Key Points

Standard therapy leaves 70-80% of cardiovascular risk remaining, but lifelong low LDL linked to an uncommon gene cut coronary risk by about 95%.
Intestinal bacteria turn carnitine in red meat and phosphatidylcholine in egg yolk into TMAO, raising heart attack and stroke risk.
PCSK9 inhibitors lower LDL and cardiovascular events by about 50%, even in statin-intolerant patients, but are currently very costly.
Measuring carotid plaque burden with ultrasound predicts risk better than intima-media thickness; highest plaque burden carried a 19.5% five-year risk.
A 'treating arteries' strategy in high-risk patients reduced two-year stroke risk from 8.8% to 1%, but needs randomized trials.

Recent advances in the understanding and treatment of atherosclerosis (hardening of the arteries) are changing the way doctors prevent heart attacks and strokes. This 2016 review from Dr. J. David Spence at Western University's Stroke Prevention & Atherosclerosis Research Centre highlights three major breakthroughs: the discovery that intestinal bacteria convert certain foods into artery-damaging compounds, the arrival of powerful new cholesterol-lowering drugs called PCSK9 inhibitors, and advanced ultrasound techniques that can identify the 10-15% of patients with asymptomatic carotid stenosis who might genuinely benefit from surgery or stenting. The review also describes a bold "treating arteries instead of risk factors" strategy that cut the 2-year stroke risk in high-risk patients from 8.8% to 1%. For patients watching their cholesterol or managing vascular disease, these developments point toward a future of far more personalized and effective prevention. # Preventing Heart Attacks and Strokes: How New Research on Atherosclerosis Is Changing Patient Care ## Table of Contents

Why This Research Matters
Understanding the Disease Process: How Plaque Forms
The Gut Microbiome: How Intestinal Bacteria and Diet Interact
Kidney Failure and the Microbiome: A Hidden Danger
PCSK9 Inhibitors: A New Way to Lower LDL Cholesterol
Treating Arteries Instead of Risk Factors
The Debate Over Treating Asymptomatic Carotid Stenosis
Why Measuring Carotid Plaque Burden Matters
Transcranial Doppler Embolus Detection: Spotting Stroke Risk
Plaque Characteristics: What the Ultrasound Reveals
Clinical Implications: What This Means for Patients
Limitations and Unanswered Questions
Recommendations for Patients
Source Information

Why This Research Matters

Despite decades of progress, standard therapy for atherosclerosis has been only partially effective. In most clinical trials, routine treatment with currently available medications reduced cardiovascular risk by only about 9-30%, leaving patients with a residual risk of 70-80%—meaning the majority of their risk remained despite treatment. The stakes are enormous. Atherosclerosis, the buildup of plaque inside artery walls, is the underlying cause of most heart attacks and strokes. The review notes that a lifelong reduction of LDL cholesterol ("bad" cholesterol) resulting from a hereditary condition that keeps LDL naturally low leads to an approximately 95% reduction in coronary risk—suggesting that aggressively lowering cholesterol, if sustained over decades, could nearly eliminate heart attacks. Lifestyle changes also pack a powerful punch. The US Health Professionals Study and the Nurses' Health Study found that people who adopted all five healthy lifestyle choices (not smoking, moderate alcohol intake, regular exercise, a healthy diet, and maintaining a healthy weight) achieved an 80% reduction in stroke. Swedish men with coronary artery disease who followed the same pattern also achieved an 80% reduction in recurrent heart attacks. The way we eat matters enormously. The Cretan Mediterranean diet reduced cardiovascular events by 70% in secondary prevention (preventing a second event) and reduced stroke by nearly half in high-risk primary prevention (preventing the first event). ##

Understanding the Disease Process: How Plaque Forms

Atherosclerosis can be understood as a response to injury. Blood flow disturbances damage the endothelium—the delicate inner lining of the arteries. This triggers a cascade: platelets clump, macrophages (a type of white blood cell) penetrate into the artery wall, inflammation and oxidative stress ramp up, LDL becomes oxidized, and smooth muscle cells proliferate. The result resembles a scar forming inside the artery wall. Traditional risk factors identified in the famous Framingham Heart Study include hypertension, smoking, elevated LDL, diabetes, and left ventricular hypertrophy (essentially reflecting the long-term cumulative effect of blood pressure). But the importance of diet has been largely underappreciated, partly because statin drugs lower fasting LDL cholesterol and seemingly outweigh any effect of diet on fasting lipid levels. That focus on fasting lipids is misplaced, the review argues. The key effects of diet occur during the post-prandial state—the hours after a meal. A high-fat, high-cholesterol meal increases arterial inflammation and oxidative stress and impairs endothelial function for several hours. Since most of the day is spent in this post-meal state, diet is far more important than fasting LDL alone would suggest. ##

The Gut Microbiome: How Intestinal Bacteria and Diet Interact

One of the most exciting recent discoveries is the role of the intestinal microbiome—the trillions of bacteria living in our digestive tract—in cardiovascular disease. Hazen's group at the Cleveland Clinic found that dietary components are converted by intestinal bacteria into toxic compounds that aggravate atherosclerosis. The two most important dietary culprits are:

Phosphatidylcholine, found in egg yolk and other sources
Carnitine, found in animal flesh—with four times as much in red meat as in fish or chicken

Here's how the damaging chain works: Intestinal bacteria convert these substances into trimethylamine (TMA)—the compound that gives uremic breath its fishy odor. The liver then oxidizes TMA into trimethylamine N-oxide (TMAO), a substance that causes atherosclerosis in animal models. TMAO enhances the accumulation of cholesterol in macrophages, promotes foam cell formation in artery walls, and increases the risk of heart attack, stroke, and death. The clinical evidence is striking. In patients undergoing coronary angiography, high levels of TMAO following a test dose of two hard-boiled eggs markedly increased risk. Patients in the top quartile of TMAO levels had a 2.5-fold increase in the 3-year risk of stroke, death, or myocardial infarction. Remarkably, the microbiome is modifiable. Vegans who consumed L-carnitine did not produce TMAO—because they lacked the intestinal bacteria that convert carnitine to TMA. This suggests that harmful bacteria could potentially be eradicated with antibiotics and replaced with beneficial bacteria through stool transplantation, an approach entirely analogous to the "repoopulation" treatment used for Clostridium difficile infections. Dr. Spence reports that his own group is actively studying this possibility. This may also help explain why the Mediterranean diet appears so beneficial: a diet rich in plant foods, fiber, and healthy fats likely supports a healthier gut bacterial community than a diet heavy in red meat and egg yolks. ##

Kidney Failure and the Microbiome: A Hidden Danger

Patients with renal failure face cardiovascular risks that are dramatically higher than the general population. While elevated total homocysteine (tHcy) has long been suspected as a culprit, it accounts for only about 20% of the effect of impaired renal function on carotid plaque. Elevated levels of thiocyanate and asymmetric dimethylarginine (ADMA, a nitric oxide antagonist) further contribute, but these were known before. What's newly recognized is that the metabolic products of the intestinal microbiome are normally excreted in the urine. When kidneys fail, these toxins accumulate. Besides TMAO, other microbial products that likely contribute to cardiovascular risk in renal failure include:

Indoxyl sulfate
Indole-3-acetic acid
p-Cresyl sulfate
Phenylacetylglutamine

For patients at risk of cardiovascular disease, especially those with renal failure, the message is clear: limit intake of meat and egg yolk not only because of the high cholesterol content but also because of the carnitine in meat (particularly red meat) and the phosphatidylcholine in egg yolk. ##

PCSK9 Inhibitors: A New Way to Lower LDL Cholesterol

Statins, which work by blocking the rate-limiting step in cholesterol synthesis (the enzyme HMG-CoA reductase), reduce fasting LDL and cardiovascular events. Their effectiveness is enhanced by combining them with ezetimibe, a drug that blocks cholesterol absorption in the intestine. But many patients cannot tolerate statins. The review helps separate myth from reality:

Myths (not causally related effects): hepatotoxicity, nephrotoxicity, intracerebral hemorrhage, cataracts, and cognitive decline
True causally related adverse effects: myopathy (muscle damage) and a slightly increased risk of diabetes

These real side effects likely stem from impairment of mitochondrial function caused by depletion of ubiquinone (coenzyme Q10), which is essential for mitochondria—the energy-producing structures inside cells. An entirely distinct approach recently became available: blocking the action of proprotein convertase subtilisin-kexin type 9 (PCSK9), an enzyme that breaks down LDL receptors. By preventing this breakdown, the number and duration of LDL receptors on cells increase, allowing more LDL to be cleared from the bloodstream. The result: both LDL and cardiovascular events are lowered by about 50%, even in patients who cannot tolerate statins. Current approaches to blocking PCSK9—monoclonal antibodies or RNA interference—are very effective but prohibitively costly. The review expresses hope that less expensive small-molecule drugs will be developed before long, which would make this revolutionary treatment widely accessible. ##

Treating Arteries Instead of Risk Factors

A fundamentally different paradigm is to treat the actual burden of atherosclerosis—the visible plaque in the arteries—rather than targeting intermediate risk factors such as blood pressure levels or LDL numbers. This approach was developed because treating patients according to then-current guidelines was failing half of them: those patients had plaque progression and their risk was twice that of patients with stable plaque or plaque regression, even after controlling for coronary risk factors. Initiated by Dr. Spence's group in 2003 and reported in 2010, the "treating arteries" approach produced dramatic results:

Halved the proportion of patients with plaque progression (down to a quarter)
Doubled the proportion with plaque regression (up to half)
Reduced microemboli on transcranial Doppler by three quarters
Reduced the very high risk of patients with asymptomatic carotid stenosis by over 80%

The specific numbers are remarkable: the 2-year risk of stroke fell from 8.8% to 1%, and the 2-year risk of myocardial infarction fell from 7.6% to 1%. Efforts are now underway to conduct randomized trials comparing usual care with the "treating arteries" approach, using measurement of 3D plaque volume—the most sensitive method available to assess how well therapies are working against the underlying disease. ##

The Debate Over Treating Asymptomatic Carotid Stenosis

Carotid stenosis is a narrowing of the main arteries in the neck that supply blood to the brain. Patients with severe symptomatic carotid stenosis (meaning they've already had a stroke or mini-stroke) clearly benefit from either carotid endarterectomy (CEA, surgical removal of plaque) or carotid artery stenting (CAS, insertion of a mesh tube to hold the artery open). However, the periprocedural risk of stroke or death with CAS is approximately twice that with CEA. The management of asymptomatic carotid stenosis (narrowing found incidentally, without prior symptoms) is far more controversial. The risk of asymptomatic carotid stenosis with modern medical therapy has declined markedly in recent years, to about 0.5% per year. Some experts have even suggested that randomized trials in symptomatic stenosis should be repeated, comparing intervention against intensive medical therapy. The statistics on current practice are startling:

~90% of carotid interventions in the United States are performed for asymptomatic stenosis
~60% in Italy and Germany
~15% in Canada and Australia (which the author considers about right)
0% in Denmark

Even though the most recent trials report that the risk of stroke or death with intervention—after deducting periprocedural risk—is similar to that with modern intensive medical therapy (about 0.5% per year), the total risk with intervention remains much higher once periprocedural complications are counted: ~3% with CAS and ~1.5% with CEA. There are also important caveats about higher risks in real-world practice, as opposed to results achieved by carefully vetted, highly experienced interventionalists in randomized trials. Dr. Spence argues that these international discrepancies "call into question not only the advisability but also the ethics" of routine intervention for asymptomatic stenosis as practiced in the United States, noting that 90% of patients with asymptomatic carotid stenosis would be better treated with intensive medical therapy. ##

Why Measuring Carotid Plaque Burden Matters

Although carotid intima-media thickness (IMT)—an ultrasound measurement of the inner two layers of the artery wall—is widely regarded as an indicator of "preclinical atherosclerosis," it is actually a different phenotype that doesn't truly represent plaque. The measurement is complicated by two different approaches (with and without plaque thickness), and when plaque thickness is included, participants with and without plaque are often combined, which muddies the results. It is increasingly clear that measuring carotid plaque burden is superior to measuring IMT, both for risk stratification and for assessing the effects of therapy. Plaque burden can be measured as:

Total plaque area (TPA): the sum of the areas of all plaques seen in the extracranial carotid arteries, ranging from 0 to about 1200 mm²
Total plaque volume (TPV): measured with 3D ultrasound

IMT has a very narrow dynamic range—only about 0.5 to 1.5 mm—which is a key reason it is a weak predictor of cardiovascular risk. The two-dimensional TPA and three-dimensional TPV ranges are far greater, offering much more room to detect meaningful changes. The predictive power of TPA is compelling. After adjustment for age, sex, blood pressure, smoking, serum cholesterol, diabetes, homocysteine, and treatment of blood pressure and cholesterol, TPA strongly predicted risk among patients attending a vascular prevention clinic. The 5-year risk of stroke, death, or myocardial infarction by quartile of TPA was:

5.6% (lowest quartile)
10.7%
13.9%
19.5% (highest quartile)

Plaque progression is equally ominous. Patients whose plaque progressed in the first year of follow-up had twice the risk of those with stable plaque or regression. These findings were confirmed in a population-based study in Tromsø, Norway, where both heart attack and stroke were strongly predicted by TPA but not by IMT in the common carotid artery where there was no plaque. IMT also has a technical limitation: the annual change is only about 0.15 mm, while the resolution of the method is about 0.2-0.3 mm—meaning real changes are smaller than the measurement error. IMT progression does not predict risk, even in large populations, whereas progression of 3D plaque volume predicted cardiovascular events even in a small population. In the High Risk Plaque study, 3D plaque burden was highly correlated with coronary calcium (a marker of heart artery plaque), while IMT was not; plaque burden predicted cardiovascular risk to a similar extent as coronary calcium. For patients without existing plaque, a more useful measurement is vessel wall volume—a 3D measurement of the intima-media layer that has a much greater dynamic range than IMT and, unlike IMT, is sensitive to the effects of therapy. ##

Transcranial Doppler Embolus Detection: Spotting Stroke Risk

Perhaps the best validated method for identifying high-risk patients with asymptomatic carotid stenosis is transcranial Doppler (TCD) embolus detection. This painless ultrasound technique monitors the blood flow in the brain's arteries and detects microemboli—tiny particles traveling to the brain that can break off from plaque in the carotid arteries and increase stroke risk. The evidence is striking: patients with asymptomatic carotid stenosis who had two or more microemboli in 1 hour of monitoring had a 1-year stroke risk of 15.6%, indicating that they could indeed benefit from CEA or CAS. TCD embolus detection is remarkably accessible. The cost of a TCD machine is less than the cost of two carotid stenting procedures, and training and certification in TCD embolus detection can be completed in a course of 3 or fewer days. The review argues that TCD embolus detection—or some other procedure to identify higher-risk patients—should be considered before patients undergo CAS or CEA for asymptomatic stenosis. ##

Plaque Characteristics: What the Ultrasound Reveals

Beyond plaque volume, certain characteristics of the plaque itself predict risk. In patients with asymptomatic carotid stenosis:

Presence of three or more ulcers in either or both carotid arteries carried a risk similar to that of microemboli: an 18% 3-year risk of stroke or death
Those with two or more microemboli had a 20% 3-year risk

Combining TCD embolus detection with detection of three or more ulcers increased the proportion of patients with asymptomatic stenosis who could benefit from intervention from 5% to 10%—a significant improvement in our ability to pick out those who need more than just medication. The Asymptomatic Carotid Emboli Study (ACES) confirmed the power of plaque characteristics to predict risk:

Plaque echolucency (areas of plaque that appear dark on ultrasound, indicating soft, unstable material such as lipid or hemorrhage) at baseline increased the risk of ipsilateral stroke with a hazard ratio (HR) of 6.43 (95% confidence interval [CI] 1.36-30.44, P=0.019). This means patients with echolucent plaque had more than six times the stroke risk of those without it.
A combination of plaque echolucency plus TCD microemboli markedly increased the risk of ipsilateral stroke: HR 10.61 (95% CI 2.98-37.82, P=0.0003). This association remained significant even after controlling for risk factors, degree of carotid stenosis, and antiplatelet medication.

Other plaque features under study include juxtaluminal black plaque—plaque or thrombus so echolucent (ultrasound-dark) that it can be seen only by observing a gap between the artery wall and the Doppler flow signal. Advanced plaque texture analysis of ultrasound images is also being explored to identify dangerous plaque that may not yet show up as overt ulcers or echolucent material. For context, a hazard ratio is a statistical measure of how much more likely one group is to experience an event compared with another group. A HR of 10.61 means the risk was more than ten times higher—an enormous increase that strongly suggests these patients should be considered for more aggressive therapy. ##

Clinical Implications: What This Means for Patients

This review carries several important messages for patients and their doctors: Risk stratification is improving. Measuring carotid plaque burden is far more useful than traditional IMT for deciding who needs intensive therapy. Patients with high plaque burden or plaque progression on follow-up scans face two to three times the risk of those with stable or regressing plaque. For the 90% of patients with asymptomatic carotid stenosis who would be better treated with intensive medical therapy, modern imaging can now identify many of the 10-15% who would genuinely benefit from surgery or stenting. Diet matters more than we thought. The discovery of the gut microbiome's role means that the carnitine content of red meat and the phosphatidylcholine in egg yolk contribute to cardiovascular risk through bacterial conversion to TMAO. This is especially critical for patients with renal failure, who cannot efficiently excrete these toxic metabolites. New drugs are on the horizon. PCSK9 inhibitors represent a powerful new way to lower LDL by 50% or more, though current costs are prohibitive. The hope of cheaper alternatives makes this a treatment to watch. Treating the artery, not just the numbers, works. The "treating arteries" strategy produced dramatic reductions in stroke and heart attack risk—over 80%—in high-risk patients. This approach is now heading toward randomized trials. The ethics of intervention. The vast differences in how countries approach asymptomatic carotid stenosis raise serious questions about whether many invasive procedures are justified. Patients should understand that modern intensive medical therapy may be as good as—or better than—surgery or stenting for many asymptomatic patients. ##

Limitations and Unanswered Questions

This is a review article, not a randomized controlled trial, so it reflects the author's expert interpretation of the published literature rather than new patient data. Several important limitations deserve mention:

The "treating arteries" approach, while promising, needs confirmation in randomized trials before it becomes standard practice
Current PCSK9 inhibitor strategies are prohibitively expensive, limiting access
Microbiome-based therapies (antibiotics, stool transplantation, or targeted elimination of harmful bacteria) are still under investigation and not yet ready for patient care
The review was based on research available as of 2016; the field has continued to evolve since that time
Dr. Spence's group has a financial interest in software for vascular risk reclassification based on carotid plaque burden, and he has received consulting and research support from multiple pharmaceutical companies, which should be considered when interpreting his recommendations about the value of plaque imaging

Recommendations for Patients

Based on this research, here's what patients can reasonably consider discussing with their doctors:

If you already have atherosclerosis, or significant risk factors for it, ask whether a simple carotid ultrasound to measure plaque burden (TPA or TPV) would help clarify your true risk level. The 5-year risk range is wide—from 5.6% to 19.5% depending on plaque burden—and knowing where you stand can guide how intensively to treat.
If you've been told you have carotid stenosis found incidentally (asymptomatic), ask about transcranial Doppler embolus detection. If you have two or more microemboli in an hour of monitoring, your 1-year stroke risk is 15.6% and intervention may be worthwhile. If not, intensive medical therapy may be just as good—and far safer—than surgery or stenting.
Limit red meat and egg yolk consumption, particularly if you have kidney disease. The gut bacteria convert carnitine and phosphatidylcholine into TMAO, which is linked to a 2.5-fold higher risk of stroke, death, or heart attack. This is true even if your fasting LDL cholesterol looks fine, because the damage happens in the post-meal state.
Follow a Mediterranean-style diet, which has been shown to reduce cardiovascular events by 70% in secondary prevention and to cut stroke risk by nearly half in high-risk primary prevention.
Make all the lifestyle changes that work. Not smoking, moderate alcohol intake, regular exercise, healthy diet, and maintaining a healthy weight together produced an 80% reduction in stroke and recurrent heart attack risk in large observational studies.
If you're unable to tolerate statins, ask about PCSK9 inhibitor therapy. While expensive, it lowers LDL and cardiovascular events by about 50%, and less costly alternatives are likely in development.
If a carotid intervention is being recommended for an asymptomatic stenosis, ask for a frank discussion of the periprocedural risks (about 1.5% with CEA and 3% with CAS in trials) versus the risk of modern intensive medical therapy (about 0.5% per year). In Denmark, no symptomatic carotid stenoses are routinely treated with intervention—consider getting a second opinion.

Frequently Asked Questions

What is the 'treating arteries' approach and how did it affect stroke risk?

Instead of only targeting risk factors such as LDL cholesterol or blood pressure, this approach directly treats the burden of plaque visible in the arteries. In one high-risk group, the two-year risk of stroke fell from 8.8% to 1% after this strategy was introduced in 2003 and reported in 2010.

What are PCSK9 inhibitors and who might benefit from them?

These drugs block an enzyme that breaks down LDL receptors, allowing more LDL to be cleared from the blood. They lower LDL and cardiovascular events by about 50%, even in people who cannot tolerate statins. They are effective but currently very expensive, so cheaper alternatives are being developed.

How can ultrasound help decide if carotid stenosis needs surgery or stenting?

Carotid plaque burden measured by ultrasound predicts five-year risk of stroke, death, or heart attack, ranging from 5.6% in the lowest quartile to 19.5% in the highest. Transcranial Doppler can also detect microemboli; two or more in one hour meant a 15.6% one-year stroke risk, suggesting intervention may help.

Should I limit red meat and egg yolks even if my cholesterol looks normal?

Yes, according to this review. Gut bacteria turn carnitine in red meat and phosphatidylcholine in egg yolk into TMAO, which promotes artery plaque. This effect occurs after meals and may not show up in fasting LDL cholesterol. Limiting these foods is especially important for people with kidney disease.

What lifestyle changes reduce stroke and recurrent heart attack risk by 80%?

In large observational studies, people who adopted all five healthy habits—not smoking, moderate alcohol intake, regular exercise, a healthy diet, and maintaining a healthy weight—achieved an 80% reduction in stroke and, in Swedish men with coronary disease, an 80% reduction in recurrent heart attacks.

Is surgery or stenting always needed for asymptomatic carotid stenosis?

No. Modern intensive medical therapy lowers yearly stroke risk to about 0.5%, while intervention adds periprocedural risks—roughly 1.5% for carotid endarterectomy and 3% for stenting. About 90% of asymptomatic patients may be better treated with medication. Ask about transcranial Doppler embolus detection to identify higher-risk patients.

Spence Recent advances in pathogenesis, assessment, and treatment of atherosclerosis