Understanding the New Frontier in Medicine

A Picture is Worth a Thousand Words!

If you look at the LAD heart artery you can easily see that it supplies most of the entire front half of the heart. If you block that artery where it first takes off with a clot, that kills the heart muscle on the front half of the heart. That greatly impairs the pumping function of the heart because that dead muscle does not contract. Patients with that extensive damage often die of shock or heart failure.

This picture from 1988 is from one of the studies that proved that heart artery stents don’t prevent heart attack in stable patients. The heart catheterization on the left was done two weeks before the patient had a heart attack as shown on the right. Notice that the artery on the left is normal prior to the heart attack. The artery before the heart attack is wide open. There is no blockage. It would not need a stent. The heart attack artery is completely blocked by clot. That is why stents don’t prevent heart attack. We have known that conclusively for nearly 40 years. It is obvious.

This is an artery from a fatal heart attack that helps you understand how the heart attack in the previous slide happened. This is a microscopic slide of the artery cut crossways. This artery was not blocked until the red blood clot formed. The opening in the artery before the clot was normal. The blue material is cholesterol. In the earlier stages of heart artery disease, the cholesterol deposits push out rather than blocking the opening. The white area is from a small collection of pus that forms in cholesterol deposits that ruptured like a pimple. When that pus hits the blood stream it causes a clot and that is what causes heart attacks. Optimal medical therapy reduces soft cholesterol deposits, decreases inflammation, prevents pus formation, and pimple rupture. It stabilizes the artery. That is how it prevents heart attack.

This picture is worth a thousand words! The top artery slice in the middle is a normal heart artery. It is wide open with no cholesterol deposit. Now, look at the third artery slice down from the top in the middle. The artery is wide open but there is a very large collection of cholesterol that is largest at the three o’clock position. Soft, early cholesterol deposits have the consistency of cooked oatmeal. They don’t block the artery. They push the wall out, and may occupy up to 40% of the artery area without blocking the artery at all. There is extensive dangerous cholesterol in this artery with no blockage. The cholesterol deposit becomes inflammed and mixed with pus. It ruptures like a pimple and initiates the clotting process. If the clot is small and blockage is small, there are no symptoms. If the blockage is partial there may be only pain (unstable angina). If the blockage by clot is complete, a heart attack occurs. Now notice the third picture down on the left. As the rupture and clot heals if the patient survives, that causes a blockage made of scar tissue and calcium. That part of the artery is stable. Heart attacks seldom occur at a chronically blocked area like that. This picture of heart attack occuring where the artery is not chronically narrowed is more frequent in women.

This picture also helps you understand how this same process causes stroke and damage to other organs. Optimal medical therapy is the best practice treatment for arterial disease. Now look at the three artery slices on the right. You can see that the soft cholesterol plaque is shrinking. That is why optimal medical therapy is so effective. It stabilizes the artery. Now look at the three artery slices on the left without optimal medical therapy

If you achieve the same blood pressure for a year with losartan vs atenolol, the losartan treated artery becomes more normal (thinner with better expansion) while the atenolol treated artery remains unchanged. You are not just lowering the blood pressure. You are addressing a root cause of arterial disease and you are restoring arterial health while lowering the blood pressure. The way you lower the blood pressure to restore arterial health matters more than the blood pressure reduction itself. This is precision medicine in chronic disease management.

Best practice medical treatment or optimal medical therapy for heart artery disease as it is currently understood by most people is about controlling “risk factors” (high blood pressure, high cholesterol, and diabetes) to specified targets while not smoking cigarettes and taking an aspirin. That model produces the great results we will show later. Those results were produced based on what we knew a quarter of a century ago. Now there is an opportunity to produce optimal medical therapy that is even more effective with precision medicine based on genetics, epigenetics, and signaling cascades in molecular biology. This is an introduction to these ideas

This ia a DNA strand. As you can see there are 4 potential variables in the DNA computer code compared with our computer code which is two variables—zeros and ones. This 4 variable computer code can pack much more information into a smaller space. Mutations or changes in the DNA code involve switching variables in a segment of DNA or cutting out sections of a strand. Changes in the DNA code do not cause most chronic disease. Mutations do not cause most chronic diseases in humans.

Most chronic human diseases like type 2 diabetes, high blood pressure, and heart artery disease are due to changes in gene regulation or epigenetics. Eating fast food and highly processed food leads to weight gain which inappropriately switches genes on or off to cause diabetes, high blood pressure, heart artery disease, and kidney failure leading to dialysis. If these epigenetic changes occur before you have children, they can be passed on to the next two generations.

This picture shows how DNA is tightly wound up in a gene when it is inactive. The picture of the 7 circles at the bottom of the slide shows how methylating the hisone proteins that surround the inactive genes opens the strands of DNA in the gene to activate the gene. The activated genes that cause the conditions listed above all increase oxidant production, inflammation, and master metabolic genetic switch activity to cause these diseases and cancer. The specific medicines in our protocol block the effects of these genes precisely. That is another type of precision medicine. They are antioxidants and antiinflamatories that work to provide much better clinical and financial outcomes.

This is a diagram of an American football play. The square in the middle is the center. The circles on either side are the guards. The N in front of the center and the right guard is the noseguard. The symbol that looks like a T is a blocking simple. So, on this play, the center and the right guard are both blocking the noseguard. The arrow shows where the ball is going. These are the same symbols used in molecular biology. Don’t freak out I. You can easily learn this and that can make all the difference for you and your family. Your understanding of this topic is especially important for the children that are yet to be born in your family. If you want to be healthier longer, it is especially important for you.

Going back to the analogy of a football play diagram, this is the simplest idea in molecular biology. This is the most simple “play” in molecular signaling cascades. Eating activates mTOR. mTOR is the mechanistic target of rapamycin. It is a master metabolic genetic switch. When you activate mTOR with food, it switches on multiple genes that promote growth in the fetus and child. It also promotes growth in the mother, but in that case it is causes the walls of her arteries to get thicker to cause high blood pressure.

The serious complications of pregnancy for mothers that are related to obesity include gestational diabetes, preeclampsia, gestational high blood pressure, the need for cesarean delivery, and blood clots. When the mother overeats (especially fast and highly processed food) and gains weight, that activates the master metabolic gene regulating growth switch mTOR and deactivates the linked master metabolic gene regulating survival switch AMPK. That leads to a very large baby with an increased risk of high blood pressure, type 2 diabetes, and heart attack as an adult. Genes activated during fetal growth remain activated throughout life to increase chronic disease risk

Notice that this most simple signaling diagram is the reverse of the previous one. When the mother is starving, that activates the master metabolic gene regulating survival switch AMPK and deactivates the linked master metabolic gene regulating growth switch mTOR. That leads to a very small baby with an increased risk of high blood pressure, type 2 diabetes, and heart attack as an adult. Genes activated during fetal growth remain activated throughout life to increase chronic disease risk. AMPK and mTOR are linked. They are like dimmer switches. When AMPK is maximally activated in starvation, mTOR maximally deactivated. AMPK activates hundreds of genes in humans that promote survival. In the fetus, and child, AMPK mobilizes calories from fat and muscle to provide the energy to support life in cells and organs until there is food again. AMPK retains this survival effect throughout our lives and every intervention that helps us to live longer, healthier lives at lower cost, activates AMPK.

Increased risk of cardiovascular disease and related conditions like diabetes in families is related to family food and smoking culture. It has been known for many years that an inflammatory diet increases cardiovascular disease in offspring. Ultra-processed foods increase cardiovascular risk There are a host of hormones and enzymes that are increased in the blood of pregnant people who consume inflammatory foods. High calorie malnutrition leads to excess body fat which causes pregnancy complications in mother and child. Its not just the extra weight that causes trouble. Industrial foods have been stripped of vitamins, minerals, and antioxidants that are very important for normal fetal development and the longterm health of the child. Family history is about environmental factors like smoking and diet. You can changes your family history and make your kids healthier.

Now the signaling diagrams are going to get a little more complicated, but you can easily understand.

If you eat fast food and highly processed food and you gain abdominal fat, the fat becomes the largest gland in the body and it makes the hormone angiotensin II. Angiotensin II levels become abnormally high and again just follow the arrows. Angiotensin II increases oxidant production which activates the epidermal growth factor receptor (EGFR). The diagrams I showed you about pregnant women explained the nutrient sensing pathway. This diagram shows the growth factor pathway that activates mTOR and deactivates AMPK. This pathway contributes to the development of cardiovascular disease and cancer. It makes us age more quickly. It causes high blood pressure, and as you see, losartan precisely blocks the effects of increased aldosterone to lower the blood pressure. But, as I showed you before, losartan does not merely lower the blood pressure. By inhibiting mTOR and activating AMPK it protects cells and organs. It makes the artery more normal. That is why losartan protects every cell and organ in the body.

Compare this signaling diagram with the last one. They are almost exactly the same. Angiotensin II is a very important hormone that is a root cause of high blood pressure, chronic kidney disease, and heart failure. Aldosterone is a related hormone that is increased by abdominal fat also and it has the same effects. Aldosterone also activates insulin resistance, oxidants, and inflammation. The big difference is that aldosterone is blocked precisely by eplerenone to protect every cell and organ in the body.

Now check out the enzyme that statins blook. It also stimulates oxidant production in a major way. It activates the epidermal growth factor receptor. It also suppresses AMPK. Statins improve survival after a heart attack by reducing oxidant production, blocking EGFR activation and mTOR activation. Statins, losartan, and eplerenone produce their benefits by blocking growth factor signaling. The pathways that we discussed in pregnant women were nutrient signaling pathways. We can interfere with both nutrient and growth factor activation of mTOR and deactivation of AMPK. The mTOR and AMPK axis plays a central and critical role in chronic disease and aging. Check out this link to a discussion by the leading authority on the topic.

There is another critical fact on this slide. Look down at the bottom and you can see that metformin and Jardiance both directly activate AMPK. Meformin is an extremely interesting medication. It directly inhibits mTOR and directly activates AMPK through the nutrient sensing pathway. These medications you have reviewed so far are powerful anitoxidants and antiinflammatories that that dramatically improve clinical results at lower cost. Lowering the blood pressure, cholesterol, and sugar are important, but the main benefit of these medications is on the core signaling pathways that determine our health from the cradle to the grave.

No clinical trial of aggressive insulin therapy has ever shown a reduction in heart attack, stroke, or mortality in patients with type 2 diabetes. More people died with aggressive therapy in the ACCORD trial. On the other hand, blocking growth factor signaling with losartan, eplerenone, statins, in a protocol dramatically reduces heart attack, stroke, and mortality in these patients. If you give enough insulin, you will absolutely lower the sugar. This is more evidence that lowering the sugar is not as important as impacting the root cause of disease.

This is another side of the growth factor signaling that we have been discussing. You can see in this slide that insulin is a growth factor also. Up until this point we have been discussing EGFR in the growth factor possition. Now we are going to discuss insulin in that same position and it has the same impact as activating EGFR. It activates mTOR and deactivates AMPK. Here is the most interesting thing on this sldie. The more insulin you give, the more it activates mTOR which kicks back and blocks Insulin Receptor Substrate 1 (IRS1) to degrade it and increase insulin resistance in real time. You can easily see that increasing insulin resistance requires more insulin to achieve the same level of sugar lowering in a vicious cycle. Most importantly, research shows that higher insulin levels and insulin resistance make us age and develop chronic diseases faster. Glyburide and glipizide are oral drugs that increase insulin levels as well. This is a critical message for treating people with type 2 diabetes.

We should do everything we can to lower insulin requirements by eating real, whole food and dramtically reducing carb and sugar in the diet while losing weight. That reduces insulin resistance and the likelihood of becoming diabetic. Metformin lowers insulin resistance and should be started when people are prediabetic. Jardiance also lowers insulin resistance. These steps together all reduce insulin requirements. When you understand insulin is a growth factor, you understand we need to focus on ways to lower our requirements for insulin as a priority in our treatment.

These other growth factors can go in the EGFR or insulin growth factor position and when they are persistently activated they continuously activate mTOR and deactivate AMPK to promote cancer growth in many different kinds of tumors. This same signaling pathway causes cardiovascular disease, cancer, and more rapid aging.

This slide shows how the enormous load of oxidative particles in cigarette smoke persistently acitvates EGFR to persistently activate mTOR and deactivate AMPK. That is how cigarette smoke (and other types of smoke) cause lung cancer and emphysema.

Now, please think a minute about what you have learned about the New Frontier in Medicine. Now you understand how poor diet, weight gain, and cigarette smoke cause the same diseases of heart artery disease, diabetes, high blood pressure, heart attack, stroke, chronic kidney disease, heart failure, cancer, and faster aging. Now we understand how diet, exercise, weight loss, stopping smoking, losartan, eplerenone, statins, metformin, and Jardiance block these effects to produce dramatic reductions in heart attack, stroke, and death. Now we are goint to discuss the systems to consistently deliver the interventions.

It doesn’t matter how well you understand the New Frontier in Medical Science if you don’t have the systems to consistently deliver the product.

The prices on this slide are a bit out of date. You can buy the entire proven protocol for about $50. Now you understand why these drugs are on our protocol. I have never seen a provider organization achieve 85-90% high blood pressure control to less than 140/90 without using a protocol. Protocols are a necessary part of achieving the best results. This is a form of precision medicine that healthcare professionals call optimal medical therapy (OMT). OMT is much more effective than usual care—the care that most people receive.

Advanced Outpatient Primary Care Team are just as important as protocols in delivering the best results. Just as with the new science, there is important evidence about what systems work best to deliver the new science. Many things that we try over and over simply don’t work.

“Many approaches have been tried to improve diabetes care but, with one exception, have been mostly ineffective. These include simply reminding patients about appointments; providing laboratory information on the patient to the physician, even when specific treatment recommendations for the individual patient were included; case management when the case manager could not make independent treatment decisions; education of physicians; and multifaceted quality improvement interventions in the practice setting…. The one approach that has proven to be effective is using specially trained nurses or pharmacists, under appropriate supervision, with authority to make medication changes without consulting the physician as long as the changes fell within approved treatment algorithms.”

Optimal medical therapy or precision medicine is much more effective than the care most people are receiving today. This study compares optimal medical therapy with usual care after a heart attack . 628 people received regular care and 628 people received OMT for four and a half years. People who have had a heart attach have a very high risk of death or another heart attack. 8 times as many people receiving regular care died of cardiovascular disease. Almost 12 times as many people died of all causes. There is no more effective treatment in all of medicine.

The effect on all-cause mortality is especially interesting. Increased oxidant production, inflammation, and epigenetic activation of master metabolic switches are root causes for all chronic diseases and more rapid aging. The protocol above blocks these factors precisely to delay chronic disease development, manage chronic diseases more effectively, and slow the rate of aging. This precision medicine approach also dramatically reduces costs.

This slide compares the results of optimal medical therapy with precision medicine or usual care in people with type 2 diabetes complicated by chronic kidney disease. These folks also have a very high risk of heart attack, stroke and death. Notice that the people receiving OMT have one fourth as many heart attacks, one fifth as many strokes, and one sixth as many people go on dialysis. People on OMT live 8 years longer and they are healthier. Hospitalizations for heart failure are reduced by 70%. After 13 years of treatment, half of the usual care people were dead. Many more people survived longer with OMT.

Programs that only target type 2 diabetes have limited effect. This study shows that best practice treatment for high blood pressure, high cholesterol, not smoking, and taking aspirin are equally important. Healthcare costs are reduced by another 50% when the same team provides optimal medical therapy for patients who have had a heart attack, stroke, chronic kidney disease, or heart failure. You can’t realize the full benefit of treating cardiovascular conditions without the new science and systems.

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