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Improved reactive hyperemia test after plasma exchange in familial hypercholesterolemia
Atherosclerosts,
56 (1985)
Elsevier Scientific
231-242
Publishers
237
Ireland,
Ltd.
ATH 03665
Preliminary
Note
Improved Reactive Hyperemia Test After Plasma Exchange in Familial Hypercholesterolemia P. Rubba ’Instrtutr
‘, A. Postiglione of Internal
Cellular and Molecular
Medicme Pathology,
i, N. Scarpato
’ and M. Mancini
2, A. Iannuzzi
and Metabolic Disease and ’ Immunohematologv 2nd Medical School, Unicersity of Naples,
Unit, Department
Via S. Pansmi 5, 80131
’ of
Naples
(Italy)
(Revised,
(Received 22 March, 1984) received 24 September, 6 March and 20 December (Accepted 8 March, 1985)
1984)
Summary By using a non-invasive methodology of vascular diagnosis, ECG-triggered strain-gauge plethysmography, 5 patients with familial hypercholesterolemia (FH) (3 homozygous, 2 heterozygous) were evaluated before and during the 1st and 2nd week after plasma exchange (PE). In order to obtain data on the responsiveness to vasodilating stimuli in FH patients undergoing PE, reactive hyperemia test and peak flow determination were also performed. Resting arterial flow over the calf was found to be significantly enhanced after PE. Reactive hyperemia test demonstrated persistent improvement of peak flow following exchange. This study demonstrates useful hemodynamic effects of PE in patients with FH. Key words:
Arterial flow - Familial hypercholesterolemia Strain gauge plethysmography
Plasma exchange
-
Introduction Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, which is characterized by severe elevation of plasma cholesterol and premature onset of atherosclerotic cardiovascular disease [1,2]. Patients with FH are extremely refractory to most conventional lipid-lowering treatments. However they improve their condition through the therapeutic procedure of plasma exchange, which
0021-9150/85/$03.30
0 1985 Elsevier
Scientific
Publishers
Ireland,
Ltd.
238
produces marked reduction of plasma cholesterol [3,4] together with some interesting hemodynamic effects [5,6]. In particular we have recently shown an improvement of resting calf arterial flow during the 1st week after plasma exchange in FH patients
[71. After this first experiment some questions were still open: (a) Is the baseline arterial flow abnormally reduced in FH? (b) Is the response to vasodilating stimuli (exercise, ischemia, drugs) improved by PE? (c) Is the hemodynamic effect lasting during the 2nd week after PE? In order to answer these questions we have performed, in addition to rest flow determination, the reactive hyperemia test. This test is more sensitive and reproducible [S] than resting flow determination and allows determination of the skeletal muscle vasodilator reserve. Patients and Methods PE was performed on 5 patients (age lo-52 years; 3 M, 2 F) with FH (3 homozygous, 2 heterozygous). They showed the typical picture of tuberous xantomata, xantelasma and bruits over the aorta, carotids and renal or femoral arteries. The patients did not smoke cigarettes in the week before and during the study. They continued their usual lipid-lowering diet and drug treatment (cholestyramine 20 g/day and nicotinic acid, 2,4 g/day or fenofibrate 300 mg/day). PE was performed by using a discontinuous flow cell separator (Transfer 90 Bell Co. centrifuge, U.S.A.). Anticoagulation was maintained with A.C.D. (citric acid, hydrate 0.8%, sodium citrate, dihydrate 2.2%, dextrose 2.45%) in a 1 : 8 ratio to total blood. The plasma was removed and exchanged with isotonic saline containing 5% human albumin (ISI, Italy). Arterial blood flow over the right leg was determined by a strain-gauge plethysmograph (Periflow, Janssen, Belgium) at days -2, 0, 1, 4, 7, 8, 11 and 14. ECG-triggered venous occlusion [8,9] plethysmography allows semicontinuous registration of arterial flow variables. Using wide tubings connected with controlled pressure reservoirs and provided with electromagnetic valves, whose opening is regulated by the ECG-triggered unit of the plethysmograph, venous return can be interrupted over 1 or more heart cycles. Because of the very short occlusion time, resistance changes in the vascular bed of the measured segment are negligible. The volume increase during the venous outflow occlusion, for a few heartbeats, is measured with a mercury in silastic gauge with high-frequency response, connected with an amplifier and a function analyzer allowing automatic calculation of the arterial blood flow in volume/mm/d1 of calf volume (or volume/min/lOO g of calf tissue). The cuff inflation pressure is 50 mm Hg and 90% of this pressure level is reached within 18 ms. Inflation begins in the leg cuffs with a delay of 150 ms after the QRS interval of the ECG which is the time interval needed till the entry of stroke volume at the level of occlusion cuff, around the thigh. Arterial flow is measured over 3 cardiac cycles, so that a semicontinuous flow measurement is being performed over a period of 5 heart beats.
239
Each study was performed at 22°C after at least 20 min of supine rest. After 10 min of rhythmic venous occlusion, blood flow registration was performed for 2 min. Results were expressed in ml/mm/d1 of leg volume. In all the patients the reactive hyperemia test was performed. The same cuff used for venous occlusion was inflated at a suprasystolic pressure for 3 min, in order to produce transient ischemia. After the release of the arterial occlusion, reactive hyperemia took place, and maximal postischemic flow (peak flow) could be determined. Vasodilator reserve was estimated by peak flow/rest flow ratio. Plasma cholesterol and triglyceride concentration were determined by semiautomated enzymatic methods on a Carlo Erba Analyzer (CLA) at the time of each arterial flow study [lo]. Plasma fibrinogen determination was performed by radial immunodiffusion technique [ll]. Statistical comparisons were done by using the Student paired t-test [12].
Results
About 50% of plasma could be exchanged with the present discontinuous flow technique. The amount of cholesterol withdrawn with a single PE averaged 5 g. Table 1 reports mean plasma cholesterol, triglyceride, haematocrit and fibrinogen before PE (days - 2,0), during the 1st week (days 1, 4, 7) and the 2nd week (days 8, 11, 14) after PE in the FH patients under study. Plasma cholesterol was significantly reduced during the 1st week of treatment, then rose to a value intermediate as compared to pretreatment. The mean reduction of plasma fibrinogen during the 1st and 2nd week after PE was not statistically significant. Resting arterial flow was slightly increased after plasma exchange. At the same time significant improvement of reactive hyperemia test occurred with increase in peak flow over the calf by about 25% (Table 1). The vasodilator reserve was not significantly changed after PE. Rest
TABLE
1
REACTIVE HYPEREMIA TEROLEMIA (3 M, 2 F)
TEST AFTER
PLASMA
EXCHANGE
IN FAMILIAL
HYPERCHOLES-
Values are mean + SEM. Baseline: mean of values obtained on days - 2 and 0; week 1: mean of values obtained on days 1, 4, 7; week 2: mean of values obtained on days 8. 11, 14. f Tot. plasma cholesterol Plasma TG (mmol/l) Packed red cell (W) Fibrinogen (mg/dl) Rest flow (ml/min/dl) Peak flow (ml/min/dl) Peak flow/rest flow * P < 0.05.
(mmol/l)
Baseline
Week 1
Week 2
19.1 f 3.1 1.87+ 0.74 42 +6 324 &36 2.1 f 0.6 13.3 k 0.6 10.1 k 3.8
13.8 f 2.8 * 1.72* 0.68 41 k6 300 +29 2.6 + 0.5 16.7 + 1.3 * 6.1 + 1.0
16.8 f 2.1 1.705 0.74 42 +6 310 *41 2.9 + 0.5 * 15.4 * 0.9 * 6.1 k 1.0
240
TABLE2 REST FLOW PLASMA
VALUES
IN THE INDIVIDUAL
PATIENTS AT DIFFERENT
TIMES
AFTER
EXCHANGE
Baseline: mean of values obtained on days - 2 and 0; week 1: mean of values obtained 7; week 2: mean of values obtained on days 8, 11 and 14. Patient (sex, age)
Rest flow (ml/mitt/d1
M.P. hmz (F, 10) O.M.G. hmz (F, 12) S.L. hmz (M, 21) D.S. htz (M, 42) M.U. htz (M, 52) hmz = homozygous;
on days 1. 4 and
leg volume)
Baseline
Week 1
Week 2
1.2 0.5 1.9 2.9 3.9
1.5 2.1 2.3 3.0 4.3
1.5 1.9 2.8 4.2 4.0
htz = heterozygous.
TABLE3 PEAK
FLOW
PLASMA
VALUES
IN THE INDIVIDUAL
PATIENTS AT DIFFERENT
TIMES AFTER
EXCHANGE
Baseline: mean of values obtained on days - 2 and 0; week 1: mean of values obtained 7; week 2: mean of values obtained on days 8, 11 and 14. Patient (sex, age)
M.P. hmz (F, 10) O.M.G. hmz. (F, 12) S.L. hmz (M, 21) D.S. htz (M, 42) M.U. htz (M, 52) hmz = homozygous;
on days 1, 4 and
Peak flow (ml/mitt/d1
leg volume)
Baseline
Week 1
Week 2
12.6 12.3 12.8 13.0 15.8
13.9 14.2 16.5 20.5 18.5
14.0 14.0 14.5 15.9 18.5
htz = heterozygous
flow and peak flow values in the individual reported in Tables 2 and 3.
patients
at different
times after PE are
Discussion Abnormalities in reactive hyperemia test have been detected in patients with FH and partially corrected by PE. The mean value of calf arterial flow at rest was 2.1 + 0.6 ml/min/dl. This value is within the normal range according to our laboratory (81. However, it has been demonstrated that resting arterial flow over the calf gives poor information on the maximal flow available in the district; this also explains why rest flow is not correlated with the symptom of intermittent claudication [8]. On the other hand, the quantitative information given by reactive hyperemia test and peak flow determination is more valuable in regard to the evaluation of the
241
maximal flow available to the tissue in condition of high oxygen demand (such as during exercise). Peak flow (mean: 13,3 ml/min/dl) was on average reduced in our FH patients to about 60% of normal value. Arterial flow over the calf in FH ranks intermediate between normal people and arteriosclerotic patients with mild symptoms of intermittent claudication [8]. This defective reactive hyperemia response cannot be attributed to the young age of some FH patients, since it has been shown that peak flow over the calf is not affected by age in normal people [13]. It is therefore likely that impaired peak flow is related to premature atherosclerotic obstructions in the leg arteries and/or abnormal rheological properties of blood in FH. PE produces significant improvement of resting arterial flow, in agreement with previous findings [5,7]. These results, although interesting, give no information on the responsiveness of FH patients to vasodilating stimuli (such as ischemia, exercise or drugs). It is therefore remarkable to observe that after PE a significant improvement of reactive hyperemia test occurs. Enhancement of peak flow response both during the 1st and the 2nd week after this treatment indicates more marked response to vasodilating stimuli. This occurs without significant change in the vasodilator reserve. The mechanism underlying enhanced flow and improved reactive hyperemia test after PE is probably,related to the reduction of blood viscosity, which has been clearly demonstrate&. in FH patients treated by this procedure [14]. Improved erythrocyte filtration rate, also demonstrated after PE [15] might contribute to the fall in blood viscosity. On the other hand changes in fibrinogen concentration do not seem to be related to flow improvement. Plasma cholesterol is markedly lowered during the 1st week after PE; however a dissociation from flow changes is observed afterwards. Despite a marked rise in plasma cholesterol during the 2nd week, the hemodynamic effects are not reduced at the same time. There are other methods producing significant flow increase to the leg, such as defibrination [16] or reduction of packed cell volume [17]. PE is preferred in FH patients because the aim of treatment in this condition is removal of plasma and tissue cholesterol. However, improved arterial flow to the lower limbs is an additional benefit.
References 1 Slack, J., Risk of ischemic heart disease in familial hyperlipoproteinemic states, Lancet, ii (1969) 1380. 2 Goldstein, J.L., Schrott, H.G., Hazzard, W.R., Bierman, E.L. and Motulsky, A.G., Hyperhpidemia in coronary heart disease, Part 2 (Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia), J. Clin. Invest., 52 (1973) 1544. 3 Thompson, G.R., Lowental, R. and Myant, N.B., Plasma exchange in the management of homozygous familial hypercholesterolemia, Lancet, i (1975) 1208. 4 Thompson, G.R., Myant, N.B., Kilpatrick, D., Oakley, CM., Raphael, M.J. and Steiner, R.E., Assessment of long term plasma exchange for familial hypercholesterolemia, Brit. Heart J., 43 (1980) 680. 5 Postiglione, A., Rubba, P., Scarpato, N., Iannuzzi, A. and Mancini, M., Increased blood flow to lower limbs in two patients with familial hypercholesterolemia after plasma exchange, Atherosclerosis, 41 (1982) 421.
242 6 Postiglione, A., Soricelli, A., Scarpato, N., Lamenza, F. and Mancini, M., Increased cerebral flow after plasma exchange in patients with familial hypercholesterolemia, Clin. Haemorheol., 2 (1982) 195. 7 Post&hone, A., Rubba, P., Scarpato, N., Marotta, G., Montefusco, S. and Mancini, M., Metabolic and haemodynamic effects of plasma exchange in familial hypercholesterolemia. In: G. Schettler, A.M. Gotto, G. Middlehoff and A.S. Habenicht (Eds.), Atherosclerosis VI, Springer-Verlag. Heidelberg, 1983, p. 336. 8 Rubba, P., Iannuzzi, A., Ferrara, L.A., Postiglione, A., Strazzullo, P. and Mancini, M., Strain gauge plethysmography and peripheral atherosclerosis - An important tool in research, Atheroscler Rev., 10 (1983) 155. 9 Brugmans, J., Jagenau, A., Horing, C. and Emanual, M., Modern techniques in venous occlusion plethysmography in the assessment of peripheral vascular disease, Proc. Roy. Sot. Med., 70 (Suppl. 80) (1977) 1. 10 Oriente, P., Di Marino, L., Mastranzo, P., Iovine, C. and Patti, L., Simultaneous determination of cholesterol and tryglycerides in serum and in lipoprotein fractions with enzymatic automated method. In: A. Burlina and L. Galzigna (Eds.), Clinical Enzymology Symposium 2, Piccin, Padova, 1979, p. 387. 11 Mancini, G., Carbonara, A.O. and Heremans, J.F., Immunochemical quantitation of antigens by single radial immunodiffusion, Immunochemistry, 2 (1965) 235. 12 Dixon, W.J. and Massey, F.J., Introduction to Statistical Analysis, McGraw-Hill, New York. 1969. 13 Kroese, A.J., The influence of age on calf arterial flow, Stand. J. Clin. Lab. Invest., 37 (1977) 105. 14 Kilpatrick, D., Fleming, J., Clyne, C. and Thompson, G.R., Reduction of blood viscosity following plasma exchange, Atherosclerosis, 32 (1979) 301. 15 Postiglione, A., Soricelli, A., Lamenza, F., Scarpato, N. and Montefusco, S., Plasma exchange for the treatment of cerebrovascular occlusive disease in familial hypercholesterolemia, J. Chron. Dis. Ther. Res., 6 (1983) 213. 16 Dormandy, J., Role of fibrinogen in peripheral circulatory disease. In: L.A. Carlson, R. Paoletti and G. Weber (I%.), International Conference on Atherosclerosis, Raven Press, New York, 1979, p. 409. 17 Yates, C.Y., Berent, A., Andrews, V. and Dormandy, J.A., Increase in leg blood flow by normovolaemic haemodilution in intermittent claudication, Lancet, ii (1979) 166.
56 (1985)
Elsevier Scientific
231-242
Publishers
237
Ireland,
Ltd.
ATH 03665
Preliminary
Note
Improved Reactive Hyperemia Test After Plasma Exchange in Familial Hypercholesterolemia P. Rubba ’Instrtutr
‘, A. Postiglione of Internal
Cellular and Molecular
Medicme Pathology,
i, N. Scarpato
’ and M. Mancini
2, A. Iannuzzi
and Metabolic Disease and ’ Immunohematologv 2nd Medical School, Unicersity of Naples,
Unit, Department
Via S. Pansmi 5, 80131
’ of
Naples
(Italy)
(Revised,
(Received 22 March, 1984) received 24 September, 6 March and 20 December (Accepted 8 March, 1985)
1984)
Summary By using a non-invasive methodology of vascular diagnosis, ECG-triggered strain-gauge plethysmography, 5 patients with familial hypercholesterolemia (FH) (3 homozygous, 2 heterozygous) were evaluated before and during the 1st and 2nd week after plasma exchange (PE). In order to obtain data on the responsiveness to vasodilating stimuli in FH patients undergoing PE, reactive hyperemia test and peak flow determination were also performed. Resting arterial flow over the calf was found to be significantly enhanced after PE. Reactive hyperemia test demonstrated persistent improvement of peak flow following exchange. This study demonstrates useful hemodynamic effects of PE in patients with FH. Key words:
Arterial flow - Familial hypercholesterolemia Strain gauge plethysmography
Plasma exchange
-
Introduction Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, which is characterized by severe elevation of plasma cholesterol and premature onset of atherosclerotic cardiovascular disease [1,2]. Patients with FH are extremely refractory to most conventional lipid-lowering treatments. However they improve their condition through the therapeutic procedure of plasma exchange, which
0021-9150/85/$03.30
0 1985 Elsevier
Scientific
Publishers
Ireland,
Ltd.
238
produces marked reduction of plasma cholesterol [3,4] together with some interesting hemodynamic effects [5,6]. In particular we have recently shown an improvement of resting calf arterial flow during the 1st week after plasma exchange in FH patients
[71. After this first experiment some questions were still open: (a) Is the baseline arterial flow abnormally reduced in FH? (b) Is the response to vasodilating stimuli (exercise, ischemia, drugs) improved by PE? (c) Is the hemodynamic effect lasting during the 2nd week after PE? In order to answer these questions we have performed, in addition to rest flow determination, the reactive hyperemia test. This test is more sensitive and reproducible [S] than resting flow determination and allows determination of the skeletal muscle vasodilator reserve. Patients and Methods PE was performed on 5 patients (age lo-52 years; 3 M, 2 F) with FH (3 homozygous, 2 heterozygous). They showed the typical picture of tuberous xantomata, xantelasma and bruits over the aorta, carotids and renal or femoral arteries. The patients did not smoke cigarettes in the week before and during the study. They continued their usual lipid-lowering diet and drug treatment (cholestyramine 20 g/day and nicotinic acid, 2,4 g/day or fenofibrate 300 mg/day). PE was performed by using a discontinuous flow cell separator (Transfer 90 Bell Co. centrifuge, U.S.A.). Anticoagulation was maintained with A.C.D. (citric acid, hydrate 0.8%, sodium citrate, dihydrate 2.2%, dextrose 2.45%) in a 1 : 8 ratio to total blood. The plasma was removed and exchanged with isotonic saline containing 5% human albumin (ISI, Italy). Arterial blood flow over the right leg was determined by a strain-gauge plethysmograph (Periflow, Janssen, Belgium) at days -2, 0, 1, 4, 7, 8, 11 and 14. ECG-triggered venous occlusion [8,9] plethysmography allows semicontinuous registration of arterial flow variables. Using wide tubings connected with controlled pressure reservoirs and provided with electromagnetic valves, whose opening is regulated by the ECG-triggered unit of the plethysmograph, venous return can be interrupted over 1 or more heart cycles. Because of the very short occlusion time, resistance changes in the vascular bed of the measured segment are negligible. The volume increase during the venous outflow occlusion, for a few heartbeats, is measured with a mercury in silastic gauge with high-frequency response, connected with an amplifier and a function analyzer allowing automatic calculation of the arterial blood flow in volume/mm/d1 of calf volume (or volume/min/lOO g of calf tissue). The cuff inflation pressure is 50 mm Hg and 90% of this pressure level is reached within 18 ms. Inflation begins in the leg cuffs with a delay of 150 ms after the QRS interval of the ECG which is the time interval needed till the entry of stroke volume at the level of occlusion cuff, around the thigh. Arterial flow is measured over 3 cardiac cycles, so that a semicontinuous flow measurement is being performed over a period of 5 heart beats.
239
Each study was performed at 22°C after at least 20 min of supine rest. After 10 min of rhythmic venous occlusion, blood flow registration was performed for 2 min. Results were expressed in ml/mm/d1 of leg volume. In all the patients the reactive hyperemia test was performed. The same cuff used for venous occlusion was inflated at a suprasystolic pressure for 3 min, in order to produce transient ischemia. After the release of the arterial occlusion, reactive hyperemia took place, and maximal postischemic flow (peak flow) could be determined. Vasodilator reserve was estimated by peak flow/rest flow ratio. Plasma cholesterol and triglyceride concentration were determined by semiautomated enzymatic methods on a Carlo Erba Analyzer (CLA) at the time of each arterial flow study [lo]. Plasma fibrinogen determination was performed by radial immunodiffusion technique [ll]. Statistical comparisons were done by using the Student paired t-test [12].
Results
About 50% of plasma could be exchanged with the present discontinuous flow technique. The amount of cholesterol withdrawn with a single PE averaged 5 g. Table 1 reports mean plasma cholesterol, triglyceride, haematocrit and fibrinogen before PE (days - 2,0), during the 1st week (days 1, 4, 7) and the 2nd week (days 8, 11, 14) after PE in the FH patients under study. Plasma cholesterol was significantly reduced during the 1st week of treatment, then rose to a value intermediate as compared to pretreatment. The mean reduction of plasma fibrinogen during the 1st and 2nd week after PE was not statistically significant. Resting arterial flow was slightly increased after plasma exchange. At the same time significant improvement of reactive hyperemia test occurred with increase in peak flow over the calf by about 25% (Table 1). The vasodilator reserve was not significantly changed after PE. Rest
TABLE
1
REACTIVE HYPEREMIA TEROLEMIA (3 M, 2 F)
TEST AFTER
PLASMA
EXCHANGE
IN FAMILIAL
HYPERCHOLES-
Values are mean + SEM. Baseline: mean of values obtained on days - 2 and 0; week 1: mean of values obtained on days 1, 4, 7; week 2: mean of values obtained on days 8. 11, 14. f Tot. plasma cholesterol Plasma TG (mmol/l) Packed red cell (W) Fibrinogen (mg/dl) Rest flow (ml/min/dl) Peak flow (ml/min/dl) Peak flow/rest flow * P < 0.05.
(mmol/l)
Baseline
Week 1
Week 2
19.1 f 3.1 1.87+ 0.74 42 +6 324 &36 2.1 f 0.6 13.3 k 0.6 10.1 k 3.8
13.8 f 2.8 * 1.72* 0.68 41 k6 300 +29 2.6 + 0.5 16.7 + 1.3 * 6.1 + 1.0
16.8 f 2.1 1.705 0.74 42 +6 310 *41 2.9 + 0.5 * 15.4 * 0.9 * 6.1 k 1.0
240
TABLE2 REST FLOW PLASMA
VALUES
IN THE INDIVIDUAL
PATIENTS AT DIFFERENT
TIMES
AFTER
EXCHANGE
Baseline: mean of values obtained on days - 2 and 0; week 1: mean of values obtained 7; week 2: mean of values obtained on days 8, 11 and 14. Patient (sex, age)
Rest flow (ml/mitt/d1
M.P. hmz (F, 10) O.M.G. hmz (F, 12) S.L. hmz (M, 21) D.S. htz (M, 42) M.U. htz (M, 52) hmz = homozygous;
on days 1. 4 and
leg volume)
Baseline
Week 1
Week 2
1.2 0.5 1.9 2.9 3.9
1.5 2.1 2.3 3.0 4.3
1.5 1.9 2.8 4.2 4.0
htz = heterozygous.
TABLE3 PEAK
FLOW
PLASMA
VALUES
IN THE INDIVIDUAL
PATIENTS AT DIFFERENT
TIMES AFTER
EXCHANGE
Baseline: mean of values obtained on days - 2 and 0; week 1: mean of values obtained 7; week 2: mean of values obtained on days 8, 11 and 14. Patient (sex, age)
M.P. hmz (F, 10) O.M.G. hmz. (F, 12) S.L. hmz (M, 21) D.S. htz (M, 42) M.U. htz (M, 52) hmz = homozygous;
on days 1, 4 and
Peak flow (ml/mitt/d1
leg volume)
Baseline
Week 1
Week 2
12.6 12.3 12.8 13.0 15.8
13.9 14.2 16.5 20.5 18.5
14.0 14.0 14.5 15.9 18.5
htz = heterozygous
flow and peak flow values in the individual reported in Tables 2 and 3.
patients
at different
times after PE are
Discussion Abnormalities in reactive hyperemia test have been detected in patients with FH and partially corrected by PE. The mean value of calf arterial flow at rest was 2.1 + 0.6 ml/min/dl. This value is within the normal range according to our laboratory (81. However, it has been demonstrated that resting arterial flow over the calf gives poor information on the maximal flow available in the district; this also explains why rest flow is not correlated with the symptom of intermittent claudication [8]. On the other hand, the quantitative information given by reactive hyperemia test and peak flow determination is more valuable in regard to the evaluation of the
241
maximal flow available to the tissue in condition of high oxygen demand (such as during exercise). Peak flow (mean: 13,3 ml/min/dl) was on average reduced in our FH patients to about 60% of normal value. Arterial flow over the calf in FH ranks intermediate between normal people and arteriosclerotic patients with mild symptoms of intermittent claudication [8]. This defective reactive hyperemia response cannot be attributed to the young age of some FH patients, since it has been shown that peak flow over the calf is not affected by age in normal people [13]. It is therefore likely that impaired peak flow is related to premature atherosclerotic obstructions in the leg arteries and/or abnormal rheological properties of blood in FH. PE produces significant improvement of resting arterial flow, in agreement with previous findings [5,7]. These results, although interesting, give no information on the responsiveness of FH patients to vasodilating stimuli (such as ischemia, exercise or drugs). It is therefore remarkable to observe that after PE a significant improvement of reactive hyperemia test occurs. Enhancement of peak flow response both during the 1st and the 2nd week after this treatment indicates more marked response to vasodilating stimuli. This occurs without significant change in the vasodilator reserve. The mechanism underlying enhanced flow and improved reactive hyperemia test after PE is probably,related to the reduction of blood viscosity, which has been clearly demonstrate&. in FH patients treated by this procedure [14]. Improved erythrocyte filtration rate, also demonstrated after PE [15] might contribute to the fall in blood viscosity. On the other hand changes in fibrinogen concentration do not seem to be related to flow improvement. Plasma cholesterol is markedly lowered during the 1st week after PE; however a dissociation from flow changes is observed afterwards. Despite a marked rise in plasma cholesterol during the 2nd week, the hemodynamic effects are not reduced at the same time. There are other methods producing significant flow increase to the leg, such as defibrination [16] or reduction of packed cell volume [17]. PE is preferred in FH patients because the aim of treatment in this condition is removal of plasma and tissue cholesterol. However, improved arterial flow to the lower limbs is an additional benefit.
References 1 Slack, J., Risk of ischemic heart disease in familial hyperlipoproteinemic states, Lancet, ii (1969) 1380. 2 Goldstein, J.L., Schrott, H.G., Hazzard, W.R., Bierman, E.L. and Motulsky, A.G., Hyperhpidemia in coronary heart disease, Part 2 (Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia), J. Clin. Invest., 52 (1973) 1544. 3 Thompson, G.R., Lowental, R. and Myant, N.B., Plasma exchange in the management of homozygous familial hypercholesterolemia, Lancet, i (1975) 1208. 4 Thompson, G.R., Myant, N.B., Kilpatrick, D., Oakley, CM., Raphael, M.J. and Steiner, R.E., Assessment of long term plasma exchange for familial hypercholesterolemia, Brit. Heart J., 43 (1980) 680. 5 Postiglione, A., Rubba, P., Scarpato, N., Iannuzzi, A. and Mancini, M., Increased blood flow to lower limbs in two patients with familial hypercholesterolemia after plasma exchange, Atherosclerosis, 41 (1982) 421.
242 6 Postiglione, A., Soricelli, A., Scarpato, N., Lamenza, F. and Mancini, M., Increased cerebral flow after plasma exchange in patients with familial hypercholesterolemia, Clin. Haemorheol., 2 (1982) 195. 7 Post&hone, A., Rubba, P., Scarpato, N., Marotta, G., Montefusco, S. and Mancini, M., Metabolic and haemodynamic effects of plasma exchange in familial hypercholesterolemia. In: G. Schettler, A.M. Gotto, G. Middlehoff and A.S. Habenicht (Eds.), Atherosclerosis VI, Springer-Verlag. Heidelberg, 1983, p. 336. 8 Rubba, P., Iannuzzi, A., Ferrara, L.A., Postiglione, A., Strazzullo, P. and Mancini, M., Strain gauge plethysmography and peripheral atherosclerosis - An important tool in research, Atheroscler Rev., 10 (1983) 155. 9 Brugmans, J., Jagenau, A., Horing, C. and Emanual, M., Modern techniques in venous occlusion plethysmography in the assessment of peripheral vascular disease, Proc. Roy. Sot. Med., 70 (Suppl. 80) (1977) 1. 10 Oriente, P., Di Marino, L., Mastranzo, P., Iovine, C. and Patti, L., Simultaneous determination of cholesterol and tryglycerides in serum and in lipoprotein fractions with enzymatic automated method. In: A. Burlina and L. Galzigna (Eds.), Clinical Enzymology Symposium 2, Piccin, Padova, 1979, p. 387. 11 Mancini, G., Carbonara, A.O. and Heremans, J.F., Immunochemical quantitation of antigens by single radial immunodiffusion, Immunochemistry, 2 (1965) 235. 12 Dixon, W.J. and Massey, F.J., Introduction to Statistical Analysis, McGraw-Hill, New York. 1969. 13 Kroese, A.J., The influence of age on calf arterial flow, Stand. J. Clin. Lab. Invest., 37 (1977) 105. 14 Kilpatrick, D., Fleming, J., Clyne, C. and Thompson, G.R., Reduction of blood viscosity following plasma exchange, Atherosclerosis, 32 (1979) 301. 15 Postiglione, A., Soricelli, A., Lamenza, F., Scarpato, N. and Montefusco, S., Plasma exchange for the treatment of cerebrovascular occlusive disease in familial hypercholesterolemia, J. Chron. Dis. Ther. Res., 6 (1983) 213. 16 Dormandy, J., Role of fibrinogen in peripheral circulatory disease. In: L.A. Carlson, R. Paoletti and G. Weber (I%.), International Conference on Atherosclerosis, Raven Press, New York, 1979, p. 409. 17 Yates, C.Y., Berent, A., Andrews, V. and Dormandy, J.A., Increase in leg blood flow by normovolaemic haemodilution in intermittent claudication, Lancet, ii (1979) 166.