This is How You Will Die (and How to Stop It)
Although you cannot predict when you will die, you can easily predict how you will die.
For the last one hundred years, the most common killer of Americans of all ages was heart disease. It is also the leading cause of morbidity and mortality worldwide.
“Heart disease” is an expansive category, encapsulating heart attacks, arrhythmias, heart valve disease, heart muscle disease, and heart failure.
Virtually all heart attacks and many cases of heart failure and valvular disease stem from atherosclerosis, the formation of cholesterol plaques in artery walls. Although not all forms of heart disease are caused by atherosclerosis, most heart disease is driven by the same health behaviors that fuel the growth of atherosclerotic plaques.
Such behaviors are likely already regarded as “unhealthy”:
Poor diet (i.e., consuming excessive amounts of refined carbohydrates, sugar, sodium, and saturated fats; not consuming enough fiber or protein)
Insufficient physical activity
Tobacco use
Beyond heart disease, these behaviors contribute to conditions such as high blood pressure, diabetes, kidney disease, and obesity, which in turn increase risk for nearly every other common cause of death:
#2 most common cause of death, cancer
Diabetes: increased risk of colon, breast, and pancreatic cancer
Obesity: increased risk of esophageal, pancreas, thyroid, gallbladder, colon, breast, endometrial, and kidney cancer
Low-fiber, high saturated-fat diet: increased risk of colon cancer; may influence breast cancer
Smoking: increased risk of lung, cervical, esophageal, stomach, pancreatic, bladder, liver, and kidney cancer
#4, COVID-19
Increased risk of mortality from diabetes, heart disease, obesity, poor exercise habits, smoking
#5, stroke
Caused by atherosclerosis and high blood pressure
#6, chronic lower respiratory disease
Deeply influenced by smoking; influenced by obesity
#7, Alzheimer disease
#8, diabetes
Deeply influenced by diet and exercise
#9, kidney disease
Influenced by smoking and obesity
#10, chronic liver disease and cirrhosis
Influenced by obesity
Atherosclerosis and its causal health behaviors can thus be conceptualized as a keystone disease process that significantly influences the leading causes of mortality.
If we intend to forestall death for as long as possible, we must get serious about preventing and treating atherosclerosis.
Before addressing strategies we can put into practice, we must first understand what drives this atherosclerosis and why taking action is so beneficial to our long-term well-being.
Too Long; Didn’t Read (TL;DR)
What to do:
Measure resting blood pressure at least weekly to monthly, aiming to maintain below 120/80
Measure HbA1c at least annually, aiming to maintain below 5.7%
Measure LDL-C with a lipid panel at least every three years, aiming to maintain below 70 mg/dL, ideally as low as possible beginning as early in life as possible
Note that this recommendation diverges from current guidelines for cholesterol management. How Low Should You Go? discusses my rationale for this discrepancy.
Cessation of tobacco use
How to achieve these goals:
Regular moderate and vigorous cardiovascular exercise and resistance training
Before embarking on a novel exercise program, it is best to consult with a trusted health care provider, particularly if you have pre-existing cardiovascular conditions. Please also note my disclaimer about medical advice.
Consume a largely plant-based or Mediterranean-style diet consisting of vegetables, fruits, nuts, whole grains, and plant-based or lean animal-based proteins
Leverage tobacco cessation aids
Utilize medication to manage blood pressure, blood sugar, and cholesterol, if warranted
The Bedrock of Atherosclerosis
Arteries form part of a beautifully dynamic system: layers of smooth muscle expand and contract based on an interplay of chemical and physical signals. The inside surface of an arterial wall is known as the intima. Atherosclerosis starts with weakening of the intima, most commonly from the shearing stress of high blood pressure but also from smoking, chronically elevated blood sugar, and natural stiffening as we age.
Once the integrity of the intima is breached, immune cells and cholesterol-carrying molecules called “lipoproteins” begin to invade the lining. Among those lipoproteins is low-density lipoprotein (LDL). By virtue of crafty marketing, cholesterol carried by LDL (called LDL-C), is now commonly known as “bad cholesterol.”
Platelets also adhere to the damaged intima and signal for smooth muscle-building cells (SMCs) to begin a crude attempt at healing. SMCs ingest cholesterol delivered by lipoproteins, which are degraded and absorbed by immune cells. Together, those immune cells and SMCs form a “fatty streak” along the intima, the forerunner to a plaque.
(A landmark 1998 study of 3,000 forensic autopsies found that all U.S. teenagers sampled already had fatty streaks present in segments of their arteries.)
Over time, cholesterol continues to feed into the fatty streak, prompting SMCs to deposit collagen and other fibrous material on top of the lesion, forming a plaque. This fibrous cap, however, is very weak and even minor stresses can cause it to rupture. This rupture leads additional platelets to quickly form a blood clot at the site. The blood clot might then completely block that artery (already narrowed by atherosclerosis) or the clot might break off and travel to block another artery.
The result is the same: blood can no longer reach part of an organ, starving it of oxygen and prompting the tissue to die. This process is called “ischemia.” If this blockage occurs in the heart, it causes a heart attack. If this blockage occurs in the brain, it causes an ischemic stroke.
The process of atherosclerosis takes place silently over decades, amidst holiday barbeques and smoke breaks. For most, the effects will only manifest in the second half of life, just as the carefree joy ride of youth is coming to a close. And those effects do not come knocking lightly.
The most common presenting symptom for heart disease is not chest pain nor shortness of breath nor nausea and vomiting. It is sudden death.
This is a fate, I expect, that we would all like to avoid.
Preventing Intimal Damage
Although it is vital to manage cholesterol and lipoproteins, our efforts should first focus on preventing the foundation of atherosclerosis. As noted, the presence of high blood pressure, chronically elevated blood sugar, and toxins from smoking cigarettes or vaping damage the intima, initiating the process of atherosclerosis.
Managing High Blood Pressure
Elevated blood pressure is known as “hypertension.” Conventionally, a resting blood pressure consistently above 130/90 is termed hypertension. A resting blood pressure at or below 120/80 is considered optimal. (The top number is your “systolic” blood pressure; the bottom number is your “diastolic” blood pressure.)
Similar to atherosclerosis, hypertension is a silent killer. Only at the extremes will signs and symptoms become readily apparent. In the absence of regular screenings, a patient is likely to be unaware they harbor this substantial risk factor for heart disease, stroke, kidney disease, and dementia.
I recommend frequent monitoring of blood pressure, ideally at least once a month. This can be performed by using an at-home blood pressure cuff or a free machine at a pharmacy or grocery store.
Even if you are currently “normotensive” with a resting blood pressure consistently below 120/80, you should continue regular monitoring and work to maintain your blood pressure in a healthy range.
If your blood pressure places you into the hypertensive range, work with a trusted healthcare provider to determine the best approaches to lower your blood pressure. If your blood pressure is already above 140/90, your clinician may recommend starting a medication to lower your blood pressure.
We can expect a single anti-hypertensive medication to lower systolic blood pressure (SBP) by about 10 to 15 points. Every 10-point decrease in SBP corresponds to a decreased risk of 20% in developing atherosclerotic cardiovascular disease (ASCVD), 27% in stroke occurrence, and 13% in overall mortality.
In conjunction with medication or in its absence, it is safe for most to undertake lifestyle changes on their own to reduce their blood pressure. There are three key levers we can pull to lower blood pressure in the form of exercise, diet, and smoking behavior.
Exercise
Aerobic exercise: obtain moderate intensity (Zone 2) exercise for at least 150 minutes per week. See my post about Zone 2 and Zone 5 training. Various research suggests that consistent aerobic exercise will decrease SBP by 4 points to 12 points.
Isometric resistance training: contraction exercises held for two minutes for four rounds three times a week was recently found to decrease SBP by 8 points.
With the appropriate exercise regimen, we can mirror the effects of a single medication.
Diet
DASH diet: consuming whole grains, fruits, vegetables, and lean proteins while limiting consumption of fatty meats, dairy, sugar-sweetened beverages, and other sweets can reduce SBP by 7 points to 11 points.
Again, with the appropriate dietary changes we can mirror the effects of a single medication.
Weight Reduction
As achieved through exercise and dietary changes, every 2.2 pounds (1 kg) lost corresponds to a one-point reduction in SBP.
Optimizing protein intake can be an additional strategy to promote weight loss through reducing hunger.
Tobacco Use
Smoking cessation can decrease SBP by about 4 points.
Emerging research consistently suggests that vaping still promotes the same intimal damage that precedes the formation of atherosclerotic plaques.
More research is needed, as some work suggests that switching from cigarettes to vaping can lower SBP by as much as 10 points.
As an aside, the use of nicotine gum, lozenges, and pouches as a cognitive aid is increasingly popular. In isolation, nicotine acutely raises SBP by about 5-10 points, an effect that persists for 90 minutes or longer and likely ceases around 120 minutes. There is little evidence regarding the effects of long-term non-tobacco nicotine use on blood pressure.
Despite the dearth of evidence, I do expect long-term use of non-tobacco nicotine to increase systolic blood pressure as well as other risk factors of ASCVD. This rationale is explained in Up in Smoke:
Managing High Blood Sugar/Diabetes
High blood sugar is known as “hyperglycemia.” Similar to hypertension, someone may only become aware their blood sugar is high when it reaches an extreme level.
To understand a patient’s risk for diabetes (which contributes to atherosclerosis as well as kidney disease and cancer), we need to understand trends in their blood sugar over time. The best clinical test available is hemoglobin A1c (HbA1c), which measures the degree to which red blood cells have carried sugar over the last three months.
Higher A1c values correspond to higher average blood sugar levels. Conventionally, a patient has type two diabetes if their A1c is 6.5% or higher. An A1c in between 5.7 and 6.4% places them in a pre-diabetic range at heightened risk for the disease.
You should work with a healthcare provider to obtain a baseline HbA1c. Depending on the result, the provider may suggest a plan to routinely recheck this level, ideally every three to six months.
If your A1c is above 7.5%, your provider will likely recommend starting a medication. Between 6.4% and 7.5%, a trial of lifestyle modifications is usually recommended before considering medical therapy. Reducing A1c below 7% can decrease ASCVD by 37% over eleven years.
In conjunction with or in the absence of medical therapy, implementing changes to exercise and dietary habits can also have substantial impact on blood sugar levels.
No single diet has proven to be consistently optimal for blood sugar regulation, although adherents to the DASH diet do tend to show lower rates of diabetes. Generally, a diet that is rich in legumes, nuts, and whole grains as well as limited in red and processed meat, sugar-sweetened beverages, and excess alcohol tends to have the biggest impact on the risk of developing diabetes.
Regular aerobic exercise, such as Zone 2 training, can reduce A1c by 0.5 to 0.7%. Comparable improvements have been observed with regular resistance training.
Dietary changes and consistent exercise can in turn spur weight loss: losing 5 to 10% of body mass (about 10 to 20 pounds for an individual who weighs 200 pounds) is also associated with A1c reduction of 0.6 to 1.0%.
Managing Smoking
The use of cigarettes and vaping can increase atherosclerosis directly through the interaction of toxins with the intimal wall and indirectly through effects on blood pressure.
This lifestyle modification is the most straightforward: stop smoking.
At the same time, overcoming an addiction to nicotine can be just as difficult as consistently consuming a healthy diet or exercise five days a week. Given the length of this piece at present, I will not exhaustively discuss tobacco cessation here. There are numerous resources available online, including SmokeFree and information from the American Cancer Society.
Either on your own, or with the help of a healthcare provider, you can pursue nicotine replacement therapy in the form of patches, gum, or lozenges (recall the above caveat that long-term use of nicotine replacement therapy may increase ASCVD risk). A clinician can also recommend the use of prescription medication (Wellbutrin and Chantix are among the most common) and behavioral therapy to further aid in quitting.
The Fatty Elephant in the Room
We will next address the role of cholesterol and lipoproteins in atherosclerosis.
Along with implementing the above modifications, it is imperative to regularly monitor your lipid panel. Most clinicians will recommend obtaining this blood work at least annually.
Perhaps the most important component of a lipid panel is LDL-C, the so-called “bad cholesterol.” As mentioned above, LDL and other minor lipoproteins fuel atherosclerosis. Although LDL-C is not the most precise measurement of atherosclerotic risk, it is a robust surrogate and the most studied.
Apolipoprotein B (ApoB) is regarded as the most accurate test available for assessing atherosclerotic risk and is usually cheaper than a lipid panel. Still, measuring ApoB has yet to be broadly integrated into clinical practice. Medicine can at times advance at a snail’s pace.
The goal in measuring (and subsequently decreasing) LDL-C is step-wise:
prevent the formation of new atherosclerotic plaques;
stabilize current plaques and stop them from growing further;
decrease the size of current plaques.
All three goals are likely met starting at an LDL-C of 70 mg/dL or lower. For an even higher degree of certainty of meeting all three goals, I recommend achieving the lowest possible LDL-C starting as early in life as possible.
These recommendations are notably lower than those used by most clinicians in the United States. Some providers may recommend no intervention for an LDL-C level of 190 mg/dL in younger patients with no or few risk factors for ASCVD. This is severely misguided.
A more exhaustive explanation of my reasoning is addressed in How Low Should You Go? In short, LDL-C should be measured serially (ideally annually or at least once every three years) in all adult patients (including those as young as 18) and target LDL-C should be 70 mg/dL or lower, ideally as low as possible.
The most powerful lifestyle modifications at our disposal are again diet and, to a much lesser degree, exercise.
A diet low in saturated fats and refined carbohydrates and high in unsaturated fats, protein (especially plant-based protein), and fiber can reduce plasma LDL-C levels by up to 30 to 40 mg/dL. (See Yokoyama et al. (2017) and Ference et al. (2018).)
Regular aerobic exercise, such as the Zone 2 regimen already discussed, can decrease LDL-C by about 3.4 mg/dL, a much smaller effect than that achieved by dietary intervention.
Ultimately, if dietary modification alone does not achieve target LDL-C level, one should consider the use of medical therapy to reduce cholesterol:
Statins, the most common cholesterol-lowering medication, work by decreasing the amount of cholesterol made endogenously in the liver. Although statins can lead to muscle soreness in about 10% of patients, they are otherwise well tolerated and safe. They are also incredibly cheap. Even at its lowest dose (2.5mg once daily), Lipitor, the most common statin, decreases LDL-C by as much as 25%. A daily dose costs $0.08 to $0.25.
Ezetimibe decreases absorption of dietary and endogenous cholesterol in the small intestine, contributing to 17% lower LDL-C on average.
A class of medication known as PCSK9 inhibitors prevent degradation of LDL receptors, allowing LDL to be more effectively removed from the blood. When used alone, PCSK9 inhibitors reduce LDL-C by 30% to 60%; when added to a statin, they can reduce LDL-C another 60 to 65% above that achieved with the statin alone.
The “Good” Cholesterol
Cholesterol carried by high-density lipoprotein (called “HDL-C”) has long been lauded as the “good” type of cholesterol. Unlike LDL (and certain other lipoproteins), HDL does not deposit its cholesterol into vessel walls but instead shuttles cholesterol to the liver to be eliminated from the body.
It was once thought that having more HDL particles available to carry cholesterol would cut off the fuel source for atherosclerosis. Less cholesterol would be available to be transported into vessel walls, and the cholesterol already deposited there could be removed. As a result, there would be fewer atherosclerotic plaques.
Sadly, large epidemiologic studies, targeted interventions to increase HDL-C in isolation, and studying individuals with a genetic predisposition for high HDL-C have routinely found no evidence that high HDL-C levels protect against atherosclerotic disease despite the noted theoretical relationships.
HDL-C should no longer be thought of as “good cholesterol” and aiming for high levels should not be among our objectives.
Let’s summarize:
We should first address the root cause of atherosclerosis: intimal damage.
Regularly monitor resting blood pressure (aim to be lower than 120/80) and hemoglobin A1c (aim for less than 5.7%).
Manage blood pressure with DASH diet, Zone 2 exercise, isometric resistance training, weight loss, and medication (if indicated)
Manage blood sugar with a largely plant-based diet, Zone 2 exercise, weight loss, and medication (again, if indicated)
Stop smoking by utilizing nicotine replacement therapy, adjunct medication, and behavioral therapy
We should then address the source of the “fuel” for atherosclerosis and work to lower LDL-C
Regularly monitor LDL-C at least every three years, ideally annually. Aim for 70 mg/dL or as low as possible.
Manage LDL-C with a largely plant-based diet, Zone 2 exercise, and medication (if indicated)