Can Atherosclerosis Be Cured?

Abstract

Purpose of review:

Determine if evidence supports interventions to prevent development of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) events and death.

Recent findings:

An extensive body of evidence supports the fundamental causal role of apoB lipoproteins in the development of atherosclerosis. Recent epidemiologic studies have shown that LDL-C and non-HDL-C levels in early adults are associated with accelerated subclinical atherosclerosis and an excess of atherosclerotic cardiovascular events later in life. Animal and human data have shown that intensive LDL-C lowering can regress earlier stages of atherosclerosis.

Summary:

The next research priority is evaluating the impact of lowering LDL-C earlier in life to regress early atherosclerosis, followed by trials to demonstrate this approach will eradicate later-life ASCVD events and death. This approach of curing atherosclerosis will likely be the most effective strategy for reducing the huge global burden of atherosclerosis.

Introduction

Heart attack and stroke are the leading causes of death in the US and worldwide¹. The underlying pathologic process that predisposes patients to most forms of heart attack and stroke, atherosclerosis, begins in childhood and early adulthood, progresses over decades eventually causing clinical events in some^2,3. Once a clinical event occurs, affected individuals require life-long treatment, which reduces but does not completely remove risk for recurrent atherosclerotic cardiovascular disease (ASCVD) events⁴. Consequently, the population prevalence of ASCVD, the associated morbidity, and disability due to ASCVD continues to climb rapidly¹. Further, due to increasing rates of obesity, diabetes, and hypertension, particularly in young adults, a levelling off in the decline in mortality from ASCVD in the US has been observed^5–7. The increasing prevalence of risk factors in young adults also contributes to an increase in incident CVD events in adults < 65 years old⁸. Thus, there is substantial need for prevention of this category of diseases, particularly as it pertains to risk development the early life course.

Current Prevention Approaches Are Too Late

Many advances in the prevention of ASCVD have been made over the last 50 years⁹, but a high risk for recurrent events persists long after an index event. This high risk of recurrent events is the result of the large burden of atherosclerotic plaque, which even if stabilized following statin therapy may erode and result in in acute coronary syndromes¹⁰. Therefore, earlier intervention to prevent the progression to a large plaque burden is needed to substantially reduce ASCVD risk. Emerging data suggest intensive treatment much earlier in the course of atherosclerosis can reverse atherosclerosis and even restore normal arterial structure and function. This may be the most effective strategy for minimizing ASCVD risk for an individual and ultimately eradicating the population burden of atherosclerosis.

Curing Atherosclerosis

However, it is unclear if, once present, atherosclerosis can in fact be “cured”. We theorize that the answer to this question depends on the stage of atherosclerosis and the definition of “cure”. Vascular health can be extended well into middle age through the maintenance of ideal cardiovascular risk factors and lifestyle behaviors¹¹ and early stages of atherosclerosis can likely be reversed restoring normal vascular structure and function. However, advanced atherosclerosis, defined as complex plaque with fibrosis and calcification, may not be completely reversible with currently available therapies¹². Thus, the best chance to prevent and “cure” atherosclerosis may occur in young individuals before complex and potentially irreversible plaque can develop.

The pathobiology of atherosclerosis has been extensively studied and is well understood. The central process that underlies the initiation and progression of atherosclerotic plaque is the entry and retention of apolipoprotein B (apoB)-containing lipoproteins and the cholesterol within in the subendothelial space of arteries³. Low density apoB-containing lipoproteins (LDL) cross from the serum into the subendothelial space and vice versa. However, in the presence of disturbed laminar flow or specific risk factors like, high apoB concentrations, high blood pressure, and diabetes, and other factors, LDL particles can be retained in the subendothelial space leading to progressive accumulation of apoB particles over time in the arterial wall.

Retained apoB particles are phagocytized by macrophages that convert into foam cells. Eventually the accumulation of apoB, the migration of macrophages, the development of foam cells, and the chronic release of cytokines and other inflammatory and thrombotic mediators leads to maladaptive inflammation, apoptosis, and activation of prothrombotic pathways^13,14. This process occurs in series, over decades in most individuals^15,16, which results in different “stages” of atherosclerosis with variable degrees of associated risk. The first stage is pre-lesional susceptibility, defined by alterations in the vascular endothelium and subendothelial space that renders the artery susceptible to apoB deposition. Eventually, after deposition and retention of apoB particles and the migration of leukocytes early atherosclerosis develops. Then, after continual retention of apoB particles and chronic inflammation the plaque matrix contains fibrotic, thrombotic, and lipid components with significant vascular remodeling and the deposition of calcium in some.

This progression of early atherosclerosis has been confirmed in the Pathobiological Determinants of Atherosclerosis in Youth Study. In late adolescence, the prevalence of reversible atherosclerotic lesions (American Heart Association Class 1–3) was directly linked to conventional ASC VD risk factors, by age 30–35 years, advanced lesions (American Heart Association class 4–5) develop in the same locations and have a similar relationship to risk^17,18. The rate and extent to which this occurs is variable across individuals but progression is clearly linked to age². Larger complex plaques can rupture or erode and initiate arterial intraluminal vessel thrombosis, occlusion, and subsequent end-organ infarction¹⁹. Thus, the fundamental driving pathologic process that underlies most forms of heart attack and many forms of stroke is the development of high-risk atherosclerotic plaque. Therefore, early recognition and aggressive prevention and treatment of atherosclerosis may be the best strategy to eliminate ASCVD risk.

As the pathobiology would suggest, the aggregate exposure to apoB lipoproteins is one of the strongest predictors of ASCVD event risk in epidemiological studies²⁰. Familial hypercholesterolemia provides a natural model confirming this hypothesis²¹. Similarly, individuals with very low aggregate exposure the apoB lipoproteins have very low (and negligible in some) risk for ASCVD events^22,23. Similarly, Mendelian randomization and epidemiologic studies suggest that long-term exposure to low LDL-C levels, or non-HDL- levels, largely prevents development of atherosclerosis and ultimately ASCVD events^20,24,25. Furthermore, optimal levels of blood pressure, blood glucose, body-mass index, as well as specific eating patterns, physical activity, and the avoidance of tobacco are associated with much lower relative risk, less premature atherosclerosis, and, notably, very low absolute risk (<1%) for ASCVD²⁶. Thus, the avoidance of CVD risk factors early in life can clearly prevent (or at least delay until late life) the development of atherosclerosis^27,28.

Early Life Risk Factor Exposure

The epidemiology that supports the strength of early life risk factors on later life CVD risk is substantial. Multiple studies reported in the last 2 years further support the notion that early life cardiovascular risk factor profiles are strong determinants of later life risk factor levels and ASCVD risk. Although ASCVD risk is not, in of itself, vascular health it is a reasonable surrogate for the prevention or cure of atherosclerosis.

The causal relationship between the aggregate exposure to atherogenic lipoproteins has been demonstrated in multiple observational and genetic studies^20,29–31. Recent work from ongoing CVD cohort studies has enhanced our understanding of how lipid levels change over time and the relative importance of the patterns of change to the risks for CVD events later in life. Pencina et al. carried out a trajectory analysis of non-HDL-C in the Framingham Offspring Study³². They found that on average individuals’ non-HDL-C levels generally tracked over 30 years of adult life and those in the higher trajectory group had approximately 16% higher absolute risk for CVD over 25 years of follow-up. An important implication of these findings is that measurement of early life atherogenic lipid levels can, on average, be a strong indicator of lipid levels later in life. Thus, the aggregate exposure to atherogenic lipoproteins can be assessed in early adulthood and individuals who may benefit from lipid lowering may be identifiable with routine lipid testing.

Using pooled data and imputation analysis, Zhang et al. quantified associations between early life lipid and blood pressure values and CVD risk²⁴. Notably, they assessed the relative contribution of early to later life risk factor levels. Interestingly, they report that early life LDL-C vales > 100mg/dL were associated with a HR of 1.64 when compared to LDL-C < 100mg/dL early life after this association was adjusted for later life LDL-C levels. Interestingly, this association persisted even after adjustment for statin use later in life. This adds to the work of Pencina et al, as it clearly demonstrates that there is independent and added importance of early life lipid levels on the long-term risk for CVD. More modest associations between early life diastolic blood pressure and CVD risk were observed as well. Similar work from the CARDIA study demonstrated associations between the duration of pre-DM and DM and the risk for subclinical atherosclerosis in midlife as well³³.

Interestingly, waiting to pharmacologically treat risk factors until middle age, does not restore low risk in all individuals. For example, observational data from the Mult-Ethnic Study of Atherosclerosis suggest that risks associated with hypertension may not be completely reversible with treatment as Liu et al. reported that hypertensive patients treated to blood pressure levels <120/80mmHg still have 2 times the risk for ASCVD as those who entered the cohort with optimal BP levels³⁴. Familial hypercholesterolemia is an extreme phenotype illustrating the impact of early exposure to elevated LDL-C levels, resulting in premature clinical ASCVD events, often in the 3^rd and 4^th decade³⁵. Data collected from families affected by familial hypercholesterolemia suggests the earlier LDL-C is lowered, the greater the ASCVD risk reduction^36,37. Less well studied is the comparative risks between early vs. delayed treatment of more modest elevations in LDL-C.

Mid- and Late-Life Treatment is Inadequate

Pharmacologic treatment of individuals at high risk for ASCVD events and those with established ASCVD results in substantial (30–50%) reductions in the relative risks for events³⁸. However, data from clinical trials also demonstrates the persistent risks observed in individuals treated after prolonged exposure to non-optimal risk factor levels, as the absolute risks for events in statin-treated individuals with high risk (likely due to established atherosclerosis) remains significant. For example, in the JUPITER study, statin treated individuals had observed event rates of 0.77/100 person*years, which is equivalent (assuming rates are constant over time) to a 7.7% observed 10-year event rate³⁹. Similarly, secondary prevention trials like IMPROVE IT the observed event rate in the simvastatin + ezetimibe arm was 32.7%⁴⁰. As stated above, we posit that high risks recurrent events despite best therapy are likely the consequence of residual plaque; specifically, complex, high-risk atherosclerotic plaque. Although current therapies can reduce apoB lipoprotein concentrations, reduce inflammation, and attenuate the pro-thrombotic state, the plaques themselves still persist in the artery. Therefore, reversing atherosclerosis earlier in the disease process and restoring normal arterial structure and function may be the best strategy for achieving a low risk state.

In aggregate, these studies suggest that measurement of early life risk factor levels predicts future risk factor levels and future CVD risk. Given the well-validated causal associations between these risk factors and CVD and the persistence in risk that is observed when treatment is delayed until midlife or after atherosclerosis develops suggests that treatment of early life risk factors, before advanced atherosclerosis develops, may be a viable prevention approach. We posit that treatment of early life risk factors will maintain vascular health and reverse early atherosclerosis and thus restore a low-risk state. However, to date, there are no specific RCT’s that address this critical question.

Treatment Options for Early Atherosclerosis

Lifestyle efforts to prevent the development of risk factors or to optimize non-optimal risk factor levels is a must for population-level and individual-level approaches to prevention, as the evidence supporting the primacy of primordial prevention is incontrovertible^27,28,41. However, the burden of dyslipidemia and elevated blood pressure in young adults is unacceptably high in today’s obesogenic environment^42,43. Thus, many young adults may benefit from early pharmacologic risk factor modification.

Multiple pharmacologic therapies that safely reduce atherogenic lipoproteins are currently available: statins, ezetimibe, and PCSK9 inhibitors^38,44. A growing body of literature demonstrates that aggressive LDL-C lowering can reverse early atherosclerosis, regress advanced plaque, and reduce near- and long-term ASCVD risk. For example, in several animal models LDL-C lowering has been shown to regress and, in some cases, reverse atherosclerotic plaque and improve vascular function^45,46. However, in more advanced plaque regression can occur, but vascular function remains abnormal and plaque persists^46,47.

In humans, studies of statins and PCSK9 inhibitors has been shown to regress advanced plaque⁴⁸. Statins, ezetimibe and PCSK9 inhibitors reduce ASCVD events in middle aged and older adults with an excellent record of safety, even at very low LDL-C levels.^49–52 PCSK9 inhibiting antibodies lower LDL-C 50–65% when added to background statin therapy, with the achievement of mean LDL-C levels of approximately 30 mg/dl in cardiovascular outcomes trials. This makes very intensive LDL-C lowering possible and for the first time we may be able to determine if humans will respond with extensive regression and functional normalization as has been observed in animal models.

Interestingly, the effect of statins on plaque regression may be more substantial in individuals without calcified plaque⁵³. This is consistent with the Cholesterol Treatment Trialists Meta-Analysis suggest that the relative reduction in ASCVD risk may, in fact, be greater in lower risk (<5% estimated 10y ASCVD) primary prevention adults than in higher risk adults²⁹. The mechanistic data showing greater regression in non-calcified plaque as well as the suggestion of higher relative risk reduction in low risk (<5%, 10 year estimated risk) statin treated patients suggests that aggressive LDL-C lowering interventions targeting early atherosclerotic plaque may yield the greatest relative benefits to patients.

The potential for regression of early plaque to normalize vascular function could also have a significant impact on prevention of vascular stiffening, which precedes blood pressure elevations in younger adults^54–56. Statin-treated patients experience reductions in blood pressure and lower rates of hypertension⁵⁷. PCSK9 inhibitors have also recently been shown to improve endothelial function in proportion to the magnitude of LDL-C lowering⁵⁸. A significant reduction in hypertension incidence or age of onset would be an important finding since hypertension is a leading cause not just of ASCVD, but also heart and renal failure⁵⁹.

Therapy with statins, even after discontinuation, is associated with durable and persistently reduced ASCVD risks for up to 20 years after statin therapy was discontinued suggesting a substantial “legacy” effect⁶⁰. We posit that the legacy effect is the result of lower aggregate exposure to apoB during the adult life course, stabilization (or even regression) of existing plaque and prevention of new plaque formation in treated patients when compared to the control. Legacy effect has important implications for clinical strategies that involve treatment of young adults, as it implies that individuals started on therapy at a young age may not need continuation of therapy throughout their entire life course. Perhaps, young and middle-aged adults could be treated with aggressive LDL-C lowering therapies for a period of 2–3 years to completely regress the earliest stages of atherosclerosis and regress or stabilize the few existing advanced plaques. Then, therapy could be stopped, with the potential to repeat intensive LDL-C lowering to regress any plaque that developed in the intervening decade(s).

In summary, the cumulative exposure to apoB-containing lipoproteins is the central, driving process in the development of atherosclerosis, which often begins in childhood and early adulthood. ASCVD is highly prevalent in the US and patients experiencing an ASCVD event remain at high risk of recurrent events despite aggressive secondary prevention measures. Thus, avoidance of advanced atherosclerosis would likely result in the large and durable reductions in ASCVD risk. Furthermore, we know that aggressive LDL-C lowering can lead to regression of advanced atherosclerotic plaque in humans.

Trials Needed

An extensive body of evidence supports the next generation of trials to support a new prevention paradigm. Trials are needed to determine if aggressive LDL-C lowering in young adults with early atherosclerosis can indeed “cure” early atherosclerosis, and prevent the subsequent burden of ASCVD events. This approach would recapitulate the low rate of ASCVD events observed when lifetime exposure to LDL-C levels is low, as in PCSK9 loss-of-function mutations (Figure).³ Multiple safe and highly effective LDL-C lowering therapies are currently available, which make this a potentially practical clinical strategy.

Figure. Interventions to prevent ASCVD events later in life.

Life course trajectory of atherosclerotic progression is illustrated for individuals at very high, high and low risk of atherosclerotic cardiovascular disease events (ASCVD): (1) individuals with heterozygous familial hypercholesterolemia who have severe LDL-C elevation from birth have markedly accelerated atherosclerosis and premature onset of clinical ASCVD events; (2) individuals with cardiovascular risk factors from young adulthood and “average” LDL-C levels of 130 mg/dl are more likely to experience clinical ASCVD events in early n middle age; and (3) individuals with a proprotein convertase subtilisin/kexin type 9 PCSK9 loss-of-function (PCSK9 LOF) mutation have lower LDL-C levels throughout the lifespan and may be at markedly reduced risk of clinical ASCVD events. LDL-C lowering with statins can stabilize and modestly regress plaque but does not eradicate the plaque burden and remain at increased risk of clinical ASCVD events. Intensive LDL-C lowering to 20–40 mg/dl may have a greater impact on plaque regression in earlier stages of plaque. A new paradigm of “regression” treatment with intensive LDL-C lowering earlier in the course of atherosclerosis or at younger ages could then be followed by intermittent retreatment to “maintain” a low plaque burden until late in life.

Reprinted with permission. Robinson J, Williams K, Gidding SS, et al. Eradicating the Burden of Atherosclerotic Cardiovascular Disease by Lowering Apolipoprotein B Lipoproteins Earlier in Life. J Am Heart Assoc. 2018;7:e009778.

We have proposed a pilot trial in obese younger adults with multiple cardiometabolic risk factors and a measureable uncalcified coronary artery plaque burden to evaluate the effect of 3 years of intensive LDL-C lowering compared to usual care on the primary endpoint of regression of low attenuation coronary plaque volume (LAPV) measured by coronary tomographic angiography (CTA) (Figure)³. Screening would be based on ASCVD risk estimated by a modified Pathologic Determinants of Atherosclerosis in Youth (PDAY) Score, which uses age, sex, non-HDL-C, HDL-C, smoking, hemoglobin A1c, body mass index, and blood pressure to predict risk of atherosclerotic plaque on autopsy.^61,62 Published and unpublished data support the use of a PDAY score >25 for predicting a 40% probability of advanced plaque in younger adults. Screening efficiency would likely be enhanced by further application of a genetic risk score to identify individuals with a genetic predisposition placing them at increased risk of accelerated atherosclerosis.

Participants would be randomized in a a 1:1 ratio to intensive LDL-C lowering with statin and PCSK9 inhibitor (±ezetimibe) therapy to lower LDL-C to 20–40 mg/dl or to usual care as the control for a treatment period of 3 years. In addition to the endpoint of LAPV, secondary endpoints would include other imaging and biomarker endpoints. A sample size of 134 would have >90% power to detect a 38% reduction in LAPV, the amount of regression observed in another study of high intensity statin therapy in a younger Chinese population.⁶³ A larger reduction in LAPV might be expected for ≥80% reductions in LDL-C.

This initial pilot trial should facilitate identification of the most responsive patient genotype/phenotype for regression/normalization, although a larger trial would be desirable to further refine risk prediction for a larger trial. Two sufficiently sized imaging trials could support an indication for atherosclerosis treatment if supportive evidence from a cardiovascular outcomes trial is available for that drug.⁶⁴ However, at least one cardiovascular outcomes trial would be needed to change clinical guidelines. A highly efficient ASCVD outcomes trial enrolling individuals with the most responsive risk factor/genetic profiles to intensive LDL-C lowering with statin and PCSK9 inhibitor (±ezetimibe) therapy could be expected to have a >80% reduction in the relative risk of ASCVD events. Such a trial could be performed in <10,000 subjects treated for <5 years. Long-term follow-up or subsequent trials would then be needed to identify the optimal interval for re-treatment.

By 2035, the direct and indirect costs of cardiovascular disease in the US alone are predicted to excess US$1.1 trillion per year⁶⁵. If intermittent intensive early LDL-C lowering shown to largely regress atherosclerosis and reduce the vast majority of ASCVD events, a reasonably-priced treatment regimen should be cost-saving over a long-term time horizon.

Conclusion

An extensive body of evidence supports the fundamental causal role of apoB lipoproteins in the development of atherosclerosis. The next research priority is evaluating the impact of lowering LDL-C earlier in life to regress early atherosclerosis and eradicate later-life ASCVD events and death, which is likely the most effective strategy to cure atherosclerosis. If effective, such an approach applied widely could largely eliminate the burden of ASCVD within a generation.

Key points.

• ApoB lipoproteins play fundamental role in development of atherosclerosis.

• LDL-C and non-HDL-C levels in early adults are associated with accelerated subclinical atherosclerosis and an excess of atherosclerotic cardiovascular events later in life.

• Intensive LDL-C lowering may regress earlier stages of atherosclerosis and normalize vascular function in humans

• The next research priority is to determine if intensive LDL-C lowering in early adulthood will eradicate the burden of ASCVD later in life