Heart disease and stroke are the leading cause of death in the United States (5, 52). Every year close to a million people diedue to these two diseases, which accounts about one-third of all deaths (5). Furthermore, they cost the United States’ health care system $199 billion annually, and cause a productivity lose of $131 billion (5). The primary risk factors for these diseases include hyperlipidemia, high blood pressure, diabetes, kidney disease, vascular calcification, (hardening of the artery), inflammation, and oxidative stress (11, 12, 43, 52, 102).
In healthy state, the body has the ability to prevents or slow down the development and progression of heart disease by suppressing promoters and inducing inhibitors. Thus, disease development occurs, when this balance between promoter and inhibitors is disturbed (11, 12, 60).
Opticel Heart Health formula is designed to promote healthy heart health by targeting the different triggers thereby stimulating expression of inhibitors, and suppressing expression of promoters at the cellular level (11, 12, 53, 60). To accomplish this goal, OptiCel Heart Health is formulated to contain multiple bioactives that work synergistically by complementing each other at the cellular level.
In nature, vitamin K occurs in the form of K1(phylloquinone) and K2(as menaquinone). Vitamin K1is mainly found in green vegetables, whereas vitamin K2 is obtained from fermented soy, cheese, meat and egg (61-64). K2 asMenaQ7®is used in OptiCel Heart Health formula, since it has been shown clinically to be 10 times more bioavailable than K1 (64).
Vitamin K2plays important role in preventing heart disease by functioning as inhibitor to vascular calcification or hardening of the artery (63-65). In a clinical study, Vitamin K2 (MenaQ7®) supplementation promoted heart health by significant reduction of vascular calcification mediated arterial stiffness (66).
The benefit of vitamin K2on heart health is due to its ability to function as a cofactor for the carboxylation of various proteins that prevent the development of heart disease (61-65). In multiple studies (in-vitro, animal models and humans), K2 has been shown to inhibit the calcification of arterial cells by enhancing the carboxylation of matrix Gla protein (MGP), which has been shown to be a potent inhibitor of vascular calcification (61-65). In contrast, increased uncarboxylated MGP in the blood has been shown to be strongly corelated with increased risk of atherosclerosis in humans (61).
Magnesium plays important role on health in general, and heart health in particular. It is involved in several biological functions, including glucose utilization, fat synthesis, muscle contraction, and energy production (67).
Magnesium’s rich dietary sources include green leafy vegetables, nuts, beans, and whole grains (67, 68). However, according to the national dietary survey (NHANES 2003-2006), about 38% of the children and adolescents and 61% of the adults do consume belowthe estimated recommended daily allowance for magnesium (69, 70).
Poor magnesium intake is strongly associated with all causes of mortality, stroke, heart diseases, hypertension, type 2 diabetes, and vascular calcification (71,46). Also, low serum level of magnesium is associated with an increased risk coronary artery disease and carotid atherosclerosis (67).
In multiple clinical studies, magnesium supplementation has been demonstrated to significantly reduce many of the triggers of heart disease, including hypertension (72,73), type 2 diabetes (74, 75), triglycerides (68,74), low density lipoprotein (LDL) (68, 103), cholesterol (103 ), arterial stiffness (76), and arterial calcification (68, 103). In addition, magnesium supplementation has been shown clinically to significantly increase the good cholesterol, high density lipoprotein (HDL) cholesterol (74, 103).
Magnesium provides heart health benefits through modulating various pathways and mechanisms, which the multiple triggers mediate disease development at the cellular level. Data from in vitro and animal studies have shown magnesium prevents arterial calcification by inhibiting the transformation of vascular smooth muscle cells (VSMCs) to osteogenic-like cells(mineralizing cells) through downregulating the expression of growth factors (e. g. morphogenic matrix proteins), transcription factors (e. g. runt related transcription factor 2), and signal pathways (e. g. went/β-catenin) (41, 48, 49, 68). In addition, magnesium prevents vascular calcification by inducing the expression of osteogenic differentiation and calcification inhibiting proteins, including osteoprotegerin (OPG), matrix Gla Protein (MGP) and osteopontein (OPN) (49, 102 ).
Also, magnesium prevents or reduce the development of heart disease by reducing blood pressure through blocking the transport of calcium into cells, and promoting vasodilation by increasing the production of nitric oxide through the induction of endothelial nitric oxide synthase (102). In addition, magnesium has been demonstrated to reduce hyperlipidemia by inhibiting critical limiting steps involved in the metabolism of cholesterol (103). These includes increasing HDL-cholesterol level by acting as a cofactor for the enzyme that inhibits hydroxy methylglutaryl coenzyme A, key enzyme involved in cholesterol biosynthesis, and inducing lecithin cholesterol acyl transferase, a critical enzyme involved in clearing cholesterol from blood, and increasing HDL cholesterol level (103).
Quercetin is one of the most abundant bioflavonoids in plants (51, 77). It is commonly found in fruits and vegetables such as anion, apples, grapes, cranberries and cherries, broccoli, and kale (77) . Multiple epidemiological studies have shown significant association between flavonoids (mostly quercetin) intake and decrease in mortality from coronary heart disease (78). In clinical studies, quercetin supplementation significantly reduced blood pressure in hypertensive and overweight subjects (77-79).
In multiple invitro and animal studies, quercetin has been shown to modulate multiple inhibitor and inducers of VC(48). In an in vitro study, quercetin prevented VCby inhibiting the differentiation of VSMCs to osteoblastic-like cells, which at a cellular level is mediated by the reduction in β-catenin signaling pathwayactivity (48). In an animal study, quercetin supplementation suppressed VCby inhibiting the differentiation of VSMCs to osteoblastic-like cells through downregulation of induced nitric oxide synthase (INOS)/p38 mitogen activated protein kinase (p38MAPK) signaling pathway (80).
However, quercetin’s health benefits in preventing coronary artery disease has been limited by its extremely poor bioavailability,which is attributed to its poor solubility in aqueous environment (51). Thus, OptiCel Heart Health is formulated with a highly bioavailable form of quercetin known as EMIQ®. In a clinical study, EMIQ®has been shown to be 17 times more bioavailable than the standard quercetin powder (51, 81).
Curcumin is polyphenol, which is commonly found in turmeric plant (82, 83). It is commonly used globally as spice and medicine (82, 83). Multiple published results from clinical studies have demonstrated curcumin supplementation to be effective in preventing and/or lowering triggers of coronary artery disease, including diabetes in prediabetes subjects (82), triglycerides in healthy individuals (83), blood pressure in postmenopausal women (84), LDL cholesterol and VLDL cholesterol in patients with coronary artery diseases (85), and inflammatory cytokines (IL-1β, IL-4) in obese individuals (86). Also, curcumin supplementation has been shown to significantly increase HDL cholesterol (87). Unlike pharmaceutical drugs, curcumin has no demonstrated serious adverse effect (52)
Curcumin prevents and/or treats cardiovascular disease by acting on multiple targets and through multiple mechanisms. In an animal studies, curcumin supplementation suppressed biosynthesis of cholesterol in the liver by inhibiting the transcription of hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme involved in the biosynthesis of cholesterol (88). Furthermore, results from in vitro studies showed curcumin prevents arterial calcification by suppressing the expression of bone forming transcription factors (Runx2) (89), inhibits adipogenesis (pre-adipocyte differentiation to adipose cells) by activating signaling pathway (b-catenin signaling), AMP activated protein kinase (AMPK), and down regulating the expression of transcription factors, PPAR gamma andCAAT/enhancer binding protein-α (C/EBP α) (90, 91).
Similar to quercetin, curcumin’s health impact is hindered by its low bioavailability, which is due to its poorly solubility in an aqueous system (50). However, the form used in Opticel Heart Health formula is a highly bioavailable form called Theracurmin® (50). Result from a clinical study showed curcumin from Theracurmin® is 27 times more bioavailable than the standard curcumin powder (50).
Resveratrol is a non-flavonoid polyphenol found in multiple plants, including Japanese Knotweed, grapes, peanuts, and berries (43). Published clinical studies have demonstrated resveratrol supplementation prevents coronary heart disease by suppressing the development and progression of multiple risk factors(43, 92-97). These include reduction in arterial stiffness (92), high blood pressure (93, 94), diabetes (93-95, 97), chronic inflammation (94,96), total cholesterol and low-density lipoprotein (LDL) cholesterol (93, 97), plasma triglycerides (94). In addition, resveratrol supplementation has been shown to increase high density lipoprotein (HDL) cholesterol (93).
In vitro and animal studies have shown resveratrol prevents and/or treats heart disease by targeting multiple organs and tissues through multiple mechanisms at cellular and molecular levels (43, 98-100). These incudes inhibition of oxidative stress through enhancing the expression of endognous antioxidants such as superoxide dismutase (SOD), and prevention of arterial wall inflammation by inhibiting production of inflammatory cytokines (TNF-α, IL-6) (43). In addition, resveratrol increases the vascular dilator, nitric oxide (NO), by upregulating the expression and activity of endothelial nitric oxide synthase (eNOS) (98-100).
These mode of actions of resveratrol are mediated by increasing the expression and activation of key metabolic, oxidative and inflammatory regulators at the cellular and molecular levels. These transcriptional regulators, include the energy sensor, AMPactivated protein kinase (AMPK), the silent information regulator 1 (SIRT1), NAD-dependent deacetylase protein, and nuclear factor erythroid-2 related factor 2 (Nfr2), an inducer of cellular antioxidants expression (98-100).