Is it possible to reverse plaque?

Atherosclerosis is the primary cause of cardiovascular diseases (CVDs), which are among the leading causes of death globally.¹ In 2019, the World Health Organization reported that CVDs were responsible for 17.9 million deaths which constituted 32% of all deaths worldwide.² Among these, coronary heart disease accounted for approximately 7.4 million deaths, while stroke caused around 6.7 million deaths.²

What is atherosclerosis?

Atherosclerosis is a condition where the inner walls of arteries become gradually narrowed and hardened due to buildup of plaque or fatty deposits. These deposits are made up of cholesterol, fatty substances, cellular waste products, calcium and fibrin - a clotting material in the blood. This narrowing restricts blood flow, diminishing the amount of oxygen reaching the heart, brain or extremities and heightening the risk of heart disease, stroke or peripheral vascular disease.^2,3

What is the science behind plaque formation?

Atherosclerotic plaque formation begins with endothelial dysfunction, triggered by prolonged exposure to pathogenic factors such as diabetes, hypertension, tobacco smoking, and stress. This dysfunction increases the permeability of the endothelium, allowing low-density lipoprotein-cholesterol (LDL-C) to infiltrate the intima. This infiltration recruits inflammatory cells that consume LDL-C and transform into foam cells. Concurrently, vascular smooth muscle cells proliferate, forming a fibrous cap over the growing plaque.⁴ At this early stage, plaque accumulation often remains asymptomatic. However, as fats and cholesterol continue to accumulate, they lead to inflammation, cell death, and eventually the hardening and calcification of the artery walls. Complications arise when the plaque ruptures, prompting the formation of a blood clot.⁵ This clot can obstruct the artery entirely or travel through the bloodstream, causing blockages elsewhere (thrombosis). Such blockages can trigger severe, life-threatening conditions like acute coronary syndrome (ACS).^1,4,5

What factors contribute to the buildup of plaque in the arteries?

High levels of plasma lipids, especially low-density lipoprotein (LDL) or "bad cholesterol," can cause atherosclerosis. This is particularly true in genetic conditions like familial hypercholesterolemia (FH) and other genetic hyperlipidemias.

However, even with lower LDL levels, several other risk factors can contribute to the disease. These include smoking, hypertension, diabetes mellitus, male sex, physical inactivity, unhealthy diet, excessive alcohol consumption and psychosocial factors such as stress.^3,5,6 In fact, the likelihood of developing coronary heart disease rises exponentially with each additional risk factor.⁷

Can Atherosclerosis be reversed?

The objective of plaque regression in prevention strategies involves reducing overall plaque volume and altering plaque composition to mitigate the risk of plaque rupture. While eliminating plaque entirely is not possible (e.g. calcified plaque is rarely modifiable), it can be reduced and stabilized through (1) diet and lifestyle changes and (2) medication.^6,8

Plaque can be measured using various imaging techniques such as ultrasound and CT scans. These methods allow physicians to see inside the arteries and measure the amount of plaque present before and after treatment and/or intervention.

• Intravascular Ultrasound (IVUS): IVUS is an invasive imaging technique that can be used to quantify plaque burden. Using a dedicated catheter with ultrasound-based technology, an image from the inside of an artery with a 360-degree view can be obtained. IVUS is the main tool used to image plaques and is currently considered the gold standard when quantifying and assessing plaque morphology. ⁹
• Computed Tomography coronary angiography (CTCA): CTCA is a non-invasive method that uses x-rays to create detailed cross-sectional images of the body to help visualize and quantify the amount of plaque in the arteries, providing a clear picture of the plaque and helping to assess plaque characteristics (i.e. non-calcified, or calcified plaques). Quantification of plaque burden quantified using CT has shown good correlation with IVUS, although with less spatial resolution.^10,11

Diet and Lifestyle

Lifestyle modifications can provide lasting benefits for cardiovascular health. According to the World Health Organization (WHO), most cardiovascular diseases can be prevented by addressing behavioral risk factors such as smoking, unhealthy diet, obesity, lack of physical activity, and excessive alcohol consumption.^2,6,12

Diet

A diet that's low in fat and mainly plant-based can keep cholesterol levels healthy, regulate blood pressure, and prevent plaque from forming in arteries.³ This is why vegetarian and vegan diets are linked to a 13% lower risk of developing heart disease compared to diets that include meat.¹³ The DASH (Dietary Approaches to Stop Hypertension) diet is another example of a heart-healthy eating plan. It reduces high-sodium foods and boosts intake of foods rich in potassium, magnesium, and calcium, such as fruits, vegetables, whole grains, and low-fat dairy products.^6,14

The Mediterranean diet is also well-regarded for its cardiovascular benefits. It emphasizes plant-based foods such as vegetables, whole grains, legumes, nuts, and seeds. Olive oil is the main source of healthy fats, and the diet includes moderate amounts of fish and poultry, while red meat is limited.⁷

Additionally, incorporating anti-inflammatory foods like fatty fish, nuts, and seeds as well as high fiber diets have been linked to improved cardiovascular health.^7,14,15

However, data showing plaque regression through dietary changes alone is limited. Ornish et al. demonstrated that patients with moderate to severe coronary disease who adhered to intensive lifestyle modifications (including a 10% fat whole foods vegetarian diet, aerobic exercise, stress management training, smoking cessation, and group psychosocial support, n=20) could significantly reverse coronary atherosclerosis (defined as percent change in coronary diameter stenosis measured through angiography). In addition, there was a reduction in cardiac events in the patients who adhered to these lifestyle modifications over five years.¹⁶

Henzel et al.¹⁷ observed that combining the DASH diet, increased physical activity, and optimal medical therapy (antiplatelet agents, beta-blockers, and statins) led to significant regression of high-risk coronary plaque in patients with non-obstructive coronary disease. Here, patients were randomized to receive dietary intervention along with optimal medical therapy (n=46) or medical therapy alone (n=46). Plaque volume was assessed using CTCA prior to enrollment and was repeated at, on average, 66 weeks. Those in the experimental, diet + medical therapy arm saw a greater reduction in noncalcified plaque versus the control arm that received medical therapy alone (−1.7% ± 2.7% versus −0.7 ± 1.9%, respectively; p=0.045). Dietary intervention also resulted in reductions in total cholesterol, LDL, non-HDL, and high-sensitivity C-reactive protein levels, indicating both structural improvements in the coronary arteries and a decrease in inflammatory response. Together, these above studies show that combining diet and lifestyle changes with medical treatments may be effective in treating atherosclerosis versus medical treatment alone.

Exercise

While exercise is linked to a reduced risk of coronary artery disease (CAD), its precise effects on the composition and behavior of coronary plaques are not yet fully understood. Nonetheless, regular physical activity serves as both a primary and secondary prevention tool for lowering cardiovascular risk.⁸ It helps reduce blood pressure, enhance insulin sensitivity, lower the risk of metabolic syndrome and type 2 diabetes, and improve cholesterol levels. The impact of exercise on plasma lipids and plaque, however, can vary depending on the type, intensity, and duration of the activity, as well as individual dietary habits.^18,19

Previously, studies by Madssen et al.²⁰ and Nishitani-Yokoyama et al.²¹ evaluated the impact of intensive physical exercise on plaque volume in patients with acute coronary syndrome.

• Madssen et al²⁰ – Patients were randomized to aerobic interval training (n=19) or moderate continuous training (n=22) 3 times a week for 12 weeks. Plaque burden was reduced by roughly 10% with no difference between exercise groups.
• Nishitani-Yokoyama et al²¹ – Patients were randomized to intensive cardiac rehabilitation (cardiac rehabilitation participation greater or equal to twice per week and daily physical activity of ≥9000 steps; n=25) or standard cardiac rehabilitation (cardiac rehabilitation participation ≥ once every 2 weeks, daily physical activity of ≥ 6000 steps; n=26). At 8-month follow up, the percent change in plaque volume was −8.9 ± 14.2% versus −4.5 ± 5.5% in the intensive and standard groups, respectively (p=0.28).

While the studies found that plaque regressed in the exercise arm of each study, neither study showed a significant difference between treatment arms. Interestingly, a post-hoc analysis of the study by Nishitani-Yokoyama et al found that patients who walked ≥ 7000 steps per day had greater plaque regression compared with patients who walked less than 7000 steps per day. ¹⁹ Both studies used IVUS to assess plaque before and after treatment. ^20,21

Pharmacological

In recent decades, significant advancements have been made in lipid-lowering therapies, crucial for preventing atherosclerotic cardiovascular disease. These therapies focus on modifying the size, composition, and vulnerability of atherosclerotic plaque, all pivotal in disease progression. For instance, patients with non-obstructive calcified or thick-capped plaques typically benefit from optimized medical therapy. Conversely, those with thin-capped plaques prone to rupture may require percutaneous coronary intervention (PCI) in addition to medication. Lowering lipid levels significantly improves the plaque microenvironment, reducing inflammation and macrophage content.¹²

Statins

Since the early 1990s, statins have been essential in managing cholesterol levels. Numerous trials and meta-analyses have consistently shown that they are effective in lowering cardiovascular events and mortality^{22–26, 9}. Statins work by inhibiting HMG-CoA reductase, a key enzyme in cholesterol production. This inhibition decreases cholesterol levels within cells, leading to an increase in LDL receptors on cell membranes, which helps clear LDL cholesterol (LDL-C) from the bloodstream.²⁵ This process not only reduces LDL-C levels in the blood but also helps stabilize atherosclerotic plaques, lowering the risk of cardiovascular events. Additionally, statin therapy positively affects plaque structure. IVUS imaging has repeatedly demonstrated that statins increase fibrous and calcified plaque volumes while reducing fibrofatty, necrotic core, and noncalcified plaque volumes.^22,27

The first randomized trial assessing the effect of statin treatment on plaque response, conducted by Takagi et al.²⁸ demonstrated a 7% reduction in atheroma volume (evaluated with IVUS) with pravastatin 10 mg (n=13) compared to a 27% increase with placebo (n=12). Subsequent small, randomized trials consistently supported this reduction by statins, though not all achieved statistical significance.^29–31 In addition, numerous studies have compared high- versus moderate- intensity statins in their effect on plaque regression including the following trials:

• REVERSAL (Atorvastatin vs. Pravastatin)³²: This study was undertaken to determine if there is a difference in coronary artery atherosclerosis burden and progression in patients receiving moderate (40 mg of pravastatin) or high intensity statin therapy (80 mg of atorvastatin) for 18 months. IVUS was used to measure progression of atherosclerosis. Patients receiving high-intensity statin saw reduced disease progression (-0.4%, n=253; p=0.98 compared with baseline) compared to those who received pravastatin (2.7%, n=249; p=0.001 compared to baseline).
• SATURN (Rosuvastatin vs. Atorvastatin)³³: This study included patients with coronary artery disease who were at high risk of cardiovascular events. Patients were randomized to receive either rosuvastatin (20 mg daily) or atorvastatin (40 mg daily) for a period of 2 years. The progression/regression of plaque was assessed using IVUS. The SATURN trial found that treatment with rosuvastatin (n=520) or atorvastatin (n=519) reduced plaque volume (-1.22% versus -0.99% change from baseline, respectively; p=0.17). However, a higher percentage of patients treated with rosuvastatin had regression (68.5% versus 63.2% with atorvastatin; p=0.07).
• JAPAN-ACS (Atorvastatin vs. Pitavastatin) trials²⁷: In this trial, patients with acute coronary syndrome were randomized to receive pitavastatin (4 mg daily) or atorvastatin (20 mg daily). IVUS was used to examine coronary lesions at baseline and at 8-12 weeks. Treatment with pitavastatin (n=125) or atorvastatin (n=127) both resulted in significant plaque regression (-16.9% versus -18.1% change from baseline, respectively; p=0.5).

However, concerns about potential harmful effects of statin therapy on muscle, liver function, new-onset diabetes mellitus, cognitive impairment, and hemorrhagic stroke have always been present. These adverse effects have posed challenges for patient adherence to therapy.

Ezetimibe

Ezetimibe is a medication used in the management and treatment of hypercholesterolemia. Ezetimibe selectively inhibits cholesterol absorption from the intestinal lumen resulting in reduced delivery of cholesterol to the liver and an increase in clearance of cholesterol from the blood. Several randomized trials using intravascular imaging techniques, such as IVUS, have assessed the effect of ezetimibe on atherosclerosis, and have shown that ezetimibe can improve plaque volume and burden.

In the PRECISE-IVUS (Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial, patients randomized to receive combination therapy of atorvastatin plus ezetimibe experienced a greater reduction in percent plaque volume at 9-12 month follow-up (-5.2%, n=100) than those who received monotherapy (atorvastatin alone; -1.3% change from baseline, n=102; p<0.001 between groups. Both treatment strategies were well tolerated and there was no difference in CV events between groups. IVUS imaging was used to evaluate plaque progression and/or regression.³⁴

In the ZEUS (eZEtimibe Ultrasound Study) trial³⁵, plaque volume was also assessed using IVUS and there was a greater change in plaque volume with combination therapy (atorvastatin + ezetimibe, n=50) compared to those receiving atorvastatin alone (n=45) in patients with ACS but this difference was not statistically significant (-12.5% versus -7.6%, respectively, p=0.06). Similarly, HEAVEN (Virtual Histology Evaluation of Atherosclerosis Regression During Atorvastatin and Ezetimibe Administration) trial found that aggressive dual lipid-lowering therapy (atorvastatin + ezetimibe, n=42) decreased % plaque volume (-0.4%) compared to standard therapy (routine statin therapy or atorvastatin 10 mg for statin-naïve patients; n=47) but did not lead to significant changes in plaque composition.³⁶ Here, coronary arteries were examined by IVUS and virtual histology.

A recent meta-analysis including 11 studies (with a total of 926 individuals (460 in the dual-lipid-lowering therapy group and 466 in the statin monotherapy group)) found that combination therapy with ezetimibe and a statin resulted in a significant regression in total plaque volume, but there was no statistically significant difference in lumen volume or in measures of plaque stabilization.³⁷ The authors, however, note that many of the studies included in the meta-analysis were of relatively small sample size, and additional randomized control studies with larger sample sizes are still needed.

PCSK9 inhibitors

PCSK9 works to reduce liver LDL receptors, interfering with LDL clearance from plasma. As such, inhibition of PCSK9 activity (with evolocumab or alirocumab) results in increased clearance of serum LDL-C by the liver.³⁸

Previous trials have shown a benefit of PCSK9 inhibitorson plaque regression albeit to a lesser extent in relation to LDL-C and CV outcomes. The GLAGOV (Global Assessment of Plaque Regression with PCSK9 Antibody as Measured by Intravascular Ultrasound) trial³⁹ previously reported an greater reduction in total plaque volume assessed using IVUS in patients who received evolocumab in addition to statin medication after 76 weeks of treatment (-0.95%, n=425; p<0.001 compared to baseline) compared to patients in the placebo treatment group which demonstrated no reduction (0.05%, n=423; p=0.78 compared to baseline). More recently, the PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) trial showed a significantly greater reduction in % change in plaque volume (from baseline) in patients who received alirocumab (-2.13% change from baseline to week 52, n=130) compared with placebo (-0.92%, n=135; p<0.001 between groups).⁴⁰ To evaluate plaque progression/regression, the authors applied a combination of 3 imaging techniques: IVUS, Optical Coherence Tomography (OCT) and Near-Infrared Spectroscopy (NIRS). The authors also note that the extent of plaque volume regression in the treatment group may have been larger compared to previous trials, including GLAGOV, because of the majority of patients enrolled (in PACMAN-AMI) were statin-naïve with higher baseline LDL-C levels whereas the GLAGOV trial included patients with stable coronary disease already receiving a statin at the time of randomization.

What is the clinical significance of plaque regression?

Several studies have shown that lowering cholesterol, specifically LDL-C levels, is associated with lower rates of major adverse cardiac events like heart attacks and strokes.⁴¹ In terms of the association between plaque regression and clinical outcomes, analysis of studies looking at the association of (plaque) regression and cardiac events have shown every 1% decrease in average plaque volume is associated with approximately a 20-25% reduction in odds of a cardiovascular event.^42,43

Conclusion

Numerous studies have shown that several different types of interventions – including diet and lifestyle changes, or pharmacological – can favourably reduce overall plaque burden. The bulk of evidence for plaque regression comes from clinical trials involving statins and the use of intravascular imaging techniques (i.e. IVUS) to monitor and track atherosclerosis over time. More recently, however, studies have also shown that PCSK9 inhibitors can lead to additional plaque regression. Importantly, reducing plaque has been shown to be associated with a lower risk of heart attack and stroke and by reducing plaque even by as little as 1%, there is as much as a 25% reduction in odds of adverse cardiovascular events.