Hyperlipidemia is an important risk factor for ischemic stroke; the Stroke Prevention by Aggressive Reduction in Cholesterol Level and Treat Stroke to Target studies have shown that statins are beneficial for patients with stroke and that a low target for low-density lipoprotein cholesterol (LDL-C) concentration may maximize this benefit. Based on these results, recent guidelines have emphasized the application of “high-intensity statins” and “low LDL-C target” strategies in patients with stroke. However, it should be kept in mind that the role of blood lipids as a risk factor and benefit of lipid-lowering therapy are different among patients with different levels of cerebral arterial diseases. Studies have suggested that hypolipidemia, but not hyperlipidemia, is a risk factor for small vessel diseases (SVDs) such as intracerebral hemorrhages, microbleeds, white matter hyperintensities, and perhaps, lacunar infarction. Although lipid-lowering agents might benefit certain patients with SVD, high-intensity statin and low LDL-C target strategies cannot be applied. In contrast, these strategies are important in patients with extracranial atherosclerosis, such as internal carotid disease, considering ample evidence of the benefits of lipid-lowering agents. Imaging studies have shown that statins stabilize vulnerable plaques in these patients. Although lipid-lowering agents are likely to benefit patients with intracranial atherosclerosis, the degree of their benefit and appropriate target LDL-C level for these patients remain unclear. More studies are needed to elucidate the appropriate lipid-modifying strategies in patients with stroke with different levels of cerebral artery disease.
Hyperlipidemia is an important risk factor for coronary and cerebral artery atherosclerosis. However, its impact may differ according to stroke subtype. In the Atherosclerosis Risk in Communities cohort study [
Indeed, trials suggest that statin use is beneficial in patients with stroke as well. In the Heart Protection Study (HPS) [
In the binational (French and Korean) Treat Stroke to Target (TST) study [
Based on these results, recent guidelines have recommended the use of a high-dose statin with a low LDL-C target in patients with ischemic stroke [
Finally, in the TST trial, although the lower target strategy was superior to the higher target strategy in the French population, the benefit of the “lower target” was not evident when South Korean patients were separately analyzed. Three hundred and seven and 355 patients were assigned to the lower target and higher target groups, respectively. After a median 2.0-year follow-up, the average LDL-C levels achieved were 66 and 96 mg/dL in the lower target and higher target groups, respectively. Preliminary analysis showed neutral results for the primary endpoint. Although the “lower target” strategy was clearly more favorable in the prevention of coronary diseases, it apparently was less effective than the “higher target” strategy in the prevention of stroke and TIA (unpublished data).
Considering that extracranial atherosclerosis (ECAS) is less common in Asian than in French subjects, this difference may be attributed to the lower incidence of ICA disease and a higher incidence of ICAS or SVD among South Koreans than their French counterparts. However, the results should be cautiously interpreted given the relatively small outcomes and shorter follow-up period in the South Korean than in the French counterparts (median 2.0 years vs. 5.3 years, respectively). Therefore, the South Korean extension study is currently ongoing with an estimated average follow-up duration of 5.0 years.
The purpose of this narrative review was to describe the role of blood lipids as a risk factor for various subtypes of non-cardioembolic stroke. The differences in the efficacy of lipid-lowering therapy on various stroke subtypes are also described. Because most lipid-lowering agents studied to date are statins, this review will primarily focus on statin therapies.
SVD manifests as white matter hyperintensities (WMHs), LI, cerebral microbleeds (CMBs), or intracerebral hemorrhage (ICH).
Although hyperlipidemia is an important risk factor for coronary heart disease and ischemic stroke, it may protect individuals from developing ICH. A study in the United States of America (USA) examined the relationship between the serum total cholesterol level and risk of death from a stroke during a 6-year follow-up in 350,977 men aged 35 to 57 years. They found that the 6-year risk of death from ICH was three times higher in men with serum total cholesterol levels <160 mg/dL [
Since the SPARCL study showed that patients on statin treatment had a significant increase (HR, 1.66; 95% CI, 1.08 to 2.55) in the ICH risk [
Subsequently, a large population-based Swedish study was published that included 7,696 ICH cases and 14,670 age-sex-matched stroke-free controls [
A recent meta-analysis examined the relationship between statin use and the development of CMBs [
Unfortunately, there have been no randomized controlled trials examining the efficacy or hazards of lipid-lowering therapy in patients with ICH. A retrospective study from Taiwan, which used the National Health Insurance Research Database data, compared the outcomes of early statin users (n=749) and statin non-users (n=7,583). During follow-up, the incidence of recurrent ICH was similar between the two groups: 9.2% and 8.9% in the statin and control groups, respectively. However, the mortality rate was significantly lower in patients in the statin group: 90 (12.0%) and 1,519 (20.0%) in the statin and control groups (adjusted HR, 0.742; 95% CI, 0.598 to 0.919), respectively [
A retrospective study from Japan [
Thus, statin use after ICH may not increase the risk of further ICH and may improve the functional outcome and mortality in patients with ICH. However, excessive lowering of cholesterol levels by statins may have to be avoided. However, these retrospective studies have limitations. Details were frequently unknown, such as why and when the statin was initiated, the type and dose of statin, and the duration of treatment. Prospective, controlled trials are needed to elucidate whether statin therapy is needed in patients with ICH, and if so, when and with what dosage should be initiated.
The results of studies on WMH should be interpreted cautiously for the following reasons: First, WMH may not always be an ischemic lesion but can be due to demyelinating diseases or degenerative gliosis. Second, hyperlipidemia may play a role in the development of LAA, and resultant brain hypoperfusion may lead to WMH. Thus, its effect on the underlying large cerebral artery may, in turn, affect the presence of WMH. Third, WMH development may be associated with certain genetic factors, the prevalence of which may differ across ethnicities [
While WMHs are known to be associated with old age and hypertension [
In the Cardiovascular Health Study (CHS), a population-based longitudinal study, 1,919 participants underwent two magnetic resonance imagings (MRIs) at approximately 5-year intervals. Overall, 538 (28%) patients showed worsening of WMH by one grade in most patients (85%). The study analyzed the risk factors associated with WMH worsening separately in patients with initially low-grade (grade 0-1) WMH and those with a higher initial grade. Age, high diastolic blood pressure, and decreased LDL-C levels were associated with worsening of WMH. Although statin use was not related to WMH changes in general, it was associated with an increased WMH progression risk in patients with initially high-grade WMH [
In the Prospective Study of Pravastatin in the Elderly at Risk study [
The Regression of Cerebral Artery Stenosis study was a randomized, double-blind, placebo-controlled study that primarily evaluated the effects of statins on middle cerebral artery (MCA) stenosis progression among stroke-free individuals. Two hundred and eight subjects were randomly assigned to either the placebo (n=102) or simvastatin 20 mg daily (n=106) group. After 2 years of follow-up, there was no significant change in WMH volume between the statin and placebo groups as a whole. However, in individuals with severe baseline WMH, the median volume increase was less in the statin group (1.9 cm3) than in the placebo group (3.0 cm3;
Thus, it appears that mid-life hypocholesterolemia is associated with late-life WMH. However, the relationship between statin use and late-life WMH remains unclear. As statin use is closely related to hyperlipidemia, the association between serum cholesterol and WMH may be confounded by statin use. Additionally, statins may have two faces: they may increase late-life WMH by decreasing serum cholesterol but may prevent WMH via other pleiotropic effects. Finally, as addressed above, statins may improve cerebral perfusion by preventing underlying LAA, which may, in turn, prevent late-life WMH.
Before we discuss the role of blood lipid or lipid-lowering therapy in patients with an LI, we need to consider the heterogeneous nature of LIs that has not been appropriately considered in previous studies on lipids.
LI, a small, deep infarction, is caused by deep perforating arterial disease and is pathologically characterized by lipohyalinosis or fibrinoid degeneration rather than by significant lipid deposits in the vessel wall. However, recent studies have shown that the pathology of “LI,” defined using imaging criteria, may be heterogeneous. Local thrombi or atheromas in patients with ICAS may obliterate the orifice of the perforator and produce LI associated with clinical “lacunar syndromes”; this is called branch atheromatous disease (BAD) [
Consequently, Nah et al. [
In a cross-sectional study conducted in China [
Several Asian studies have investigated the possibility that the effect of lipid-lowering therapy may differ according to the stroke subtype. In the randomized Japan Statin Treatment Against Recurrent Stroke (JSTAR) [
On the other hand, a retrospective study from Spain [
Thus, hyperlipidemia does not play an important role in the development of LI compared with LAA, and the effect of lipid-lowering therapy on LI remains unclear. As discussed above, it should be remembered that LI is a heterogeneous condition; among patients with LI, pLI may be more closely associated with hyperlipidemia and may respond better to statin therapy than dLI. Further studies are needed to determine whether lipid-lowering therapy is effective, at least in patients with a certain subtype of LI.
Similar to atherosclerosis in other vessels, ICAS is caused by vascular risk factors, such as age, hypertension, diabetes mellitus, cigarette smoking, and hyperlipidemia. However, studies that compared the risk factors between ICAS and ECAS have shown that hyperlipidemia is a less important risk factor for ICAS than for ECAS [
Although there may be differences in the pathological features between ICAS and ECAS, few studies have explored this issue. A recent autopsy study from Hong Kong [
There have been few studies on lipid-lowering therapies that exclusively focus on ICAS. In a recent study [
To the best of my knowledge, there is only one controlled study on statins for asymptomatic ICAS. In a single-center prospective study [
Thus, although statins probably benefit patients with ICAS, further studies including a control group, assessment of clinical endpoints, and comparison of the effects of statin therapy in patients with ICAS and ECAS are required. Changes in vessel stenosis or plaque volume should also be assessed more meticulously. Considering the heterogeneity of ICAS, other issues should be considered in future trials. First, strokes in patients with ICAS are caused by various mechanisms, including atherosclerotic steno-occlusion, BAD leading to perforator occlusion, artery-to-artery embolism, and hemodynamic impairment [
As discussed above, hyperlipidemia is an important risk factor for ECAS, probably more so than in ICAS. Thus, the effects of lipid-lowering agents should also be robust under these conditions.
Proximal ICA atherosclerosis has many similarities to coronary artery disease, and hypercholesterolemia is an important risk factor. Of the 4,731 SPARCL participants, a subset of 1,007 participants had ICA disease. In this subgroup, atorvastatin therapy was associated with a 33% reduction in the risk of recurrent stroke, which was far greater than the 16% reduction observed in all SPARCL participants [
Statins appear to influence the composition of the carotid plaques. A recent meta-analysis of seven studies (361 patients) [
Subsequently, a population-based Rotterdam Study [
A more recent Treat Stroke to Target–Plaque Ultrasound Study study [
The benefits of statins in patients who underwent carotid revascularization have also been investigated. A population-based, retrospective cohort study in Ontario, Canada, evaluated the statin effect in individuals aged ≥66 years who underwent carotid endarterectomy or stenting during 2002-2014 [
Unlike ICA, VA atherosclerosis has rarely been examined in clinical studies of lipid-lowering agents. Similar to ICA, VA atherosclerotic disease produces artery-to-artery embolism, leading to posterior circulation ischemia. Therefore, the plaque-stabilizing effect of statins may be equally important in patients with VA disease. Thus, statins have been recommended in patients with atherosclerotic VA disease [
The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) task forces reported guidelines on the management of blood cholesterol [
However, in subsequent guidelines, the term “atherosclerotic” was often omitted. One example was a guideline for the management of patients with “acute ischemic stroke (AIS)” published in 2019 [
These recommendations were based on the TST, JSTAR, and SPARCL trials [
The roles of blood lipids and lipid-lowering therapies differ among stroke subtypes (
The author has no financial conflicts of interest.
Classification of lacunar infarction (LI) according to the location of the lesion and presence/absence of parental arterial disease (PAD). (A) Distal LI without PAD, (B) proximal LI without PAD, (C) proximal LI associated with PAD. Adapted from Nah et al.[
Role of blood lipid and lipid lowering therapy in various subtypes of stroke
Variable | Role of hyperlipidemia as a risk factor | Preventive effect of lipid lowering therapy | Therapeutic effect |
|
---|---|---|---|---|
Small vessel disease | ||||
Intracerebral hemorrhage | – | – | + | |
Microbleeds | – | ? | ? | |
White matter hyperintensities | – | ± | ? | |
Lacunar infarction | ± | ? | ± | |
Large artery atherosclerosis | ||||
Intracranial atherosclerosis | + | + | + | |
Extracranial atherosclerosis | ++ | ++ | ++ |
–, negatively associated; +, positively associated; ?, unknown; ±, equivocally associated; ++, strong positively associated.
Effect of lipid lowering agent in improving clinical or imaging outcomes.