Dr. Ferda Ayhan Yalcin Even before the Covid-19 pandemic began, the medical community was in consensus regarding to the epidemiological and clinical data that today’s main public health concern was the “Non-Communicable Chronic Diseases”. Now we are dealing with a big communicable disease problem, but still the former mentioned non-communicable chronic conditions, like obesity, diabetes, cardiovascular disease, cancer, chronic respiratory disease remain standing as the main predisposing factors to be infected with the virus or to have severe disease progress which means more morbidity and mortality. So, the chronic diseases are still the biggest burden for the individuals, families, public, health systems and for governments.   Despite the advances in early detection techniques in modern medicine, the therapeutic approach to chronic disease is not focused on prevention, is mostly not curative where its focus is to find an immediate pharmaceutical solution for a relief to defined symptom or cure for the acute disease. That is why these chronic conditions can not be treated correctly, there is no positive progress and the need for pharmaceuticals and side effects of these medications are on the rise accompanying further morbidities and lower quality of life of these patients. Most importantly the subclinical stages of disease development, the causality and ability and incentive to properly address disease-promoting lifestyles are mostly ignored (1). Most important of all, the root causes of these diseases and an in-depth analysis of causalities and their development stages remain ignored and underinvested. It is now widely recognised that pathogenesis of diseases is often the result of interactions between genes and environmental factors. Functional medicine investigates the sum of these environmental exposures from conception until the old age, known as exposome, covering the full spectrum of impacts of nutrition, toxic substances, physical and psychological stressors and their associated biological responses (2).   Avicenna (973-1037) says: ‘The knowledge of anything, since all things have causes, is not acquired or complete unless it is known by causes. Therefore, in medicine we ought to know the causes of sickness and health.’   The functional medicine model of care provides an operating system that works to reverse illness, promote health, and optimize function by addressing underlying causes, symptoms, and functional imbalances in interconnected biological networks(3). These imbalances may impair principal biological functions which are classified regarding to Functional Medicine as: assimilation, defense and repair, energy production, biotransformation, communication, transport, and structural integrity. These dysfunctions may be the result from gene environment interactions, including lifestyle, environmental toxins, and the microbiome. Functional medicine removes triggers for illness and provides inputs to restore and optimize health. Functional medicine also addresses social determinants, including the psychological, emotional, and spiritual aspects of health and disease(4). A foundation of functional medicine is the use of food as medicine to prevent, treat, and reverse chronic disease. The functional medicine model of care may have the ability to improve patient’s health-related quality of life (HRQoL), including physical function and well-being. (3)   Functional medicine practitioners are trained to think in terms of functions derived from biological and social systems and network biology. They skillfully utilize a dual perspective in analysis of their patients, namely both a telescopic and microscopic view. (5) Functional medicine practitioners use a highly innovative way of rep­resenting the patient’s signs, symptoms, and common pathways of disease. Orga­nizing seven biological systems and clinical imbalances into the Functional Medicine Matrix Model creates an intel­lectual bridge between the basic science literature on physiologic mechanisms of disease and the relevance of clinical appli­cations. Functional medicine postulates that, with scientific rigor, clinical wisdom, and innovative tools, we can identify many of the underlying drivers (both triggers and mediators) of chronic disease, allowing us to reverse these clinical imbalances, often before overt disease is even present.   These imbalances in assimilation, energy production and nutrition are ac­tivators of overall imbalance, manifesting itself as symptoms and multiple comorbidities. In this case, one expression of disease may arise from the interconnection of multiple clinical imbalances, whereas one clinical imbalance may be the root cause of mul­tiple, seemingly different conditions. Functional medicine interprets health and disease as a continuum. An essential precept in functional medicine is that restoring balance—in every particular patient’s environmental inputs and in their body’s fundamental physiologic processes—is the key to restoring health.   Many clinical trials represented that the neuroendocrine and immune influences that act on the vascular endothelium, influence its function. As an analogy, “on endothelial cells acts a real neuro-endocrine-immune symphony in which the melody is played by vitamin D, parathyroid hormone, renin angiotensin-aldosterone system axis in concert with thyroid and thyroid stimulating hormones, growth hormone and insulin-like growth factor 1, cortisol and ACTH, sex hormones, insulin and glucagon-like protein-1, adipokines, oxytocin, vasopressin, prolactin, melatonin, bilirubin, heme catabolic pathway, and gamma-glutamyl transferase. Conducting the orchestra is the immune system, along with uncontrolled inflammation as a key process in the pathogenesis of atherosclerosis, coagulation and the autonomic imbalance, where the predominance of the sympathetic system on the parasympathetic, is a determining factor for endothelial dysfunction(6). In this perspective, practitioners can see the cardiometabolic disease spectrum with different lenses and deal with every biological systems dysfunction in order to identify and solve them, rather than relieving symptoms of one particular organ or system.   Since the inflammation and its failure to resolve are firmly established as central to the development and complications of several cardiovascular diseases, the best starting point for functional medicine clinicians may be to find the source of the inflammation. (7) But this oversimplification does not accurately convey the heterogeneity of the processes involved. Currently available tools to measure and monitor inflammation are often nonselective, represent downstream sequelae of inflammation, and do not provide any information about presence, extent of activity, or location. (7) There has been recognition that the majority of cardio-vascular diseases can be characterized as having an imbalance between the formation of reactive oxygen species (ROS) and ROS-degrading antioxidant systems all of which result in elevated mitochondrial superoxide, diminished endothelial nitric oxide bioavailability, and aggravation of hypertension and endothelial dysfunction. Mitochondrial ROS can increase mitochondrial permeability (by opening of the mitochondrial permeability transition pore) with subsequent release of (oxidized) mtDNA, which represents a damage-associated molecular pattern (DAMP) and initiates a process called “sterile inflammation”. Because mitochondria as energy centrals are more abundant in highly functional tissues like heart, brain and kidney, this dysfunction relates more importance regarding to homeostasis. (7)   Inflammatory disease may seem unpredictable, but close observation often reveals identifiable trends. The respiratory and gastrointestinal system mucosa are the single biggest sources of entrance of the triggers for chronic inflammation mediated trough the mucosal associated lymphoid tissue (MALT) for genetically susceptible persons. These triggers differ from allergens, toxins, infections (including dysbiosis in the gastrointestinal tract), trauma, lowered oxygen, drugs, alcohol and food elements like sugar and refined carbohydrates, advanced glycation end products, oxidized lipids, trans fats, rancid polyunsaturated fatty acids, food additives, gluten and lectin. Additionally, nutrient deficiencies related to poor nutritional habits, digestion absorption and elimination difficulties, microbiome imbalances can also be cause for initiating chronic inflammation, later disseminating through the body’s systems. Functional medicine looks for these triggers first.   Excess nutrient intake, weight gain and obesity result in expansion of adipose tissue mass, adipocyte size and eventually to adipocyte death. As we know adipose tissue, in particular abdominal adiposity is related with low grade inflammation. It has recently been suggested that bone-marrow originated macrophage infiltration could explain this overexpression of proinflammatory molecules by adipose tissue as obesity develops. These macrophages release pro-inflammatory cytokines, which work in a paracrine manner to activate the intracellular proinflammatory pathways in neighboring cells and possibly through endocrine mechanisms in distal tissues. Excess weight and obesity cause insulin dysfunction, as well. Poor life-style habits like inactivity, bad food choices, inadequate sleep and poor stress management are risk factors for hyperinsulinemia and insulin resistance. Both inflammation and insulin dysfunction are related with mitochondrial dysfunction, non-alcoholic fatty liver, sarcopenia, type II diabetes, Alzheimer’s disease, hormonal dysfunctions like estrogen dominance, polycystic overs, cancer, osteoporosis and cardiovascular disease.   Hyperglycemia (HG) and increased free fatty acids (FFA), which are hallmarks of obesity, metabolic syndrome and diabetes, combined with a high-fat, high–glycemic load diet, could result in increased activation of the inflammasome complex as well as increase the activation of macrophages via increased toll-like receptor (TLR) and nuclear factor κB (NF-κB) activation, ending with cardiometabolic diseases.   Unhealthy nutrition with refined carbohydrates, saturated and trans-fats are related also with microbial imbalances in the gut. This causes increased intestinal permeability where especially bacterial endotoxins, other environmental toxins and undigested food particles can get to the blood. This situation triggers systemic inflammation, macrophage activity, toll-like receptor activation and ends up again with weight gain and metabolic dysfunction like metabolic syndrome and diabetes, which are risk factors for cardiovascular disease. (8) Non-alcoholic fatty liver (NAFLD) disease is also a result of excess intake of refined carbohydrates. Previously it was believed NAFLD to be harmless, now it is recognized that NAFLD can be a progressive liver condition that increases risk of cirrhosis, end-stage liver disease and hepatocellular carcinoma. Additionally, liver fat accumulation causes insulin resistance and increases risk of type-2 diabetes. Increasing evidence now shows that NAFLD is a risk factor for cardiovascular disease. Researchers suggest that oxidative stress could be the link between NAFLD and cardiovascular disease.  We can see the biochemical elevations of ALT, AST, GGT, hsCRP, ApoB, VLDL and triglycerides as a result of NAFLD. There are mainly elevated triglyceride levels and decreased HDL as evidence of metabolic dyslipidemia and it is mostly related with hyperinsulinemia.   The conventional target of dyslipidemia treatment is to lower LDL-cholesterol levels. However, LDL-cholesterol is unrelated to severity of insulin resistance. Two thirds of cardiometabolic risk patients have elevated lipid particle count despite normal LDL-C levels. Another aspect of cardiovascular risk assessment is lipid particle sizes where functional medicine particularly investigates the small dense LDL particles in cardiovascular high-risk patients. ApoB and ApoA1 levels are also important for risk assessment.  As advanced lipoprotein markers, lipoprotein (a), myeloperoxidase, Lp-PLA2, oxLDL, omega 3 index and ASA resistance can be investigated. Ferritin and fibrinogen levels are also beneficial to evaluate the risk of cardiovascular disease. TMAO and butyrate levels give clues for the nutritional status of the patient.   Functional medicine deals with excess weight and obesity strictly, tries to reverse metabolic syndrome and type-2 diabetes and modulates inflammation with healthy nutrition and nutritional supplements such as omega-3 fatty acids, vitamin A, D, B12, C, E, folic acid, minerals, L-arginine, L-glycine, L-glutamine, probiotics, prebiotics and other herbal and botanical therapies. Functional medicine focuses in optimizing immunity, enhancing barrier integrity on gut lining, endothelium and blood brain barrier, upregulating antimicrobial peptides, restoring redox balance and activating intracellular defense pathways. Energy optimization support to mitochondria, phase 1 and 2 liver support are also important aspects. The goal of Functional Medicine is to help high cardiovascular risk patients restore and maintain optimal wellness through dietary and other modifiable lifestyle, mental, emotional and spiritual interventions whenever possible.   In functional medicine, the most prevalent, relevant, measurable and modifiable genes related to cardiovascular disease are investigated, if possible. Cardio genomics is a relatively new term that is being used to describe the use of genomic profiling to assess risk for cardiovascular disease. An example of the advancement in this field is the recognition that polymorphisms of specific genes such as LDLR, APOB, and PCSK9 have been found to be important in establishing individual risk to cardiovascular disease(10). Almost 95% of familial hypercholesterolemia patients carry a functional mutation of one of these three genes.  The functional impact of these genes is known to be influenced by lifestyle, dietary and environmental factors. Familial hypercholesterolemia patients and their genetically investigated and diagnosed relatives should use statins, other LDL-C lowering agents and maybe PCKS9 inhibitors. But functional medicine approach doesn’t end with the medical treatment, it still optimizes the coenzyme Q10 and vitamin D levels as they are also negatively impacted during the statin treatment.   Another genetic variation among people is on the Apolipoprotein E genotype. There are three genotypes of ApoE; Apo-E2, Apo-E3, Apo-E4 as functional medicine considers these variations. We receive one allele from each parent where results of this combination can point to Apo-E2/E3, Apo-E3/E4, Apo-E4/E4 etc. Apo-E3/E4 and ApoE4/E4 genotypes have increased risk for cognitive impairment and Alzheimer disease, hyperlipidemia, type II diabetes or cardiovascular disease. Outcomes of these diseases worsen with alcohol and tobacco use. We know that diet can make difference in particular genotypes (Table1). Another frequently investigated genetic variation is on the MTHFR gene. There is an established link between elevated homocysteine levels, an indicator of methylation insufficiency, and heart disease risk. MTHFR gene codes the enzyme for Vitamin B metabolism. Methylation means the formation of methyl (CH3) groups on proteins in the body. This is related with metabolism and degradation of some hormones, neurotransmitters, stress hormones, drugs and xenobiotics. Specific MTHFR gene variations are related with autism, depression, infertility, insomnia, thyroid disease and many other conditions like cardiovascular disease. When there is a consideration related to elevated homocysteine levels, simply supplementing the patient with methyl factors like methyl B12 and methyl folate can regulate it.   From a practical point of view, Functional Medicine counts on a very high standard of care in acute setting, while in the chronic and preventive context, reconsiders the management of patients with heart disease by investing more time and resources in terms of proper nutrition, physical activity, and stress management (6 p.235).   Functional Medicine treatment for cardiovascular disease usu­ally involves a broad array of therapies, from different dietary interventions for every person needs and lifestyle changes like exercise, sleep and social networks, to high-quality nutraceuticals and targeted pharmaceuticals. The goal here is to regulate the identified imbalances in seven biologic system, which are assimilation, defense and repair, energy production, biotransformation, communication, transport, and structural integrity. Functional medicine approach also covers follow-up of symptoms and assessment of patient-reported outcomes measures. When patients embrace these foundational principles, they can accomplish improvement in function and decreased health care utilization. The functional medicine approach requires full responsibility of the patient and the practitioner in order to improve the disease progress, improve function and decrease the burden on the health care system.   In this brief review I tried to conceptualise the functional medicine approach mainly to cardiometabolic disease. In order to express the functional medicine approach in more detail for all areas of cardiology such as lipidology, endothelium and atherosclerosis, venous problems, genetics, hormonal management, functional heart healthy nutrition and nutritional supplements etc., it may be necessary to consider each topic in a separate article.   References: 1.A Systems Medicine Approach: Translating Emerging Science into Individualized Wellness, Advances in Medicine Volume 2017, Article ID 1718957,  https://doi.org/10.1155/2017/1718957 2.Precision medicine in the era of artificial intelligence: implications in chronic disease management, Subramanian et al. J Transl Med (2020) 18:472 , https://doi.org/10.1186/s12967-020-02658-5   3.Association of the Functional Medicine Model of CareWith Patient-Reported Health-Related Quality-of-Life Outcomes, JAMA Network Open. 2019;2(10):e1914017. doi:10.1001/jamanetworkopen.2019.14017  4.Beyond Statins: New Therapeutic Frontiers for Cardiovascular Disease, Cell 169, June 1, 2017 ª 2017 Published by Elsevier Inc. 5.Defining Function in the Functional Medicine Model, Integrative Medicine Vol.16, No.1, February 2017 6.Sex-Specific Analysis of Cardiovascular Function, https://doi.org/10.1007/978-3-319-77932-4, p.232  Inflammatory processes in cardiovascular disease: a route to targeted therapies,  DOI: 10.1038/nrcardio.2016.185 7.Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease, Oxidative Medicine and Cellular Longevity Volume 2019, Article ID 7092151, 26 pages https://doi.org/10.1155/2019/7092151 8.Do nutrient–gut–microbiota interactions play a role in human obesity, insulin resistance and type 2 diabetes? https://doi.org/10.1111/j.1467-789X.2010.00797.x  9.Non-alcoholic fatty liver disease and cardiovascular risk: metabolic aspects and novel treatments, Endocrine (2011) 40:332–343 DOI 10.1007/s12020-011-9530-x 10.Cardiology Meets Personalized Lifestyle Medicine, Integrative Medicine • Vol. 16, No. 6 • December 2017