Increased Cerebral CO2 Reactivity After Heparin-Mediated
Extracorporal LDL Precipitation (HELP) in Patients With
Coronary Heart Disease and Hyperlipidemia
Thomas K. Pfefferkorn, MD; Hans-Peter Knüppel; Beate R. Jaeger, MD;
Joachim Thiery, MD; Gerhard F. Hamann, MD
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Background and Purpose—There is experimental and clinical evidence that hypercholesterolemia leads to an impairment
of endothelial function in coronary and cerebral arteries. Using transcranial Doppler sonography, we examined CO2
reactivity as a marker of cerebral vasoreactivity in patients with coronary heart disease and hyperlipidemia before and
after drastic lowering of LDL cholesterol, lipoprotein(a) [Lp(a)], and fibrinogen levels by heparin-mediated extracorporal LDL precipitation (HELP).
Methods—CO2 reactivity was determined in 13 patients with coronary artery disease and hyperlipidemia undergoing
regular HELP therapy. Middle cerebral artery mean blood flow velocity (MFV) was detected by transcranial Doppler.
CO2 reactivity was calculated as the percent change of MFV during hypercapnia, induced by ventilation of carbogene
(5% CO2, 95% O2), to normocapnia. Patients with extracranial or intracranial stenoses were excluded. Other parameters
such as blood viscosity, heart rate, and blood pressure were measured to control hemorheologic and systemic influences
on CO2 reactivity.
Results—A single HELP treatment reduced total cholesterol, LDL cholesterol, Lp(a), triglycerides, and fibrinogen levels
by .50% (P,0.001). Blood viscosity significantly decreased from 1.2460.04 to 1.0760.02 mPa (P,0.001). Blood
pressure, heart rate, and MFV did not change significantly. CO2 reactivity increased from 22% 6 21% to 36% 6 18%
(P,0.05).
Conclusions—Fast and drastic removal of LDL cholesterol, Lp(a), and fibrinogen from plasma results in an improvement
of cerebrovascular reactivity in patients with coronary heart disease and hyperlipidemia. The clinical use of HELP in
patients with impaired cerebrovascular reactivity might be promising. (Stroke. 1999;30:1802-1806.)
Key Words: cerebrovascular reactivity n endothelium n hypercholesterolemia n lipoproteins, LDL n ultrasonography
H
ypercholesterolemia is a risk factor for atherosclerotic
disease. Lowering elevated LDL cholesterol levels is
effective in primary and secondary prevention of myocardial
infarction.1–3 Pravastatin, an HMG-CoA reductase inhibitor
(statin) was recently shown to reduce the risk of stroke in
patients with coronary artery disease and moderate hypercholesterolemia.4 Meta-analysis of clinical trials also suggests
that treatment with statins is effective in the prevention of
ischemic stroke.5 If pharmacological measures are not sufficient, heparin-mediated extracorporal LDL precipitation
(HELP) offers an invasive but highly efficient method to
reduce serum LDL cholesterol.6 In addition, plasma fibrinogen and lipoprotein(a) [Lp(a)], both independent risk factors
for coronary heart disease and stroke,7–9 are substantially
reduced by HELP. With this method, fibrinogen, LDL cholesterol, and Lp(a) levels can be lowered by 60% to 75% per
single treatment.10,11 Acute effects of HELP apheresis on
hemorheology are the reduction of red cell aggregability and
plasma viscosity.10
Animal and in vitro studies have shown that experimental
hypercholesterolemia enhances coronary vasoconstriction
and vascular resistance.12–15 Recently, it was demonstrated
that a single LDL apheresis shows a beneficial effect on the
acetylcholine-induced endothelial-dependent vasoreactivity
in coronary and peripheral arteries.16 –18 However, the effects
of LDL apheresis on the vasoreactivity of cerebral arteries are
still unknown.
CO2 reactivity is a marker for cerebral vasoreactivity
(CVR). Being a strong physiological stimulus, CO2 leads to
vasodilatation of the cerebral arterioles, mediated by endothelial smooth muscle cell interactions.19 Assuming a constant diameter of the middle cerebral artery (MCA), increased
blood flow in the precapillary system is correlated with
increased MCA mean blood flow velocity (MFV).20 This
Received February 2, 1999; final revision received May 27, 1999; accepted June 21, 1999.
From the Department of Neurology (T.K.P., H.-P.K., G.F.H.) and Institute of Clinical Chemistry (B.R.J., J.T.), Klinikum Grosshadern,
Ludwig-Maximilians-Universität, Munich, Germany.
Correspondence and reprint requests to Dr Gerhard F. Hamann, Neurologische Klinik, Klinikum Grosshadern, Ludwig-Maximilians-Universität,
Marchioninistr. 15, 81377 München, Germany. E-mail [email protected]
© 1999 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
1802
Pfefferkorn et al
TABLE 1.
Patient No.
Increased Cerebral CO2 Reactivity After LDL Apheresis
1803
Patient Data
Age, y
Date of
HTX, mo*
Initiation of
HELP, mo*
LDL/Lp(a)/TG Before
Initiation of HELP,
mg/dL
Concomitant Therapy
When Investigated
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1
61
189/5/176
A, C, D
52
zzz
17
12
2
7
161/99/273
A, B, C
3
71
54
40
242/11/245
A, B
4
58
66
10
167/71/128
A, B
5
58
43
23
187/56/200
A, B, D
6
49
52
37
160/53/114
B
7
57
120/63/351
A, C, D
8
69
zzz
36
2
35
152/52/349
A, B, D
9
55
85
17
186/20/204
B
10
48
zzz
28
115/53/510
A, C, D
11
61
zzz
4
165/48/194
A, B, D
12
46
13
56
18
238/245/406
A, C, D
zzz
9
152/165/149
A, C, D
zzz
HTX indicates heart transplantation; TG, triglycerides; A, antihypertensive therapy; B, immunosuppression; C, statin therapy; and D, inhibition of platelet aggregation.
*Months before investigation.
parameter can easily be detected by transcranial Doppler and
allows quantification of CO2 reactivity.21
The objective of our prospective study was to test the acute
effect of a single LDL apheresis on CO2 reactivity as a marker
of CVR in patients with coronary artery disease and
hyperlipidemia.
Subjects and Methods
Thirteen male patients (mean age 5767.5 years) with a history of
coronary heart disease (7 patients with heart transplantation due to
ischemic cardiomyopathy) and hyperlipidemia were included in the
study. All of them were on regular HELP therapy (1- to 4-week
intervals) because of elevation of LDL cholesterol or Lp(a) (threshold values: LDL cholesterol 180 mg/dL, Lp(a) 45 mg/dL) with
insufficient response to diet and drug therapy. Most patients received
antihypertensive therapy. All patients with a history of heart transplantation received immunosuppressive therapy with cyclosporine,
azathioprine, and steroids. For detailed information on the clinical
status of the patients before initiation of HELP therapy, see Table 1.
All patients had extracranial and intracranial Doppler sonography to
exclude hemodynamically relevant stenosis (.50%) or occlusion of
brain-supplying vessels and to ensure a detectable MCA signal.
For extracorporal LDL apheresis, the system Plasmat Secura
(Braun) was used. The average treatment lasted 2 hours, 2.8 to 3.0 L
of plasma were filtrated. Detailed description of this method has
been published before.22
CO2 reactivity was determined 30 minutes before and 30 minutes
after HELP apheresis. Informed consent for the Doppler examinations was obtained from all patients before the procedure. Transcranial Doppler studies were performed with the MultiDop X4 (DWL).
While the patients were sitting in a comfortable position, 2-Mhz
probes were bilaterally fixed over the temporal bone window when
highest intensity and velocity of the MCA signal in a depth of 45 to
55 mm had been obtained. Blood pressure and pulse were measured
before and after HELP apheresis. End-tidal CO2 partial pressure was
continuously monitored in 5 of our 13 patients during the Doppler
examination with a CO2 monitor (EGM I, Heyer).
Bilateral MCA MFV was continuously monitored and digitally
recorded for later off line analysis. Patients breathed through a
plastic mouthpiece, and a nose clamp kept their nostrils closed. A
valve mechanism allowed for prompt switching from room air to
carbogene (5% CO2, 95% O2). The patients started by breathing
room air for 30 to 60 seconds, until a steady state in mean MCA
blood flow velocity was obtained. They were then asked to hyperventilate for 30 to 60 seconds. Thereafter, patients were allowed to
breathe normally for another minute. In the next step, patients were
ventilated with carbogene for at least 1 minute, until mean MCA
blood velocity and end-tidal CO2 partial pressure remained stable.
Finally, patients breathed room air again until mean MCA blood
flow velocity had normalized.
For off line analysis, mean MCA blood flow velocities were
defined from the recorded Doppler curves at the following time
points: resting (normocapnia), during hyperventilation after a steady
state in flow velocity had been obtained (hypocapnia), and after at
least 1 minute of carbogene ventilation, when end-tidal CO2 partial
pressure and flow velocity had reached stable values (hypercapnia).
CO2 reactivity was calculated as the percent change of MCA MFV
in hypercapnia compared with normocapnia (CO2 reactivity5
(MFVHypercapnia2MFVNormocapnia)3100%/MFVNormocapnia). Changes in
CO2 reactivity were presented as absolute percent differences
(change in CO2 reactivity5CO2 reactivityafter HELP2CO2 reactivitybefore HELP).
Blood viscosity was measured before and after HELP apheresis.
Statistical Analysis
All data are presented as mean6SD. To compare CO2 reactivity and
other parameters before and after HELP apheresis, a non parametric
test was performed (Wilcoxon matched pairs signed ranks test). To
test an association between CO2 reactivity changes and pretreatment
CO2 reactivity or LDL cholesterol, a bivariate non parametric
correlation (Spearman) was performed.
Results
Total Cholesterol, LDL Cholesterol, HDL
Cholesterol, Lp(a), Triglycerides, Fibrinogen, and
Plasma Viscosity
HELP apheresis reduced total cholesterol, LDL cholesterol,
Lp(a), and triglycerides by .50% (P,0.001). HDL cholesterol was reduced by 15% (P,0.01). For exact individual
values and means, see Table 2. Fibrinogen and plasma
viscosity were reduced by 56% and 14%, respectively
(P,0.001; see Table 3).
1804
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September 1999
TABLE 2.
Lipid Status of Patients Before and After LDL Apheresis
Total Cholesterol, mg/dL
Patient No.
LDL Cholesterol, mg/dL
HDL Cholesterol, mg/dL
Lp(a), mg/dL
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Before
After
Before
After
Before
After
After
Before
After
1
286
128
147
70
50
41
6
6
220
53
2
211
112
113
64
49
42
91
65
111
87
3
320
107
150
62
29
24
5
5
245
119
4
230
114
187
70
42
35
83
37
112
40
5
263
118
118
53
49
44
73
27
200
63
6
245
120
90
42
44
36
99
39
444
212
7
216
106
96
54
40
38
66
31
351
111
8
252
131
122
48
38
35
112
64
312
112
9
199
94
171
66
39
31
24
14
190
102
10
225
129
163
91
35
31
53
24
510
254
11
224
126
113
61
45
39
27
15
148
39
12
332
147
231
118
40
31
245
96
406
96
13
177
91
157
88
41
33
66
41
233
50
244646
117616
143640
68620
4266
3565
73662
36626
2686128
103665
Mean6SD
Blood Pressure and Heart Rate
There were no significant changes in blood pressure or heart
rate. Mean blood pressure values were 147/88 mm Hg before
and 141/86 mm Hg after HELP (NS). Pulse rate values were
86 and 83 bpm, respectively (NS).
MCA Mean Blood Flow Velocity
Average pretreatment MFV was 54.866.4 cm/s for the left
and 56.466.8 cm/s for the right MCA. After HELP apheresis
MFV was 56.769.9 cm/s and 57.969.5 cm/s, respectively.
Combining both sides, average MCA MFV was 55.666.0
cm/s before and 57.369.3 cm/s after HELP apheresis. These
changes were not significant.
CO2 Reactivity
Pretreatment CO2 reactivity calculated as the percent change
of MCA MFV in hypercapnia compared with normocapnia
Before
Triglycerides, mg/dL
ranged from 212% to 54%, with a mean of 22%621%. After
HELP apheresis values ranged from 22% to 68%, with a
mean of 36%618% (Table 3). The relative increase in CO2
reactivity of 14% was significant (P,0.05) (Figure 1).
Changes of CO2 reactivity in individual patients are presented
in Figure 2. Pretreatment LDL cholesterol, Lp(a), triglycerides, and fibrinogen, as well as pretreatment CO2 reactivity,
were not significantly associated with change in CO2 reactivity. However, change of CO2 reactivity tended to be positively associated with pretreatment LDL cholesterol and
negatively associated with pretreatment CO2 reactivity (Figures 3 and 4). Lack of significance might be due to the low
number of patients. An estimated number of 28 patients
would be necessary to possibly reach significance.
TABLE 3. Fibrinogen, Plasma Viscosity, and CO2 Reactivity in
Patients Before and After LDL Apheresis
Fibrinogen, mg/dL
Viscosity, mPa
CO2 Reactivity, %
Before
After
Before
After
1
236
103
1.20
1.04
45
68
2
386
186
1.23
1.06
33
46
3
482
191
1.29
1.09
54
58
4
292
109
1.29
1.11
8
24
5
402
162
1.2
1.04
0
22
6
245
113
1.22
1.07
34
31
7
310
155
1.19
1.07
1
22
8
486
166
1.21
1.09
53
38
9
235
94
1.31
1.08
25
53
10
470
244
1.24
1.10
17
23
11
244
123
1.24
1.06
7
27
12
448
203
1.21
1.05
212
41
13
312
145
1.28
1.07
20
38
Patient No.
Mean6SD
Before
350699 153645 1.246.04 1.076.02 22621
After
36618
Figure 1. CO2 reactivity ((MFVHypercapnia2MFVNormocapnia)3100%/
MFVNormocapnia) before and after HELP therapy. Box plots with
median values, 25th and 75th percentiles, and total ranges.
Change in CO2 reactivity was significant (P50.011, Wilcoxon
test).
Pfefferkorn et al
Increased Cerebral CO2 Reactivity After LDL Apheresis
1805
Figure 2. CO2 reactivity before and after HELP therapy in individual patients.
Discussion
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We showed for the first time that a single LDL apheresis with
the HELP system significantly improves CO2 reactivity. This
improvement tended to be more pronounced in patients with
low pretreatment CO2 reactivity and elevated pretreatment
LDL cholesterol levels. Significant effects might have been
missed due to the small number of patients and the huge
interindividual variability in the CO2 reactivity. Intraindividual reproducibility in detecting CO2 reactivity by transcranial Doppler is known to be high.21
The reduction rates of LDL cholesterol, Lp(a), triglycerides, and fibrinogen matched well the results from previous
studies using the HELP system in patients with coronary
heart disease.6 Although all patients had a history of hyperlipidemia, only some had pathologically elevated LDL cholesterol or Lp(a) levels at the time of the HELP apheresis.
This is a consequence of repeated HELP apheresis in all and
concomitant treatment with statins in some patients (with no
history of heart transplantation). Previous studies have demonstrated a new steady state in LDL cholesterol and fibrinogen levels after 4 to 8 treatment sessions.23
As expected, blood viscosity was markedly reduced after
HELP apheresis. This alteration had no influence on systemic
Figure 3. Change in CO2 reactivity with regard to pretreatment
LDL cholesterol. The increase in CO2 reactivity seems to be pronounced in patients with high initial LDL levels.
Figure 4. Change in CO2 reactivity with regard to pretreatment
CO2 reactivity. The increase in CO2 reactivity seems to be attenuated in patients with high initial CO2 reactivity.
hemodynamic parameters such as mean arterial blood pressure or heart rate. Interestingly, mean MCA blood flow
velocity did not change after HELP apheresis.
This is in contrast to the investigation of Izumi et al,24 who
found a small but significant increase in MCA blood flow
velocity after pharmacological defibrination with the venom
batroxobin. The latter study was performed on normal subjects with a mean age of 32 years and no history of vascular
disease. There are 2 explanations for the discrepancy with our
results. First, there was considerable variance regarding
pretreatment MCA blood flow velocities in our patients.
Thus, our patient number might have been too small to detect
significant changes on flow velocities. Second, there might be
specific limitations of hemorheologic effects on cerebral
blood flow in our patients. These limitations include older
age, reduced cardiac output due to ischemic heart disease,
generalized vascular alterations due to atherosclerosis, and
denervation of the graft in the transplanted patients.
Despite constant blood flow velocities, a significant increase in CO2 reactivity as a marker of CVR was observed.
Izumi et al24 also observed increased CO2 reactivity after
defibrination with batroxobin. However, in their (healthy)
subjects, this increase was, as pointed out before, associated
with increased cerebral blood flow. The independent increase
in CO2 reactivity in our patients suggests a direct influence of
HELP apheresis on CVR.
HELP apheresis in our patients seemed to have a stronger
effect on CO2 reactivity if pretreatment values were low. A
low initial CO2 reactivity may represent a state of endothelial
dysfunction. In this context the effect of HELP apheresis
could be explained as the normalization of disturbed endothelial function, as it was recently demonstrated for peripheral
and coronary arteries.16 –18 Patients with high initial CO2
reactivity and normal endothelial function may have no range
for further improvement.
Considering a direct influence of HELP apheresis on endothelial
function and CVR, several mechanisms may play a role. In
experimental long-lasting hypercholesterolemia in pigs, vasocon-
1806
Stroke
September 1999
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strictive effects of endothelin-1 are pronounced while vasorelaxing
effects of endothelium-derived relaxing factor/nitric oxide are reduced. This imbalance leads to increased vascular tone.12
Regarding short-term effects, Andrews and coworkers13
demonstrated inhibition of endothelium-dependent relaxation
after exposure to native but not to chemically modified LDL
cholesterol in an in vitro model of rabbit aorta. The authors
proposed that a receptor-dependent mechanism mediated the
inhibition of endothelium-dependent relaxation. Kugiyama
and coworkers,14 however, showed that inhibition of vascular
relaxation only occurs after exposure to oxidized, but not to
native, LDL cholesterol. These controversial results could be
explained by insufficient protection of native LDL against
oxidation in the study by Andrews et al, with subsequent
intraexperimental development of oxidized LDL being the
main factor for inhibited arterial relaxation. In a more recent
study, Hein and Kuo25 investigated the influence of native
and oxidized LDL on porcine coronary arterioles. They found
an inhibition of nitric oxide–mediated vasorelaxation after 1
hour exposure to both forms of LDL. Oxidized LDL produced more severe inhibition than native LDL. The inhibitory
effects of both LDLs were prevented by administration of a
cell-permeable superoxide scavenger, suggesting a role of
superoxide anions in LDL-mediated inhibition of vasorelaxation. Galle and coworkers15 used bovine arterial endothelial
cells to investigate short-term effects of both forms of LDL.
They showed that oxidized LDL, and to a lesser degree native
LDL, inactivated endothelium-derived relaxing factor after its
release from the endothelium, which suggests a further
pathway of LDL-mediated vasomotor impairment.
The discussed mechanisms of acute impairment of arterial
relaxation by LDL cholesterol may help to explain the
observed increase in cerebrovascular reactivity detected in
our patients as early as 30 minutes after HELP apheresis. One
could speculate that reduction of LDL cholesterol acutely
reverses LDL-dependent impairment of arterial relaxation
and thus leads to normalization of CVR.
We conclude that HELP apheresis in patients with ischemic
heart disease and hyperlipidemia directly affects CVR by normalizing endothelial function. In cases of compromised cerebral
perfusion, endothelium-dependent CVR improvement may have
beneficial effects on cerebral microcirculation.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Acknowledgments
The authors thank Mrs. Judy Benson for the language editing of this
manuscript. The authors state that there are no conflicts of interest
regarding the submission.
22.
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Increased Cerebral CO2 Reactivity After Heparin-Mediated Extracorporal LDL
Precipitation (HELP) in Patients With Coronary Heart Disease and Hyperlipidemia
Thomas K. Pfefferkorn, Hans-Peter Knüppel, Beate R. Jaeger, Joachim Thiery and Gerhard F.
Hamann
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Stroke. 1999;30:1802-1806
doi: 10.1161/01.STR.30.9.1802
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1999 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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