DR. NISHTHA JAINSENIOR RESIDENT

DEPARTMENT OF NEUROLOGYGMC, KOTA.

Lipids and Cerebrovascular diseases

In most epidemiological cohorts, there is a direct relationship between cholesterol levels and ischemic stroke.

The relationship of lipids to ischemic stroke varies by stroke subtype, with associations strongest for atherosclerotic subtypes.

Conversely, there is an increased risk of intracerebral hemorrhage (ICH) and small vessel disease at low cholesterol levels.

Lipid Parameters and Stroke Risk

In most observational studies, there is an association between higher total and LDL-C levels and increased ischemic stroke risk.

In addition, most observational studies also found an association between lower TC and LDL-C levels and increased risk of hemorrhagic stroke.

In some studies, there is an inverse relationship between high-density lipoprotein-cholesterol (HDL-C) and stroke.

In systematic review of 10 prospective studies it was found that there was a decreased risk of ischemic stroke ranging from 11% to 15% for each 10-mg/dL increase in HDL-C.

HDL has 2 main subfractions: larger and less dense HDL-C (HDL2) and smaller and denser HDL-C (HDL3).

These subfractions differ in their biological activity, biochemical properties, and vascular metabolism.

HDL3, more so than HDL2, seems to inhibit LDL oxidation and protect against atherosclerosis by its action on the vascular endothelium.

In the Northern Manhattan Study (NOMAS), HDL subfractions had differential effects on the risk of carotid disease.

There was a direct relationship between HDL2 and plaque thickness and an inverse relationship between HDL3 and plaque area.

In a nested prospective case–control analysis from the Circulatory Risk in Community Study, small- and medium-sized HDL particles were associated with reduced risk of ischemic stroke, in particular, lacunar infarcts, and ICH.

Epidemiological studies evaluating triglycerides and ischemic stroke also show mixed results, partly because of differential use of both fasting and nonfasting levels.

In a meta-analysis of 64 studies, there was an association between higher triglyceride levels and relative risk of stroke for each 10-mg/dL increase in baseline triglycerides.

Studies have also shown that triglycerides levels are inversely associated with hemorrhagic stroke risk.

Lipoprotein(a) (Lp(a)) has been identified as an emerging risk factor for cardiovascular disease.

Plasma levels of Lp(a) are influenced by genetic factors, with substantial differences across ethnic groups, with levels being highest among blacks.

In Atherosclerosis Risk in Communities, Lp(a) levels ≥30 mg/mL were associated with increased risk of ischemic stroke in black and white women, but not in white men.

In a NOMAS case–control study, Lp(a) levels ≥30 mg/dL at baseline were associated with an increased risk of ischemic stroke.

This association was more pronounced among men and blacks.

The effects of Lp(a), therefore, may depend on race-ethnic and other demographic factors.

Lipids and Ischemic Stroke Subtypes

There is a stronger association between lipids and strokes because of large artery atherosclerosis.

The relationship between dyslipidemia and lacunar stroke is complex and influenced by genetic and demographic factors in different patient populations.

Although dyslipidemia is a risk factor for coronary heart disease, most studies showed no association between dyslipidemia and embolic stroke.

Studies have shown an inverse relationship between dyslipidemia and both WMH and cerebral microbleeds.

This may relate to the role that cholesterol plays in the architecture and integrity of the normal endothelium of small vessels.

Low lipid levels may interfere with the integrity of the endothelium or impair endothelial reparative processes, causing leakage or obstruction of the small vessels.

Screening for Lipid Levels After Stroke

In patients with ischemic stroke, a serum lipid profile including TC, LDL, HDL, and triglycerides should be performed.

On the contrary, routine testing for other lipid components such as Lp(a) and HDL subfractions is not recommended.

The timing of lipid measurements after stroke may be less important than after myocardial infarction.

There is evidence that lipid levels after stroke do not decline as markedly as after myocardial infarction.

In a meta-analysis of 68 studies that included >300 000 patients, the association between lipid components and ischemic stroke persisted even when measured in nonfasting patients.

Associations with triglycerides were even more prominent in the nonfasting state.

Lipid profile in cerebrovascular accidents

The study was designed to evaluate the lipid profile levels of patients who had experienced an acute stroke during the first 24-hour and to compare these levels in different patients suffering from the stroke, either hemorrhagic or ischemic, and healthy individuals.

The main goal was to determine whether hypocholesterolemia is a risk factor for primary ICH.

The second goal was to compare the serum cholesterol and Triglyceride (TG) levels in the two types of stroke.

In the patients’ group, 65 suffered from hemorrhagic stroke (group 1) and the other 193 had ischemic stroke (group 2).

Except for TG values, there was no significant difference among the ischemic and hemorrhagic lipid profile.

Age, cholesterol, and LDL influenced the risk of developing an ischemic stroke; TG was not reported as a risk factor or a protective one.

While the comparison of data retrieved from patients suffering from hemorrhagic strokes with the controls, revealed LDL as the risk factor contributing to the development of ICH whereas TG was reported as a protective factor.

It could be concluded that LDL level can be considered as a risk factor for both ischemic and hemorrhagic cerebral events.

The Multiple Risk Factor Intervention Trial (MRFIT), showed that the risk of death from nonhemorrhagic stroke increased with increasing serum cholesterol in 351 000 men aged 35 to 57 years.

Conversely, in the same study, there was a negative association with hemorrhagic stroke for cholesterol levels <5.2 mmol/L (<201 mg/dL): the lower the total cholesterol level, the higher the risk of hemorrhagic stroke.

Lipid-Lowering Therapy and Stroke

In addition to their cardiovascular benefits, statins have demonstrated efficacy in reducing stroke risk.

In primary stroke prevention trials, several statins have been associated with reductions in risk of stroke ranging from 11% to 40%.

The Heart Protection Study (HPS) randomized >20 000 patients aged 40 to 80 years with high risk of vascular disease to simvastatin 40 mg daily versus placebo.

There was a 25% reduction in stroke risk without an increase in the risk of hemorrhagic stroke.

Cells acquire cholesterol by de novo synthesis and the uptake and degradation of plasma lipo-proteins via LDL-receptors.

The delivery of cholesterol to the cell results in the down regulation of its’ own synthesis and decreased expression of LDL receptors.

Statins competitively inhibit HMG-CoA reductase, thereby decreasing cholesterol synthesis.

This stimulates the transcription of LDL receptors, increasing the acquisition of lipids and decreases plasma lipid levels.

In the Treating to New Targets (TNT) study, compared with atorvastatin 10 mg daily, atorvastatin 80 mg daily was associated with a 25% reduction in stroke risk that correlated with reductions in LDL.

Furthermore, metaanalyses of lipid therapy and stroke showed that with each 1-mmol/L reduction in LDL-C, there was ≈20% RR reduction in ischemic stroke.

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, provides the most direct evidence on the role of statins in secondary stroke prevention.

SPARCL randomized 4731 patients with stroke or transient ischemic attack and baseline LDL 100 to 190 mg/dL to atorvastatin 80 mg versus placebo beginning 1 to 6 months after their event.

Over a median follow-up of 5 years, atorvastatin was associated with an ≈2% absolute reduction in recurrent total stroke risk, with a RR reduction of 16%.

A small increase in hemorrhagic stroke was reported in the atorvastatin group.

Moreover, recent studies evaluating withdrawal of statins in acute ischemic stroke showed a higher incidence of death or dependency at 90 days.

The Long- Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study investigated cholesterol lowering with pravastatin in patients with a previous myocardial infarction (MI) or unstable angina who had cholesterol levels between 155 and 271 mg/dL and reported a remarkable reduction in MI, cardiac revascularizations, and cardiovascular deaths, as well as a 20% reduction in the risk for stroke (Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID] Study Group, 1998).

Similar findings were associated with atorvastatin in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial and the Anglo- Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) studies.

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized 19 342 hypertensive persons who also had ≥3 other cardiovascular risk factors to treatment with either a β-blocker ± diuretic or amlodipine ± angiotensin converting enzyme inhibitor with follow-up for 5 years.

A total of 10 305 patients who had a total cholesterol <6.5 mmol/L (<251 mg/dL) were further randomized in a factorial design to atorvastatin 10 mg daily or placebo.

On the recommendation of the study’s independent Data Safety Monitoring Board, the lipid-lowering arm was stopped prematurely (mean follow-up, 3.3 years) because of strong efficacy of active treatment on the primary trial end point (nonfatal MI and fatal CHD).

Despite early termination of the lipid-lowering arm of the trial, there was a significant (27%) reduction in relative risk of fatal and nonfatal stroke with atorvastatin (P=0.024), and the benefits of treatment apparently began early during follow-up.

In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial conducted in patients with unstable angina or non–Q-wave MI immediately after the qualifying event, there was a significant overall risk reduction in the secondary end point of stroke (51%; P=0.04).

Thus, statins may reduce thromboembolism to the brain by preventing early recurrent MI.

The benefits of parvastatin treatment in elderly was observed in the PROSPER trial.

It was seen that parvastatin lowered LDL concentrations by 34% and the risk of CAD and non fatal MI was also reduced.

PROSPER therefore extends the treatment strategy to elderly as used for middle aged population.

The benefits of statins on risk reduction were similar across subtypes of the index stroke subtype as well, implying that all patients with ischemic stroke, regardless of subtype, should receive statin therapy.

There are other potential mechanisms by which statins are protective which include inhibition of the inflammatory cascade, antioxidant effects, upregulation of nitric oxide synthase with consequent increase in cerebral blood flow, plaque stabilization, and modulating coagulation and platelet function.

Moreover, the benefit of statins appears to be independent of baseline cholesterol; persons with normal cholesterol experience a similar degree of risk reduction as patients with elevated cholesterol.

Statins affect multiple biological systems, including the immune system.

Prevention of vascular outcomes in trials of statins is strongly linked to a decrease in C-reactive protein.

Statins improve endothelial function and have anticoagulant, antiinflammatory, and antithrombogenic properties, all of which may foster neuroprotective effects.

Statins administered to animals 24 hours after stroke increase expression of neurotrophic factors such as vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), amplify endogenous brain plasticity, and reduce neurological deficits.

In addition to the above benefits, epidemiological studies have also identified a strong independent association between extra cranial carotid intimal medial thickness, the degree of stenosis and incidence of stroke.

Statins produce significant reductions in carotid intimal-medial thickness and decrease aortic atherosclerosis, a known source of cerebral embolization.

In lacunar arteriolopathy, there is an interaction between oxidized LDL cholesterol and endothelial function, which is important for vasoreactivity and may be impaired in small-vessel disease.

Thus, lipid abnormalities may also play a role in small-vessel disease, and statins appear to improve cerebral vasomotor reactivity.

The benefit of nonstatin lipid-lowering agents for primary or secondary stroke prevention is not as well established.

Although niacin increases HDL levels, its benefit in reducing the risk of cerebrovascular events remains uncertain.

Fibric acid derivatives can also be used to lower triglycerides and increase HDL-C levels, but their efficacy in reducing incident stroke is uncertain.

Ezetimibe inhibits the intestinal absorption of cholesterol, reducing TC levels.

The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) showed that the addition of ezetimibe 10 mg daily to simvastatin 40 mg daily resulted in a significant reduction in stroke risk.

Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a hepatic protease that degrades hepatic LDL receptors leading to increased serum LDL-C levels.

Monoclonal antibody inhibitors of PCSK9 are novel parenterally administered lipid-lowering agents that have been shown to reduce LDL by 60% to 70% when added to statin therapy.

Although evidence suggests an inverse relationship between lipids and hemorrhagic stroke, the association between statin use and ICH remains unclear.

The HPS study was the first clinical trial to show a nonsignificant increase in the risk of ICH with simvastatin versus placebo (1.3% versus 0.7%).

In SPARCL, patients on atorvastatin were more likely to have ICH than those on placebo.

Statin therapy is recommended to patients with

(1) clinical atherosclerotic cardiovascular disease (atherosclerotic stroke or transient ischemic attack and coronary artery disease);

(2) LDL-C ≥190 mg/dL;(3) age 40 to 75 years, diabetes mellitus, and LDL-C 70 to

189 mg/dL; (4) LDL-C 70 to 189 mg/dL, no diabetes mellitus, and

estimated 10-year atherosclerotic cardiovascular disease risk of ≥7.5%.

High intensity statin therapy is recommended for those <75 years and at low risk of statin complications, with atherosclerotic cardiovascular disease, LDL-C ≥190 mg/dL, or diabetes mellitus and a 10-year risk of atherosclerotic cardiovascular disease of ≥7.5%.

Moderate intensity statin therapy (ie, a lowering of LDL-C of 30%–50%) is recommended for other groups.

Conclusion

There is a direct relationship between cholesterol levels and ischemic stroke, and particularly atherosclerotic disease, and the associations are strongest for TC and LDL.

There is an increased risk of ICH at low cholesterol levels, and there is evidence that low lipid levels also increase the risk of small vessel disease.

Statins reduce the risk of recurrent stroke after ischemic stroke, but the role of adding newer lipid-lowering agents remains to be determined.

Referrences

Lipids and Cerebrovascular Disease. Shadi Yaghi, et al. Stroke November 2015.

Lipid Profile Components and Subclinical Cerebrovascular Disease in the Northern Manhattan Study. Joshua Z. Willey, et al. Cerebrovasc Dis 2014;37:423–430.

Lipid profile in cerebrovascular accidents. T Mansoureh, et al. Ir J neurol 2011; 10(1-2): 1-4.

Statin treatment withdrawal in ischemic stroke A controlled randomized study. M. Blanco, et al.

The Role of Statins in Vascular Disease. P. E. Laws, et al. Eur J Vasc Endovasc Surg 27, 6–16 (2004).

Bradley neurology, 6th edition.