Residual Risk for Heart Attack and Stroke

As the diagram shows, a heart attack usually occurs because a clot completely blocks the artery at a point where the chronic blockage before the attack was not severe enough to justify a stent. The muscle downstream of the blockage dies.

A good friend recently called me because one of his friends had just had a serious heart attack in his mid-40s. He and his friend had been close for a long time and his friend prior to the heart attack was the picture of health. His father is still living and never had a heart attack. His friend ate well, exercised, did not smoke, and had no extra body fat. His blood pressure, sugar, and cholesterol were all normal, and yet he still had a heart attack. My friend asked me why and that is a very good question. I will get to the answer after I give you a better example of residual risk.

There are people who have type 2 diabetes, high blood pressure, high cholesterol, and smoke. They get the message. They stop smoking. They improve their diet. They lose weight. They increase their exercise, and they get their blood pressure, sugar, and cholesterol down to established goals. And they still have a heart attack. That is what we mean by residual risk— there is still a risk of a cardiovascular event even after you have met all the mainstream recommendations and targets. One article describes it like this: “Residual CVD (cardiovascular disease) risk has been defined as the risk of CVD events that persists despite treatment for or achievement of targets for risk factors such as low density lipoprotein (LDL or bad) cholesterol, blood pressure, and glycemia (blood sugar levels”. Some cardiologists think of cardiovascular risk as being almost entirely related to cholesterol or lipid abnormalities. “However, many statin-treated patients remain at a significantly elevated risk of having a major cardiovascular event that is unresolved, despite statin treatment. This is commonly referred to as residual risk.”

The time has come for a major change in the way that we think about heart attack, stroke and other cardiovascular disease. We are addressing markers for the problem rather than the problem itself. The way we think about risk factors and cardiovascular disease is very old. It dates to the days of the rotary dial telephone. We were telling people not to eat eggs because they contained cholesterol since I was a child and that was a very long time ago. To reduce residual cardiac risk much further, we need to change our thinking about the best way to treat these conditions.

Patients who have already had a heart attack have the highest risk of having another heart attack. The Kaiser Permanente healthcare system has a good reputation for evidence-based care generally, but if you look at patients who have had a heart attack in that system, you can see what I mean. the ones who receive usual care –the care that most of us receive — in that system are ten times as likely to be dead in five years compared with those who receive team-based systematic care using a protocol. The patients who received focused team-based care dramatically reduced their risk of cardiovascular and all-cause death and they saved a lot of money doing it.

The reason for this huge difference is even more interesting. Lowering risk factors to established goals is important, but how you lower them is even more important. Dr. Milton Packer is an internationally famous cardiologist known for his work in heart failure. Consider his quote from a diabetes journal: “ However, regardless of how their actions are envisioned, it is now critical for physicians to reconceptualize SGLT2 inhibitors (like Jardiance) as organ-protective agents rather than glucose-lowering drugs. The antihyperglycemic (sugar lowering) action of these drugs represents a tiny fraction of their broad portfolio of effects, which (when fully exercised) cause an adaptive reprogramming of stressed cells in a manner that promotes homeostasis and survival.” In other words, lowering the sugar risk factor is just a small part of the reason Jardiance lowers heart failure hospital admissions by one third compared to other drugs that achieve the same sugar level. Jardiance produces this effect by directly activating the master genetic metabolic survival switch AMPK. AMPK is chronically deactivated in diabetes. Activating it protects every cell and organ in the body. That helps you understand why this drug developed for diabetes lowers the risk of heart failure admissions whether the patient has diabetes or not!

It also helps you understand why combining medications that activate the survival switch in a protocol reduces hospital admissions for heart failure in diabetes by 70% rather than one third. Combining these inexpensive generic drugs provides twice the benefit for one tenth of the cost. These medications that directly or indirectly activate the survival switch include lisinopril, losartan, eplerenone, statins, and metformin.

As you can see at the very beginning of this article, the cardiologist authors wonder when we will ever achieve precision medicine in heart artery disease and other related conditions like diabetes and hypertension. “Precision medicine is increasingly moving health care from a conventional one-size-fits-all approach toward a personalized medicine strategy. For example, patients with certain types of cancer can now make treatment choices based not only on the tumor’s histological type but also on tissue expression of targeted proteins and specific gene mutations. Precision medicine has made less progress in atherosclerotic cardiovascular disease (ASCVD). What will be necessary for us to achieve effective precision medicine in patients with ASCVD?” I would counter with that time is here and now. Every medicine that reduces the risk of heart attack more than it lowers the target risk factor also activates the master genetic metabolic survival switch AMPK. Activating AMPK may also delay the development of cancer.

There is another cause of residual cardiovascular risk. Chronic diseases are not caused by gene mutations or permanent changes in the DNA code itself. They are not caused by abnormal DNA or genes. They are more often caused by normal genes that are essential to healthy organ development and function. For example, the genes that make the hormone angiotensin II are required to develop a normal kidney. That is an essential function. If you gain weight as an adult, abdominal fat causes increased angiotensin II production that increased oxidant levels and inflammation and ultimately suppresses the survival switch. That causes high blood pressure, heart attacks, and heart failure. Losartan directly blocks the effect of angiotensin II and reduces oxidant production and inflammation. Losartan indirectly activates the survival switch. Losartan doesn’t just lower your blood pressure, it interferes with the biology that causes high blood pressure very precisely.

We know enough about the effect of activating AMPK and genetic regulation in cardiovascular disease to design our protocols to maximize that effect. When we do that, we dramatically reduce residual cardiac risk.