Inflammation

Antonio: While we are terrified of getting infected by a bug and dying of an overwhelming infection, nowadays it is more likely that we are hurt by an overwhelming inflammation rather than worrying about an infection.

Brent: Welcome to Death Clock. I'm your host, Brent Franson. Today we speak with Doctor Antonio about inflammation. In particular, we're talking about chronic low-grade inflammation—inflammation that is happening inside the body and can contribute to the risk for heart disease, diabetes, dementia, and Alzheimer's. I feel like it's a topic that a lot of people are aware of.

Brent: They're aware that inflammation is an issue, but we just don't know that much about it. Doctor Abbate is a wonderful resource and it's a good conversation. I hope you enjoy it and learn as much as I did.

Brent: Doctor. Antonio. Albert, welcome to the show.

Antonio: Good morning. How are you?

Brent: I'm doing very well. I was glad to be able, before we recorded, to flex a little bit of my Italian. You're Italian. I speak preschool Italian, and anytime I can break some of it out, I feel good about it.

Antonio: I don't want to say it.

Brent: So today we're going to talk about inflammation. I've been really excited about this topic because it falls into these set of episodes that we do where I think everybody knows the word and has some concept of what it is, but the depth of that understanding is pretty limited, and often what we think it is is wrong.

Brent: When I think about inflammation, I just think about redness on my arm or something. I think the meat of what we'll talk about is inflammation inside of the body. But before we get to that, can you give a little bit of your bio and your day job?

Antonio: Yes. As you mentioned, I was born and raised in Italy, came to the United States 21 years ago and joined Virginia Commonwealth University first, and then moved to the University of Virginia. I'm a cardiologist and professor of medicine, and I spend my time taking care of patients and doing research—mostly clinical trials at this time.

Antonio: And they're focused on inflammation, as you mentioned.

Brent: Can you specialize in inflammation? How is that as a subspecialty, or is it just something you pay more attention to as a cardiologist?

Antonio: Well, it's great you ask that because we are working with professional societies to create a subspecialty that would be called cardio-immunology or cardio-rheumatology. But as of now, it's really a group of cardiologists that has an interest and passion for inflammation. It can take different flavors: it can be an interest in how inflammation increases risk, or how the heart can be affected in other diseases of dysregulated inflammation.

Antonio: Depending on what angle you take, the name may change some.

Brent: When you hear the word inflammation or in the context in which you use it, what are you referring to? What is inflammation?

Antonio: It sounds like a simple question, but it's actually pretty complicated. You mentioned earlier that when you think about inflammation, you think about redness and swelling. That's where the name comes from—from the Latin for "being on fire." Having redness, pain, swelling, and dysfunction of the organ are key points of an inflammatory response.

Antonio: Now, thousands of years later, we know a lot of the molecular mechanisms and cells involved in inflammation, which has made it pretty complicated. When I try to explain what inflammation is to a patient or a friend, I say it is a coordinated response of your body, in terms of cells and molecules, that enhances your sensitivity and reaction to injury.

Antonio: I explain that this largely derives from evolution in our ability to sense and react to infection. If our body is being invaded by a microbe, we want to recognize the microbe and fight it. However, we now know that a lot of inflammation is not infectious, and we sometimes refer to that as sterile inflammation, where there is no pathogen.

Antonio: We know that inflammation can be chronic, can be dysregulated, and in some cases can be completely reactive against ourselves. We call that autoimmunity.

Brent: Maybe there's a couple of axes here in terms of inflammation. On one axis, there seems to be a spectrum of severity. Would the far end of that axis be an allergic reaction, with general inflammation somewhere along the path but much more mild, or should we think about it differently?

Antonio: It's a broad category. As you pointed out, there are different names and specialties. For example, if I think of allergy, I think of a specific form of inflammation that involves specific cells like eosinophils and mast cells, specific molecules like immunoglobulin E, and mediators like histamine.

Antonio: For me, an allergic reaction is an inflammatory reaction that includes those specific responses that can be treated with certain types of drugs. When you have an infection, the types of molecules and cells involved are usually different from an allergic reaction. It's more about neutrophils, macrophages, and cytokines like interleukin-1 and interleukin-6.

Antonio: And the treatment requires a different kind of approach.

Brent: In all cases, it's an immune response to something occurring in the body, intended to resolve an issue, but with a negative side effect. That's probably overly simple, but is that directionally correct?

Antonio: I think you're right. When we refer to immune responses, we mean the involvement of white blood cells (immunocompetent cells) or mediators involved in our natural response to infection. While we are terrified of getting infected by a bug and dying of an overwhelming infection, nowadays it is more likely that we are hurt by an overwhelming inflammation rather than an overwhelming infection.

Antonio: The reaction to an infection can be exaggerated, very severe, fail to resolve, and cause more damage. The classic example of this is what we learned from COVID-19 and SARS-CoV-2. The virus infected millions of people; some cleared the virus rapidly without issues.

Antonio: Others, as they tried to clear the virus, had an excessive reaction: the inflammation became hyper-inflammatory, and they ended up on ventilators due to severe lung inflammation. Then there's another spectrum—people who are immunodeficient and cannot mount a reaction at all.

Antonio: When immunodeficient individuals face a virus or bacteria, they may be unable to defend themselves and face grave danger. But for the most part in adult life, we deal with excessive inflammation rather than deficient inflammation.

Brent: So the immune system is well-intentioned and trying to defend itself, but the defense mechanism is actually worse for the body than the underlying issue it's fighting against.

Antonio: Perfect. You said it perfectly.

Brent: Why is that? Does it have to do with modern medicine solving things so we don't rely on the immune system as much, or has that always been the case?

Antonio: Our hygiene has changed dramatically. We are always in contact with microbes, but our ability to access clean water, clean food, and maintain hygiene around wounds has drastically reduced the number of infections we need to fight.

Antonio: What I tell my patients as an example is: if you have a cut on your foot that gets infected by bacteria, you want to sense that rapidly. You want to detect it right away so you can clean it up, remove what's hurting your foot, and let it heal so the infection doesn't spread.

Antonio: If you have trouble sensing it—for example, if severe diabetes reduces your sensation—the infection may spread so far that by the time you realize it, you could lose your foot. That's why sensing it is important. Inflammation causes pain, redness, and sometimes fever or feeling sick.

Antonio: It forces you to rest so that healing can occur.

Brent: In the context of what we want to focus on today—inflammation inside the body that you can't easily see or feel—it seems to come up more as we learn about key biomarkers like blood glucose, A1C, cholesterol, LDL, HDL, and triglycerides.

Brent: There's a growing theme that internal inflammation is a major hidden threat we should take as seriously as those other markers. Even if you can't see or feel it, it significantly impacts health. Do you agree with that?

Brent: Is that is that a reasonable summary?

Antonio: You summarized it clearly. I'll expand by saying that there are different types of inflammation. What you're referring to is chronic low-grade inflammation and inflammatory risk. This is distinct from acute inflammation following an event or injury, where inflammation serves a repair role.

Antonio: It also differs from autoimmune conditions like rheumatoid arthritis or lupus, where the system attacks self-tissue. We are discussing low-grade chronic inflammation that elevates cardiovascular risk. Modern changes in lifestyle have created new challenges in this regard.

Antonio: Poor diet and lack of exercise predispose us to a chronic inflammatory state. If a biomarker indicates elevated internal inflammation that isn't due to acute causes, you may be at higher risk for a cardiovascular event like a heart attack or stroke compared to someone without systemic inflammation.

Antonio: You can't feel this like a fever; it's a low-grade process in the body.

Brent: It sounds like heart disease, which is called a silent killer because you can't feel it happening, yet it's a huge impediment to lifespan. You don't get regular signals from your body until a blood test reveals red flags.

Brent: What is actually happening at the cellular or organ level during chronic low-grade inflammation?

Antonio: We've known about the connection between inflammation and disease risk for a long time, but we are still studying the precise molecular mechanisms. We don't know exactly what prompts chronic low-grade inflammation in every individual, and different people likely have different triggers. However, we can measure systemic markers in the blood.

Antonio: This systemic inflammation reflects both a predisposition to inflammatory responses and the presence of irritants. It alters the body's response to factors like cholesterol. When cholesterol deposits in blood vessels throughout the body, including the heart and brain, it predisposes you to heart attacks and strokes.

Antonio: When cholesterol deposits, immune cells activate to engulf and dispose of it. Because there is too much cholesterol, they fail and instead trigger injury to the vessel wall.

Antonio: In addition to cholesterol crystals in the artery wall, an inflammatory process inside the plaque makes it vulnerable. Most of us have plaques that build up over time and progress with age.

Antonio: The more circulating cholesterol you have—especially oxidized LDL, which is highly pro-inflammatory—the more it builds up, creating an inflammatory response that makes the plaque vulnerable to rupture. When a plaque ruptures, blood cells form a clot to seal it.

Antonio: Normally, platelets plug a tear so you don't bleed out. But in this setting, the reaction is exaggerated, forming an excessively large clot that completely blocks the artery. This cuts off oxygen and blood flow, causing a heart attack or stroke.

Brent: These factors are closely interrelated. When evaluating heart disease risk, standard lipid biomarkers include LDL, HDL, total cholesterol, triglycerides, ApoB, and Lp(a).

Brent: For inflammation, we use a different set of biomarkers. Is there a gold-standard marker for inflammation similar to cholesterol or blood pressure?

Antonio: Yes, absolutely. The preferred biomarker for inflammation is high-sensitivity C-reactive protein (hs-CRP). While there are many inflammatory markers, CRP was identified long ago as a protein that rises sharply during acute inflammation to assist with immune defense.

Antonio: Even within the standard normal range of CRP, individuals vary. Higher levels within that normal range indicate low-grade systemic inflammation. hs-CRP is an effective biomarker for detecting that risk and monitoring it over time.

Brent: Looking at reference ranges, high is generally considered above 10 mg/L, while optimal is 1 mg/L or below. Is that correct?

Antonio: When evaluating C-reactive protein, it is important to distinguish high-sensitivity CRP from standard CRP. Both measure the same molecule, but high-sensitivity CRP is more precise at lower levels and is reported in mg/L rather than mg/dL.

Antonio: A population study established that 99% of healthy individuals have an hs-CRP level under 3 mg/L. Within that group, levels under 1 mg/L represent the lowest cardiovascular risk, while levels between 1 and 3 mg/L indicate intermediate risk.

Antonio: Levels above 3 mg/L indicate higher risk. For simplicity, many clinical trials use 2 mg/L as a single cutoff point. However, risk exists on a continuous spectrum; it doesn't suddenly jump between 1.99 and 2.01 mg/L.

Antonio: Like LDL or blood pressure, risk increases linearly. Below 1 mg/L indicates very low risk, while 2 mg/L is a reasonable cutoff for identifying elevated risk.

Brent: How do you view the interplay between these markers? My hs-CRP is less than 0.2 mg/L, which is optimal, but I have high cholesterol.

Brent: How do you evaluate someone with low hs-CRP but elevated cholesterol, versus someone with normal cholesterol but high hs-CRP?

Antonio: I evaluate both carefully. In your case, I would check if you are on treatments that lower C-reactive protein. Total cholesterol has been recognized as a cardiovascular risk factor for decades.

Antonio: We have refined our understanding over time by focusing on LDL ("bad" cholesterol), HDL ("good" cholesterol), and ApoB as key drivers of risk.

Antonio: For LDL cholesterol, lower is generally better. If your LDL is elevated, your cardiovascular risk increases. If both LDL and hs-CRP are elevated, the combined risk roughly doubles.

Antonio: Having both LDL and hs-CRP elevated puts you in a high-risk category. If only one is elevated, risk is intermediate; if both are normal, that is the ideal scenario.

Brent: Having one marker elevated while the other is normal is better than having both elevated, but not as optimal as having both in the normal range.

Antonio: Correct. Some experts debate whether LDL or hs-CRP is a stronger predictor, with some data suggesting CRP may be more powerful depending on the LDL baseline. The simplest view remains: both normal is ideal.

Antonio: Both abnormal indicates high risk requiring immediate action, while one abnormal indicates intermediate risk.

Brent: If you had to rank key cardiovascular biomarkers—such as LDL, hs-CRP, blood pressure, HDL, ApoB, and Lp(a)—how would you prioritize them?

Brent: Would you place LDL and hs-CRP tied at the top, and what would follow in second or third place?

Antonio: It isn't a simple binary normal/abnormal evaluation. For instance, with blood pressure, having a reading of 145 mmHg carries a very different risk level than 205 mmHg. Severe hypertension dramatically elevates stroke risk regardless of other biomarkers.

Antonio: With mild elevations, lifestyle modifications are a reasonable first step. Simply labeling LDL as abnormal is insufficient on its own. Individuals with familial hypercholesterolemia have genetic defects impairing LDL clearance.

Antonio: When LDL levels exceed 300 mg/dL, those individuals are at extremely high risk and require immediate treatment regardless of other markers. Risk assessment requires a comprehensive evaluation of LDL, hs-CRP, blood pressure, blood glucose, BMI, and physical fitness.

Antonio: Lp(a) and ApoB testing further refine the LDL assessment, particularly in intermediate-risk cases.

Brent: Target blood pressure guidelines seem to be shifting lower over time—from 140/90 to 130/80 or even below 120/80 mmHg. Where do you draw the line for an optimal target?

Brent: Is lower always better?

Antonio: Optimal systolic blood pressure is generally between 110 and 120 mmHg. However, medical interventions carry potential side effects.

Antonio: When treating patients with blood pressure between 120 and 130 mmHg, responses vary. For patients who have had a heart attack or stroke, lowering blood pressure to 120 mmHg is critical.

Antonio: Blood pressure risk follows a J-shaped curve rather than a linear one: excessively low blood pressure presents its own risks.

Brent: Returning to CRP: what primary drivers cause elevated levels? How much is driven by lifestyle factors like sleep, diet, and exercise versus genetics?

Antonio: If an hs-CRP test yields a very high result—above 10 or 20 mg/L—an active, unrecognized infection or acute inflammatory process is likely present.

Antonio: In those cases, a clinical evaluation should be performed to identify and treat underlying issues, such as a tooth abscess, followed by retesting after a few weeks.

Antonio: CRP is produced by the liver rather than the heart, and its associated risk spans multiple conditions beyond cardiovascular disease.

Antonio: If hs-CRP remains modestly elevated (around 3 to 4 mg/L) without acute infection, two main factors are typically involved: a heightened innate immune system sensitivity, and specific lifestyle triggers.

Antonio: Triggers include diets high in animal fats, processed foods, and refined carbohydrates, as well as smoking and environmental toxins.

Antonio: Regular physical exercise has anti-inflammatory effects, whereas sedentary habits, poor sleep quality, and sleep apnea promote systemic inflammation.

Antonio: Occasionally, lean, fit individuals who maintain healthy habits still present with elevated systemic inflammation.

Brent: When someone presents with an hs-CRP of 3 or 4 mg/L without an active infection, are specific medications prescribed to target that inflammation directly, similar to prescribing a statin for cholesterol?

Antonio: Statins play a key role here. CRP serves primarily as a risk marker rather than the direct cause of damage, so current treatments focus on reducing the upstream drivers of inflammation rather than neutralizing CRP directly.

Antonio: If hs-CRP is elevated, a physician will evaluate overall cardiovascular risk. If elevated CRP is the sole risk factor, benefit from medication may be minimal.

Antonio: However, in individuals with low-to-moderate risk and multiple risk factors, an elevated hs-CRP supports prescribing a statin. This approach was validated in the JUPITER clinical trial.

Antonio: The study evaluated older adults with normal LDL cholesterol but hs-CRP levels above 2 mg/L and additional risk factors like hypertension. Participants were randomized to receive either rosuvastatin (Crestor 20 mg) or a placebo.

Antonio: Patients taking rosuvastatin experienced significantly fewer cardiovascular events, including heart attacks, strokes, and embolisms.

Brent: So in that study, participants with normal LDL but elevated CRP showed improved outcomes on a statin compared to the control group.

Antonio: Because rosuvastatin also significantly reduces LDL cholesterol, it remains unclear whether the benefit resulted primarily from lower LDL, reduced inflammation, or both.

Brent: It sounds like we don't currently have medications designed specifically to target inflammation itself. Do GLP-1 receptor agonists (like Ozempic) impact inflammatory markers?

Brent: Anyway. They're going to our statins. Do we know if our GLP ones, your zenpix etc. have an impact?

Antonio: Yes. Interventions that improve metabolic health, diabetes control, or blood pressure generally reduce hs-CRP and overall cardiovascular risk.

Antonio: Lifestyle factors like regular exercise and weight loss also reduce hs-CRP. Regarding dedicated anti-inflammatory therapies: targeted options are actively being developed.

Antonio: Ongoing clinical trials are testing targeted therapies aimed at inhibiting pathways that prompt CRP production. While specific new agents are not yet approved, colchicine—an older gout medication—has demonstrated efficacy in reducing cardiovascular risk in patients with coronary artery disease.

Brent: If someone with an elevated hs-CRP takes antibiotics, will that lower their score, or are antibiotics unrelated?

Antonio: If elevated CRP is not driven by a bacterial infection, antibiotics will have no effect on lowering it.

Brent: How does internal inflammation connect to metabolic health and diabetes risk?

Brent: But I feel like I'm not going to.

Antonio: Diabetes involves impaired glucose regulation, affected by pancreatic insulin secretion and how effectively muscle and liver tissues extract glucose from circulation.

Antonio: Systemic inflammation disrupts metabolic pathways. Acute severe infection causes major disruptions, but chronic low-grade inflammation also impairs glucose metabolism and significantly increases the risk of developing diabetes.

Antonio: Okay.

Brent: So inflammation interferes with processing and storing glucose efficiently. What about the link between chronic inflammation and cognitive health, including dementia and Alzheimer's disease?

Brent: Alzheimer's, cognitive health. What's the connection there?

Antonio: Systemic inflammation worsens the prognosis of many chronic degenerative conditions. Higher hs-CRP correlates with increased dementia risk, particularly vascular dementia.

Antonio: To address a common concern: the concern that statins impair cognitive function has been thoroughly evaluated and disproven in clinical trials.

Brent: Given your research into cardiovascular health and inflammation, how do you personally manage these risks through diet, lifestyle, or supplements?

Antonio: Prevention is essential. In busy schedules, routine physicals, lab testing, and healthy meal planning can easily be overlooked. Healthy living begins with sound nutrition.

Brent: Whichever one you, whichever one you want to be. It's interesting to hear both.

Antonio: A Mediterranean diet offers proven anti-inflammatory benefits. Plant-based fats, such as olive oil, provide protective effects compared to saturated animal fats.

Antonio: Pro-inflammatory foods should be minimized. Regular physical exercise serves as a powerful anti-inflammatory, and physical fitness should be tracked as a key health metric.

Antonio: Avoiding tobacco and smokeless tobacco is critical, as both promote inflammation. Given my family history of cardiovascular disease, I proactively discussed my biomarkers with my physician, which I encourage everyone to do.

Do you take daily supplements like omega-3s or creatine, or recommend specific supplements to patients?
Antonio
That applies also to smokeless tobacco. That's unnecessary, pro-inflammatory. And so but I'll tell you one more thing is that when I as I was growing, going older and I have a family history of heart disease, I did talk with my doctor about what were the my biomarkers and what can I do to reduce the risk. So that's what I would encourage people to do to have that conversation early.

Brent: But you don't have some this here, this is the go to supplement or you know, there's not some obvious I take your creatine every day or your omega three supplement.

Antonio: I do not take supplements or routinely recommend them. While most supplements are safe and some patients report feeling better, a well-balanced diet generally eliminates the need for dietary supplements to lower cardiovascular risk.

Brent: What about targeted supplements, such as CoQ10 for statin users experiencing muscle aches?

Antonio: Some patients experience muscle discomfort with statins, and a subset reports symptom relief with CoQ10 supplementation. While I do not routinely prescribe it proactively, alternative statin formulations or non-statin lipid-lowering therapies can also address muscle side effects.

Antonio: I haven't been prescribing it, certainly not proactively. And, you know, if someone has myalgia when taking a statins, there are different statins with different profile. And there are also STAT and, cholesterol lowering medications.

Brent: Looking ahead over the next 10 to 20 years, what clinical developments in inflammation research excite you most?

Antonio: It is an exciting period for inflammation research, with major advances expected over the next decade. Managing residual inflammatory risk is particularly vital for patients with established cardiovascular disease, prior stents, bypass surgery, hypertension, or diabetes.

Antonio: Persistent inflammation despite optimal standard treatment places patients in a high-risk category. Conversely, a young, physically fit individual with no additional risk factors and only mildly elevated hs-CRP remains at low absolute risk and can generally manage it through healthy lifestyle habits.

Antonio: Current research focuses primarily on high-risk patients who have experienced a heart attack, stent placement, or heart failure. Clinical trials are testing whether targeted anti-inflammatory drugs prevent secondary complications.

Antonio: Applying these specialized therapies to the broader population will take additional time and study.

Brent: Where can listeners learn more about your work and inflammation research?

Antonio: Professional organizations like the American Heart Association and the American College of Cardiology provide excellent resources. To learn more about our ongoing studies, visit the University of Virginia website.

Brent: Grazie mille, Doctor Abbate. Molte grazie.

Antonio: Grazie a lei. É stato un piacere.

Brent: Death Clock with Brent Franson is produced by Patrick Andino.

Unknown: Music by Patrick.