This document discusses the relationship between lipids and cerebrovascular diseases. It finds that higher cholesterol levels are associated with increased risk of ischemic stroke, while lower cholesterol levels are associated with increased risk of hemorrhagic stroke. Statins have been shown to reduce stroke risk by lowering LDL cholesterol levels. The document reviews several clinical trials that demonstrate the efficacy of statin therapy in both primary and secondary stroke prevention.

1. D R . N I S H T H A J A I N
S E N I O R R E S I D E N T
D E P A R T M E N T O F N E U R O L O G Y
G M C , K O T A .
Lipids and Cerebrovascular
diseases

2.  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.

3. 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.

4.  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.

5.  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.

6.  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.

7.  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.

8.  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.

9.  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.

10. 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.

11.  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.

12. 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.

13.  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.

14. 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.

15.  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.

16.  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.

17.  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.

18. 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.

19.  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.

20.  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.

21.  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%.

22.  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.

23.  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).

24.  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.

25.  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.

26.  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.

27.  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.

28.  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.

29.  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.

30.  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.

31.  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.

32.  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.

33.  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.

34.  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.

35.  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.

36.  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.

37.  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.

38.  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%.

39.  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.

40. 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.

41. 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.