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Cardiovascular disease is the result of uncontrolled inflammation.25 Inflammatory responses occur within the wall:
- Expression of adhesion molecules by endothelial cells.
- Attachment of leukocytes to the arterial wall.
- Vascular cell adhesion molecule-1 (VCAM-1) binds monocytes and T lymphocytes, preceding the appearance of macrophages.
- Oxidized lipids and cytokines IL-1 and TNF-alpha induce VCAM-1 expression via nuclear factor-kappa B.
- The presence of nitric oxide limits VCAM-1, but glucose and insulin presence retards nitric oxide production.
- Inflammation and oxidative stress drives production of monocyte chemoattractant protein-1 (MCP-1), recruiting monocytes and facilitating their penetration past the endothelium into the intima.
- Monocytes mature into macrophages and engulf lipoproteins and become foam cells.
- The atheroma is born and the atherosclerotic process is fed by daily habits.
Processed foods are by nature inflammatory foods due to their commonly low fiber content and added sugar. Processed grains may not taste sweet, but their ability to break down quickly into simple sugars drives hyperglycemia, which in turn generates insulin rise. As insulin rises, triglycerides are stored and not used as cellular fuel, leading to abundance and hypertriglyceridemia. The presence of sugar promotes yeast growth and oxidative stress in the gut, and the lack of soluble fiber hinders maintenance of proper flora, leading to gut disturbance. This collusion of events favors autoimmune vascular dysfunction and inflammation.26
The healthful antioxidant content of a whole-foods diet blunts endothelial dysfunction. Phytonutrients such as carotenoids, flavonoids, and polyphenols from a vegetable-based diet block vascular inflammation. Healthful fats such as omega 3 fatty acids and monounsaturated fats affect the caveolae of the endothelial cell wall to induce an anti-inflammatory signal.
The caveolae are invaginations in the wall of the endothelial cells and play a major role in cell signaling. Caveolin-1 is a natural protein found within the caveolae and influences cell signaling events, and can facilitate the development of atherosclerosis if stimulated by the inflammatory signaling network. Caveolin-1 is necessary to stimulate the intracellular TNF-α- induced NF-кB-dependent induction of cyclooxygenase-2 and prostaglandin E2.27 Caveolin-1 is known to contribute to endothelial dysfunction through its ability to reduce nitric oxide levels and increase ROS. Strategies to lower the level of caveolin-1 result in the opposite impact, an anti-inflammatory signal. If caveolin-1 is reduced, we see reduced levels of proatherogenic VCAM-1. Here are some of the mechanisms shown to help down regulate caveolin-1:
- Reducing TNF-alpha and lipopolysaccharides (LPS) levels inhibits caevolin-1 activity.
- Sulforaphane activates Nrf2 thus attenuating LPS induced endothelial activation.28
- Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) displace caveolin-1 from caveolae in endothelial cells, causing increased (nitric oxide (NO) production and reduced ICAM-1 expression.29
- By contrast, omega-6 fatty acids increase caveolin-1 expression.
- Green tea polyphenols, specifically EGCG, were able to reduce caveolin-1 levels.30
Caveolin-1 if provoked by inflammation promotes endothelial lipid accumulation in the subendothelial space and enhanced monocyte/macrophage recruitment.
In 2002 Dr. Mark Houston pointed out the three distinct responses of the blood vessel as a result of inflammatory exposures:
1. oxidative stress – as a result of a reduced oxidative defense
2. inflammatory response as outlined above
3. autoimmune – involvement of CD4 T-helper cells and CD8 cytotoxic cells
These three vascular responses that lead to atherosclerotic disease are commonly ignited by the simple choices that we make in the course of daily events. To defuse this bomb, we need to invest our collective energies in educating our patients about the impact of their choices. Integrative clinicians distinguish themselves by offering action, not lip service, to this important agenda.
Integrative Care and Solutions
"It is more important to know what type of person has a disease than what disease a person has," said Hippocrates. If we are to change the mindset and thus the habits of our patients, we need to understand them and their hurdles and then educate them appropriately. So let's venture into the terrain of the integrative physician. Let's explore the potential that we all have to truly reverse cardiovascular disease and exceed the standard of care.
A comprehensive lifestyle change has dramatic impact on all aspects of the inflammatory process. Exercise, optimal nutrition with fruits and vegetables, moderate alcohol consumption, and smoking cessation reduce the risk of MI by 80%.31 The Lifestyle Heart Trial included a plant-based diet, exercise, and stress management and showed a 5% regression of coronary plaque compared with the control group, who demonstrated a 8% progression in plaque size in just 1 year.32
Gut Health and Food Allergies
The gut represents the heart and soul of the immune system, as Peyer's patches line the intestines and respond to the millions of antigens that pass through us each day. Therefore, the gut microbiota are central in determining the pathogenesis of inflammatory induced obesity, CHD, atherosclerosis, and type 2 diabetes.33 Gut microbiota play a key role in an individual's potential risk for autoimmune disease, cardiovascular inflammation, and other chronic diseases.34 Microbial diversity and number are important in disease prevention and resiliency to maintain function. Lower diversity is observed in obesity, inflammatory bowel disease, meat-based dietary patterns, diabetes, and CHD. Higher diversity in vegetarian-based dietary patterns with high dietary fiber, nondigestible carbohydrates, resistant starches, SCFA prebiotics, and probiotics have a lower incidence of diabetes and CHD.35
Studies consistently show that altering lifestyle and diet is more powerful than simple drug therapy. In the Becker trial at the Mayo Clinic, a Mediterranean-style diet that removes high-glycemic carbs in conjunction with exercise, basic omega-3 fatty acid supplementation, low-dose red yeast rice, and education outperformed simvastatin (40 mg) on all fronts.36 Significant elevation in valuable HDL (high-density lipoprotein) was seen in the lifestyle group but not with statin use. Studies by Ornish and others have demonstrated reduction in plaque size with diet and lifestyle that was unobtainable through drug use.32,33
We have seen that oxidized LDL is one of the best lab predictors for CHD. This simple test is inexpensive and greater than 400% more predictive than total LDL measures.37 Addressing the cause of oxidized LDL is key to reversing CHD. There are many toxins in our environment capable of unbalancing our redox potential, but the greatest threat is the constant dietary threat from processed foods. It is estimated that Americans consume more than 150 pounds of sugar and that a full 20% of our caloric intake is from wheat. Today's wheat contains a unique amylopectin A that is produced via hybridization.11 Its branching pattern and ease of breakdown create a sharp rise in blood glucose and thus insulin that generates significant inflammation and oxidative stress.
The content of antioxidants in your diet has the ability to reduce CHD risk. In a study quantifying the antioxidant content of individual diets, those with the highest-quality foods and antioxidant content had a 20% lower risk for cardiovascular disease.38
Glutamate is an amino acid commonly found in our food supply, but in nature it is bound to protein and found in small amounts. When food manufacturers use a concentrated form known as monosodium glutamate (MSG), this is not natural or healthful and creates toxicity. Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor.39 Glutamate increases lipid peroxidation and thus increases oxidized LDL. Through its interaction in the vascular beds and the endothelium, it increases reactive oxygen species, reducing antioxidant protection such as superoxide dismutase and glutathione.40 This inflammatory food additive thus increases risk for CHD and alters neurologic balance between sympathetic and parasympathetic balance, driving hypertension and atherosclerosis.
The greatest source of antioxidants in the diet is from plant-based foods such as vegetables. Each serving of fruit has roughly 100 more calories from sugar than vegetables, so even abuse of healthful fruit can be problematic. The soluble fiber in vegetables feeds the gut flora, binds toxins, lowers both blood glucose and cholesterol levels, and is critical for proper elimination.35 Plant-based diets continue to demonstrate protection from heart disease in multiple studies, and yet physicians continue to struggle with this simple recommendation and follow-through. How is it possible that we use our powers of persuasion to convince patients to undergo colonoscopies, painful injections, digital exams, or all types of medical procedures yet struggle mightily to persuade them to eat a healthful diet?
Asking a patient to give up inflammatory foods is paramount to success. Many physicians feel ill equipped for this discussion, as food and nutrition were not taught in medical school and are not a part of our general operating procedure. There are many tools to aid success here. Work with a local dietitian, recommend reading material, offer classes and educational options in your office, but most importantly hold your patient accountable for follow-through. They will succeed if you carefully monitor and insist.
The benefits of exercise include the following41:
- Intense exercise can raise our anaerobic threshold, increase basal metabolic rate, and reduce fat stores, thus cytokine production.
- Exercise strengthens cardiovascular and respiratory systems, and cardiac output, and lowers resting heart rate.
- It stimulates osteoblast activity, increasing bone density and preventing osteoporosis.
- Exercise with intensity induces sweat, which reduces toxic burden from cells and can improve cell to cell signaling and endocrine function.
- Eases depression and helps manage pain and stress.
- Normalizes cortisol release through support of proper parasympathetic tone.
- Prevent and manage diabetes through optimization of insulin receptor function.
- Enhances better sleep patterns. Sleep loss is directly correlated with blood glucose and cortisol rise.
- Cognitive improvement: Exercise increases oxygen delivery to brain tissue, allowing us to have greater mental stamina, more creativity of thought, and greater problem-solving ability.
- It also stimulates the production of an important brain protein called brain-derived neurotrophic factor that helps in repair and function of neurons.
Naci reviewed 16 meta-analyses on the effectiveness of exercise on mortality outcomes across 4 conditions: secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, and prevention of diabetes. In CHD, the odds of mortality were reduced with use of statins, β blockers, angiotensin-converting enzyme inhibitors, and antiplatelets compared with control, whereas exercise interventions had a similar reduction but with wider confidence intervals.42 The authors stated: "When compared head to head in network meta-analyses, all interventions were not different beyond chance: there were no statistically detectable differences among any of the exercise and drug interventions in terms of their effects on mortality outcomes. … When compared head to head in network meta-analyses, exercise interventions were more effective than anticoagulants and antiplatelets." Our prescriptions need to occur beyond the prescription pad to include proper physical training.
In a well publicized trial in the New England Journal of Medicine from 2002, lifestyle including exercise was far superior to metformin in its ability to prevent prediabetics from advancing to diabetes.43 Lifestyle intervention reduced the incidence by 58% while metformin use only reduced it 31%.
Armed with this knowledge, we have a responsibility to get our patients moving. There is a huge variety of exercise options, and the knowledge base to implement different approaches can be daunting. Rely on experts to dispense this information, but not random "personal trainers." Forge a relationship with trainers in your area and discuss your specific needs for your patient population. Develop a network of trusted options and track progress as your patients engage.
A simple text that I find very helpful for patients of all abilities is The New Rules of Lifting Supercharged: Ten All-New Muscle-Building Programs for Men and Women, by Lou Schuler and Alwyn Cosgrove. Search the Internet for tools that work in your practice; learn to rely on websites of your choosing that offer sound advice that is in alignment with your preferences.
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