Cardiovascular prevention and omega-3

The synergy of specific components, including omega 3 and monacolin K, reduces blood cholesterol and triglyceride levels and improves endothelial function for effective cardiovascular prevention.

First-degree cardiovascular prevention is now one of the best strategies to prevent cardiovascular diseases such as myocardial infarction. One of the most effective preventive approaches is the consistent administration of specific supplements designed to reduce LDL cholesterol levels in the blood. These typically are based on substances that help, among other things, to keep blood vessels and the heart healthy. Cardiol Forte, the supplement that combines omega-3, monacolin k, coenzyme Q10, hydroxytyrosol folic acid, vitamins B12 and E, and piperine, thanks to its components with clinically proven efficacy, offers the possibility of significantly reducing LDL cholesterol levels in conjunction with an active lifestyle and controlled diet.

Index

1. Cardiovascular disease.

1.1 Atherosclerosis

1.2 Oxidative stress, lipids, and plaque formation

2. The ingredients of Cardiol Forte.

2.1 Omega-3

2.2 Fermented red rice

2.3 Coenzyme Q10

2.4 Hydroxytyrosol

2.5 Other components

3. Clinical study of Cardiol Forte

3.1 The results of the clinical study

4. Sources

Cardiovascular disease

Cardiovascular disease is the leading cause of morbidity, comorbidity, and mortality worldwide. The origin of most cardiovascular diseases is atherosclerosis, which is directly related to altered lipid status parameters (i.e., total cholesterol, LDL or "bad" cholesterol, and triglycerides). The current guidelines for cardiovascular prevention and treatment of these diseases are based on the Systematic Coronary Risk Evaluation System (SCORE), which can assess the 10-year risk of fatal cardiovascular disease and whose value is estimated by age, sex, systolic blood pressure, smoking habit, and total cholesterol concentration. The latter depends mainly on cholesterol synthesis and absorption capacity. The balance between these processes is responsible for maintaining cholesterol homeostasis. In addition to total cholesterol, a high LDL cholesterol value is also a well-known risk for cardiovascular disease. So both factors, in addition to oxidative stress and inflammation, conditions often associated with obesity, predispose the occurrence of a very important risk factor for cardiovascular disease: atherosclerosis.

Atherosclerosis

Atherosclerosis is a chronic disease with a complex etiology, involving early local injury to the arteries, followed by lipid deposition, proliferation of fibrous tissue, local thickening of the artery, and finally plaque formation. When atheromatous plaque forms, a narrowing is created at the level of the artery, a stenosis. This causes insufficient arterial blood supply. In addition, atheromatous plaques are highly unstable and can rupture, leading to the appearance of thrombi that occlude the artery and give rise to cardiovascular diseases such as heart attack. The pathogenesis of atherosclerosis has not been fully elucidated, but it is associated with disorders of lipid metabolism, endothelial cell damage, inflammation, and immune dysfunction, involving macrophages, endothelial cells, vascular smooth muscle cells, and platelets. Among the triggers, two are most important: oxidative stress and elevated blood lipid levels.

Oxidative stress, lipids, and plaque formation

Oxidative stress is primarily responsible for the formation of atheromatous plaques, along with elevated LDL cholesterol levels. The production of reactive oxygen species (ROS) in response to inflammatory stimuli results in the oxidation of LDL cholesterol, a phenomenon known as lipid peroxidation. When oxidized, LDL cholesterol has a tendency to form plaques that are deposited at the level of the arteries, resulting in the appearance of endothelial cell damage and the induction of the expression of pro-inflammatory factors in endothelial cells. The mechanism by which oxidized LDL cholesterol forms plaques is through macrophages. In fact, this type of cholesterol shows a strong affinity for a particular type of receptor (scavenger) present on mononuclear macrophages. The binding of oxidized LDL cholesterol to these receptors causes activation, proliferation, aggregation and degeneration of macrophages. At the end of this process, macrophages undergo cell death and become foamy cells, which then aggregate to form lipid plaques.

The ingredients of Cardiol Forte

For effective cardiovascular prevention that counteracts oxidative stress and blood lipid levels, nutraceutical-based supplements specifically for the treatment of these conditions can be used. Cardiol Forte is a dietary supplement containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), monacolin K (10 mg) from fermented red rice (RYR), the components of which have been shown to have hypolipidemic and/or endothelial protective action, hydroxytyrosol (a polyphenol that is derived from the fruit of the olive tree), coenzyme Q10, folic acid (vitamin B9), vitamin B12 and vitamin E, and piperine.

Omega 3

Gli acidi grassi omega-3 sono acidi grassi polinsaturi a catena lunga (PUFA) e comprendono l'α-linolenico (ALA; 18:3), l'acido eicosapentaenoico (EPA; 20:5) e l'acido docosaesaenoico (DHA; 22:6). EPA e DHA derivano principalmente dal consumo di pesce o di olio di pesce. L'ALA invece si ottiene principalmente attraverso l'assunzione di semi di lino, semi di chia e noci. EPA e DHA possono essere sintetizzati nel corpo umano utilizzando l'ALA come precursore. Tuttavia, questa conversione rappresenta solo il 6% di EPA e <4% di DHA. L'interesse per gli acidi grassi omega-3 è nato dalle osservazioni epidemiologiche delle popolazioni della costa occidentale della Groenlandia in cui si è osservata una ridotta incidenza di dislipidemie e mortalità per infarto miocardico rispetto ad altre popolazioni europee. La spiegazione di questo fenomeno risiede nel fatto che tali popolazioni consumano grandi quantità di pesce, e di conseguenza di omega 3 e di EPA in particolare, e dall’EPA si forma una molecola chiamata TXA3 che è una sostanza non aggregante, ovvero determina una minore efficienza dell'aggregazione piastrinica, una minore tendenza alla formazione di trombi e, di conseguenza, una minore incidenza di aterosclerosi. Pertanto, la somministrazione di omega 3 può ridurre la progressione delle lesioni aterosclerotiche, oltre a migliorare le proprietà emodinamiche e fisiche delle grandi arterie. Oltre a questo, gli omega-3 contribuiscono alla prevenzione cardiovascolare grazie ai seguenti effetti:

• Anti-inflammatory and antiarrhythmic effect;
• Reduction of plasma triglycerides;
• vasodilation and reduction of blood pressure;
• Improvement of arterial and endothelial function.

Fermented red rice

Fermented red rice nutraceutical is obtained by fermentation of rice(Oryza sativa) by yeasts(M. pilosus, M.floridanus, M. ruber and Pleurotus ostreatus). In the case of Cardiol Forte, the yeast used is Monascus purpureus. The typical red color is due to the presence of pigments produced by secondary fermentation. Fermentation of yeast and rice produces a complex of substances called monacolins that have recognized anti-cholesterol properties that support cardiovascular prevention. The most commonly used concentration of monacolins usually reaches 1.9 percent, and there are different types of monacolins depending on the yeast strain used and fermentation conditions. One of these subtypes is monacolin K, a lovastatin analogue that has the same anti-cholesterol effects as the drug but without the side effects typical of statins. Its main mechanism of action is to inhibit the enzyme that controls the rate of the cholesterol synthesis pathway. According to the latest guidelines from the European cardiology and atherosclerosis societies for the management and treatment of dyslipidemia, the use of monacolin K may be considered in patients with elevated total cholesterol levels who do not qualify for statin treatment based on their estimated overall risk of cardiovascular disease. Specifically, guidelines recommend the use of 5-10 mg/day of monacolin K in these individuals.

Coenzyme Q10

Coenzyme Q10, also known as ubiquinone, is a compound that is naturally synthesized in the human body and is used by cells for various cellular processes including:

• Aerobic respiration and aerobic metabolism;
• Cellular respiration;
• oxidative metabolism.

In addition to participating in various cellular processes, coenzyme Q10 has antioxidant properties, meaning it protects cells from the action of free radicals, substances that can cause damage to various cellular structures including membranes, membrane lipids, and DNA. For this reason, the level of coenzyme Q10 in the blood is often used in studies as a measure of oxidative stress. Antioxidant properties give coenzyme Q10 an important role in cardiovascular prevention and in the treatment of some heart diseases. For example, it has been seen that supplementation with CoQ10, in patients with moderate to severe heart failure, is associated with reduction of symptoms and reduction of major adverse cardiovascular events. In addition, it has been observed that three out of four patients with heart disease have low levels of coenzyme Q10 and that plasma levels in patients with ischemic heart disease and dilated cardiomyopathy are much lower than in controls.

Coenzyme Q10 and statins

Coenzyme Q10 is also very useful in preventing and improving muscle symptoms related to the consumption of statins or statin-like drugs. Statins or statin-like drugs are drugs commonly used to lower cholesterol. They are often known to have muscle side effects such as cramps and myopathy. Therefore, a number of clinical studies have been done on such issues, highlighting that coenzyme Q10 supplementation improved the muscle symptoms associated with statins, implying that coenzyme Q10 supplementation may be a complementary approach to manage statin- or statin-like-induced myopathy. Specifically, coenzyme Q10 improved (compared with placebo) muscle pain, muscle weakness, muscle cramps, and muscle fatigue, regardless of dose of administration (100-600 mg/day) or time of supplementation (30 days to 3 months).

Hydroxytyrosol

Hydroxytyrosol is an amphipathic phenol that is derived from the fruit of the olive tree and, according to the 2011 EFSA opinion and EC Regulation 432/2012, is the only "food" officially recognized to have a clear health effect when consumed regularly (for oils containing at least 5 mg of hydroxytyrosol in 20 g of oil). In this regard, the European Food Safety Authority (EFSA) has published the following statement on its role in protecting LDL cholesterol oxidation: "A daily intake of 20 g of olive oil containing at least 5 mg hydroxytyrosol provides the expected beneficial effects." Hydroxytyrosol exerts many bioactive properties, including antioxidant, anti-inflammatory, cardioprotective, cytoprotective, and endothelial and vascular regulatory properties. Regarding the prevention of cardiovascular disease, in addition to its antioxidant capacity, it has been claimed that hydroxytyrosol inhibits platelet aggregation, chronic cardiac toxicity, aging-related protein expression, as well as attenuation of metabolic changes in glucose, triglycerides, and total cholesterol. In particular, however, its beneficial effects are related to its antioxidant-determining capacity:

• the ability to reduce oxidation of LDL cholesterol, thus preventing the formation of atherosclerosis plaques;
• a beneficial effect on high-density lipoproteins (HDLs), which play a central role in the reverse transport of cholesterol by removing excess cholesterol from peripheral cells (cholesterol efflux capacity). Hydroxytyrosol supplementation has been observed to confer local antioxidant protection to HDLs by improving their function;
• a mitochondria-targeted antioxidant potential in the inflamed endothelium. It has been seen that treatment of endothelial cells with hydroxytyrosol suppresses inflammatory angiogenesis, reduces the production of oxidants, and increases the activity of antioxidant enzymes in our body such as superoxide dismutase.

Other components

Other components of Cardiol Forte include piperine and vitamins B9 (folic acid), B12 and E.

Piperine

Piperine (PIP) is an alkaloid found in several pepper species, mainly Linn. and P. longum, in concentrations ranging from 5 to 8 percent. In the case of Cardiol Forte, piperine is derived from Piper nigrum. It exhibits several properties including:

• Ability to protect blood vessels in cases of hypertension;
• Protection of cells from oxidative stress;
• ability to inhibit certain molecules responsible for initiating inflammatory processes.

Several studies have shown that piperine is also able to protect cardiomyocytes from ischemia/reperfusion-induced damage by reducing cell damage and the process of programmed cell death (apoptosis). In addition, piperine through its ability to increase salivary and gastric secretion stimulates digestion, improving intestinal absorption of many nutrients such as coenzyme Q10.

Vitamins B9 and B12

Vitamin B9 (folic acid) and vitamin B12 (cobalamin) belong to the B-complex vitamins, which are involved in a great many cellular processes and functions including proper red blood cell synthesis and antioxidant functions. Vitamin B12 in particular has antioxidant properties that include direct neutralization of reactive oxygen species (ROS), indirect stimulation of ROS elimination by glutathione storage, modulation of cytokine and growth factor production to offer protection from immune response-induced oxidative stress, and reduction of homocysteine-induced oxidative stress. Homocysteine is a substance that, when present in high amounts (a condition known as hyperhomocysteinemia) causes various problems and is a risk factor for cardiovascular problems. Vitamin B9 and B12 take part in several processes involved in homocysteine metabolism, such as counteracting accumulation in the body. Such accumulation is negative because it could increase the likelihood of cortical inflammation, oxidative stress, and subsequent damage to mitochondria and DNA strands. This means that a reduction in vitamin B9 and B12 levels could cause an increase in plasma homocysteine.

Vitamin E

Vitamin E (α-tocopherol) is an important fat-soluble antioxidant that removes some antioxidant substances (peroxyl radicals) and thus disrupts the oxidation process of polyunsaturated fatty acids and other cellular structures. In the presence of vitamin E, peroxyl radicals react and combine with it rather than cellular structures. Thus, the chain reaction of peroxyl radical production is interrupted and further oxidation of membrane lipids is prevented. The antioxidant activity of vitamin E may be responsible for the regulation of several enzymes involved in signal spreading. Vitamin E can bind directly to enzymes involved in the generation of lipid mediators or to transport proteins involved in signal transduction, and it has also been shown that vitamin E supplementation enhances cell-mediated and humoral immune responses with increased lymphocyte proliferation, immunoglobulin levels, antibody responses, natural killer cell activity, and interleukin production. In addition, vitamin E also has anti-inflammatory effects. This was demonstrated by the results of a randomized controlled clinical trial, in which vitamin E supplementation was seen to significantly reduce biomarkers of vascular and systemic inflammation.

Cardiol Forte clinical study

The synergy of the components of Cardiol Forte was investigated in a single-center, double-blind, placebo-controlled study published in April 2020 and performed at 4 Italian facilities:

• Cardiovascular Prevention Unit, Anesthesiology and Intensive Care Unit, and Cardiology and Cardiac Intensive Care Unit at the Frosinone ASL Hospital Department;
• Department of Medical and Surgical Sciences at Alma Mater Studiorum University of Bologna;
• Pneumology Unit at the Department of Internal Medicine, University of L'Aquila;
• Umberto I Polyclinic of "La Sapienza" University of Rome.

Of the 80 patients enrolled, 75 completed the study (37 in the Cardiol Forte group and 38 in the placebo control group), which was carried out for a total period of 18 weeks (8 weeks treatment + 2 weeks discontinuation + 8 weeks treatment). The following parameters were evaluated:

• Total cholesterol, LDL cholesterol and HDL cholesterol
• Triglycerides
• Endothelial function (by measuring flow-mediated function).

The results of the clinical study

Dopo 8 settimane di trattamento, i livelli di colesterolo LDL sono stati ridotti del 17% nel gruppo Cardiol Forte e del 6,4% nel gruppo di controllo, rispetto al basale (visita 1). Questi cambiamenti sono stati persistenti fino alla fine del periodo di wash out (visita 2), con un'ulteriore riduzione del 23,5% nel gruppo Cardiol Forte e del 14,1% nel controllo. Alla fine dello studio (visita 3), il colesterolo LDL nel gruppo che aveva utilizzato il Cardiol Forte era ridotto del 34,3%, mentre nel gruppo di controllo del 22,6%. I livelli di colesterolo totale e trigliceridi sono stati significativamente ridotti durante lo studio nel gruppo  che aveva utilizzato il Cardiol Forte, mentre nel gruppo di controllo il colesterolo totale è stato ridotto dell'8,5 ± 5,18% e non è stata osservata alcuna variazione nei livelli di trigliceridi. Il colesterolo HDL-C non è cambiato in entrambi i gruppi. Nel gruppo che aveva utilizzato il Cardiol Forte, la FMD (flow mediated dilatation) è migliorata significativamente rispetto al placebo. La funzionalità dell’endotelio e la capacità vasodilatativa del circolo arterioso è infatti aumentato del 18,8 ± 3,2% dopo 8 settimane di trattamento e un ulteriore aumento è stato osservato alla visita 2 del 22,9 ± 4,4% e alla visita 3 del 39,3 ± 5,2%. Nel gruppo di controllo, la FMD è invece aumentata del 10,9 ±4,2% alla visita 1 e del 17,1 ±5,2% alla visita 3. Questo dato è di particolare interesse perché una meta-analisi di 35 studi (17.280 pazienti totali) ha indicato che ogni aumento dell’1% della FMD (flow mediated dilatation) è associato ad una riduzione del 12% degli eventi cardiovascolari previsti (rischio relativo= 0,88, IC al 95%: 0,84-0,91, p <0,001). In conclusione, un integratore alimentare come Cardiol Forte, contenente componenti ipolipemizzanti e antiossidanti, in associazione con un cambiamento dello stile di vita e una dieta controllata, può ridurre significativamente i livelli di colesterolo e migliorare la funzione endoteliale, riducendo così il rischio cardiovascolare nei pazienti con ipercolesterolemia da lieve a moderata.

Sources

• Giammanco M, Mazzola M, Giammanco MM, Tomasello G, Carini F. Omega-3 PUFAs and gut microbiota: A preventive approach for colorectalcancer. In press on Journal of Biological Research 2021;94:9954
• Gojkovic T, Vladimirov S, Kotur-Stevuljevic J, Bogavac-Stanojevic N, Zeljkovic A, Vekic J, Antonic T, Spasojevic-Kalimanovska V. Effects of monacolin K-containing nutraceutical on cholesterol homeostasis re-establishment and CVD risk reduction in hypercholesterolemic subjects. Eur Rev Med Pharmacol Sci. 2021 Aug;25(16):5261-5267.
• Minamizuka T, Koshizaka M, Shoji M, Yamaga M, Hayashi A, Ide K, Ide S, Kitamoto T, Sakamoto K, Hattori A, Ishikawa T, Kobayashi J, Maezawa Y, Kobayashi K, Takemoto M, Inagaki M, Endo A, Yokote K. Low dose red yeast rice with monacolin K lowers LDL cholesterol and blood pressure in Japanese with mild dyslipidemia: A multicenter, randomized trial. Asia Pac J Clin Nutr. 2021 Sep;30(3):424-435.
• PDQ Integrative, Alternative, and Complementary Therapies Editorial Board. Coenzyme Q10 (PDQ®): Health Professional Version. 2021 Jun 23.
• Pecchioli V, Cicero AFG, Lomartire N, Gemmiti MP, Colangeli A, Germanò R, Corsi MP, Germanò GIW. A double-blind, placebo-controlled clinical trial to assess the effects of a combined nutraceutical on endothelial function in patients with mild-to-moderate hypercholesterolaemia. Arch Med Sci Atheroscler Dis. 2020 May 7;5:e36-e42.
• Silva AFR, Resende D, Monteiro M, Coimbra MA, Silva AMS, Cardoso SM. Application of Hydroxytyrosol in the Functional Foods Field: From Ingredient to Dietary Supplements. Antioxidants (Basel). 2020 Dec 8;9(12):1246.
• Sood B, Keenaghan M. Coenzyme Q10. 2021 Feb 24. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan.
• https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:136:0001:0040:IT:PDF