normal serum levels in many of these disease states and in some patients taking statin drugs for hyperlipidemia (Enster and Dallner 1995). Hydroxymethylglutaryl

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coenzyme A reductase inhibitors (statins), first-line agents for lowering cholesterol levels to prevent cardiovascular disease, are some of the most commonly prescribed medications (Sewright et al. 2007, Radcliffe and Campbell 2008). However, statin therapy carries a risk of myopathy, which can range from muscle aches to rhabdomyolysis (Sewright et al. 2007, Radcliffe and Campbell 2008). Statins inhibit the synthesis of cholesterol by reducing the production of mevalonate, a precursor of both cholesterol and CoQ10. Since both cholesterol and CoQ10 are produced by the same pathway, it is not surprising that statins have been reported to reduce serum and muscle CoQ10 levels (Lamperti et al. 2005, Päivä et al. 2005). Nonetheless, researchers have also hypothesized that a reduction in CoQ10 levels in muscle tissue causes mitochondrial dysfunction, which could increase the risk of statininduced myopathy (Young et al. 2007), and some believe that treatment with CoQ10 may reduce myalgic symptoms and allow patients to remain on statin therapy (Radcliffe and Campbell 2008). Researchers have investigated the potential of CoQ10 supplementation to reduce or prevent statininduced myopathy. Caso et al. (2007) performed a small pilot study in 32 patients to determine if CoQ10 supplementation would improve myalgic symptoms in patients treated with statins. In this double-blind, randomized trial, patients received either CoQ10 100 mg/day or vitamin E 400 IU/day for 30 days. The statins were atorvastatin (Lipitor) 10 mg or 20 mg, lovastatin 40 mg, pravastatin 40 mg, and simvastatin 10, 20, 40, and 80 mg. After 30 days of treatment with CoQ10, the pain intensity had decreased significantly from baseline (P < .001). In contrast, no change in pain intensity from baseline was noted in patients receiving vitamin E. Also, the interference of pain with daily activities significantly improved with CoQ10 (P < .02), whereas vitamin E did not have a significant impact on this. Similarly, Littlefield et al. (2013) also concluded that CoQ10 supplementation at a dose of between 30 and 200 mg daily might benefit those patients suffering from statin-induced myopathy with no noted side effects. In contrast, a recent study found no significant effects

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on statin-induced myopathy in patients supplemented with 400 mg Q10 and 200 ìg selenium per day for 12 weeks as compared to control group (Bogsrud et al. 2013). Coenzyme Q10 has also been postulated to improve functional status in congestive heart failure (CHF). Several randomized controlled trials have examined the effects of CoQ10 on CHF with inconclusive results (Soja and Mortensen 1997, Fotino et al. 2013, Stocker and Macdonald 2013). Morisco et al. 1993 studied the influence of CoQ10 long-term treatment on patients with chronic CHF (New York Heart Association functional class III and IV) receiving conventional treatment for heart failure. They were randomly assigned to receive either placebo (n = 322, mean age 67 years, range 30-88 years) or CoQ10 (n = 319, mean age 67 years, range 26-89 years) at the dosage of 2 mg/kg per day in a 1year double-blind trial. The results demonstrated that the addition of CoQ10 to conventional therapy significantly reduced hospitalization for worsening of heart failure and the incidence of serious complications in patients with chronic CHF. Similarly, Fotino et al. (2013) also found that supplementation with CoQ10 at a dose = 100 mg per day resulted in a net change of 3.67 percent in the ejection fraction (EF) and -0.30 New York Heart Association (NYHA) functional classification in patients with CHF. 4.2 Curcumin It is the bioactive component of tumeric (Curcuma longa). Curcumin exhibits anticarcinogenic, antiinflammatory, antioxidative, antiinfectious, hypoglycemic, and hypocholesterolemic activities as well as activities blocking TNF, vascular endothelial growth factor (VEGF), and epithelial growth factor (EGF) (Olszanecki et al. 2005). Curcumin increases the LDL receptor, slightly increases HMG-CoA reductase, and farnesyl diphosphate synthatase; increases SREBP genes and downregulates peroxisome proliferator activated receptor (PPAR), CD 36 FA translocase, and FA binding protein 1 and stimulates hepatic cholesterol-7 -hydroxylase, which increases the rate of cholesterol catabolism, liver X

receptor (LXR) expression (Peschel et al. 2007). Curcumin increases hepatic superoxide dismutase (SOD) and glutathione peroxidase (GSHPX) leading to reduced oxidation of LDL-C. Curcumin may aggravate bleeding in patients taking anticoagulants. Curcumin has protective effect against alcohol and PUFA induced hyperlipidemia. A significant decrease in serum lipid peroxides (33%), increase in HDLC (29%), and decrease in total serum cholesterol (11.6%) were noted (Soni and Kuttan 1992). It is recommended that patients consume about 500 mg of high quality curcumin (turmeric extracts) per day. 4.3 Flavonoids Recent interest in phenolic compounds in general, and flavonoids in particular, has increased greatly owing to their antioxidant capacity and their possible beneficial implications in human health (Schroeter et al. 2002). These include the treatment and prevention of cancer, cardiovascular disease and other pathological disorders (Rice-Evans 2001). Flavonoids block the angiotensin-converting enzyme (ACE) that raises blood pressure; by blocking the “suicide” enzyme cyclooxygenase that breaks down prostaglandins, they prevent platelet stickiness and hence platelet aggregation. Flavonoids also protect the vascular system and strengthen the tiny capillaries that carry oxygen and essential nutrients to all cells. Flavonoids are widely distributed in onion, endives, cruciferous vegetables, black grapes, red wine, grapefruits, apples, cherries and berries (Hollman et al. 1996). Flavanoids in plants available as flavones (containing the flavonoid apigenin found in chamomile); flavanones (hesperidin-citrus fruits; silybin-milk thistle flavonols (tea: quercetin, kaempferol and rutin grapefruit; rutinbuckwheat; ginkgo flavonglycosides - ginkgo), (Majoa 2005) play a major role in curing the cardiovascular diseases (Cook and Samman 1996, Hollman et al. 1999). A recent study by Davison et al. (2008), investigated the effects of cocoa flavanols and regular exercise in overweight and obese adults. They showed that, compared to low-flavanol, high-flavanol cocoa acutely increased flow mediated dilation (FMD) by 2.4% (P < 0.01) and chronically (over 12 weeks; P