167
CVR BEFORE AND AFTER ENDART-ERECTOMY
*p001 vs patients with negative side-to-side difference. tp < 0,05 vs baseline
intracerebral haemodynamics were not identified, but might have benefited from EC-IC bypass.6A similar claim could arise in the wake of the endarterectomy trials because none of them takes intracerebral haemodynamics into account. We have evidence that
patients with high-grade carotid artery stenosis are heterogeneous in respect of intracerebral haemodynamics and that haemodynamic determine outcome after surgery. 52 patients of average age 65 with unilateral high-grade stenosis of the internal carotid artery (ICA) were studied immediately before md 3 months after endarterectomy. Stenosis and patency of status may
.ontralateral ICA
was
diagnosed by
transcutaneous
doppler
lonography and confirmed at operation. 24 patients were symptomless (stage I); 19 had a reversible ischaemic neurological deficit lasting less than (13 patients, stage II) or more than (stage III) an hour; and 9 had a permanent but mild neurological deficit (stage IV). Transcranial doppler (TCD) studies of the middle cerebral artery were used to determine peak (systolic) and nadir (diastolic) flow velocity (Vmax and V). The TCD transducer (’Sonotron’; VingMed, Garching, West Germany) was placed on the "skull window" above the zygomatic arch, and the middle cerebral artery was studied at a depth of 50-60 mm. Pourcelot’s index (PI) which represents an index of vascular resistance was Vascular resistance can be manipulated calculated as 1 - VV. min max by varying the PaCû2: hypercapnia results in dilatation of the peripheral vascular bed whereas hypocapnia causes vasoconstriction, thereby altering blood and velocity. Vascular resistance in the middle cerebral artery varies inversely with PaC02 and reflects the vascular resistance in peripheral cerebral vessels. The patients were either connected via a mouthpiece with a non-return valve to a tank containing 5% CO2 (hypercapnia) or hyperventilated (hypocapnia). End-expiratory CO2 was monitored
by infrared analyser (’C02 Analysator’; Engstrom, Eliza, Bromma, Sweden). Flow velocity in the middle cerebral artery was recorded when a steady state was reached in end-tidal CO2 and in flow velocity. Cerebral vasomotor reactivity (CVR) was calculated as % change in PI between hypercapnia and hypocapnia divided by change in CO2, At baseline there was no significant difference in CVR between affected and unaffected hemispheres (table). 25 patients had lower CVR ipsilateral to the stenosis than contralaterally and 27 patients had higher CVR at the ipsilateral hemisphere. However, CVR ipsilateral to the stenosis was higher in patients with a positive interhemispheric difference than in those with a negative side-toside difference (table) (p < 0’0001). CVR was not significantly affected by endarterectomy. However, 18 of the 25 patients who had a negative side-to-side difference preoperatively had improved vasomotor reactivity ipsilaterally after surgery (table). For all patients combined preoperative reactivity ipsilaterally correlated with postoperative changes-the lower the CVR was before surgery, the more it was improved by the operation (r=0719; p < 00001, figure). Carotid endarterectomy also improved CVR contralaterally in all 9 patients who had, preoperatively, a positive hemispheric difference and whose contralateral CVR had been paradoxical (below zero). Our findings suggest that measurement of CVR can identify patients with inadequate formation of intracerebral collaterals (negative side-to-side difference) in association with carotid artery disease and predict the effect of carotid endarterectomy. Poor CVR corresponds to an increased intracerebral blood volume due to compensatory vasodilatation. Patients with a negative side-to-side difference in CVR and whose CVR on the side of ICA stenosis is less than 5%/vol % CO2 may benefit significantly from surgery, as may patients with a paradoxical reactivity contralateral to ICA stenosis. This test could be used on a broad basis to screen patients with carotid artery disease. Furthermore, preoperative classification by intracerebral hemodynamic status may be needed in trials of carotid endarterectomy.
Department of Surgery, Klinikum Grosshadern,
Ludwig-Maximilian University of Munich, Marchioninistr 15, D-8000 Munich 70, FRG
HEINRICH FÜRST WOLFGANG H. HARTL INGRID JANSEN THOMAS SUTTER LUTZ LAUTERJUNG FRIEDRICH W. SCHILDBERG
1. Hertzer NR. Presidential address: carotid endarterectomy—a crisis in confidence. J Vasc Surg 1988; 7: 611-19. 2. Winslow CM, Solomon DH, Chassin MR, Kosecoff J, Merrick NJ, Brook RH. The appropriateness of carotid endarterectomy. N Engl J Med 1988; 318: 721-27. 3. Wilson SE, Mayberg MR, Yatsu FM. Defining the indications for carotid
endarterectomy. Surgery 1988; 104: 932-36. 4. Cusimano MD. The carotid endarterectomy study. Can J Surg 1988; 31: 3-4. 5. Veterans Administration Cooperative Study. Role of carotid endarterectomy as asymptomatic carotid stenosis. Stroke 1986; 17: 534-39. 6. Grotta JC. Current medical and surgical therapy for cerebrovascular disease. N Engl J Med 1987; 317: 1505-16. 7. Powers WJ, Press GW, Grubb RL, Gado M, Raichle ME. The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. Ann Intern Med 1987; 106: 27-35.
24-hour variation in atrial natriuretic
peptide
Relation between preoperative cerebral vasomotor reactivity ipsilateral to ICA stenosis and postoperative change in reactivity in the same hemisphere.
SIR,-Mr Zhang De Xin and colleagues (Oct 28, p 1046) report 24 h variation of atrial natriuretic peptide (ANP) in healthy subjects, with the highest mean plasma concentration at 2000 h (25 pg/ml) and the lowest at 1200 h (79 pg/rnl). Ehlenzl and Richards2 and their colleagues’ results seem to support an ultradian rhythm of ANP but there is considerable controversy about the time points at which ANP concentrations are lowest or highest. Ehlenz at all showed peak ANP concentration at 1100 and 1800 (day) and at 2200 and 0500 h (night), whereas Richards et al2 found peak ANP at 1100 or 1300 but reported a nadir at 1700 or 1900 and low ANP values at 2200 and 0500 h. Our findings of a pulsatile pattern of ANP secretion could explain these contradictory observations.
168
Computer-assisted demonstration of pulsatilefluctuations of plasma atrial natriu retic peptide under resting conditions in a healthy subject. 8 healthy men (age 21-26 years, mm
systolic blood pressure 105-125
Hg, diastolic 75-80 mm Hg) were investigated. The volunteers
asked not to smoke or to drink caffeinated or alcoholic drinks for 12 hours before the study which was started at 0800 with a run-in period of 1 h. Throughout the study the subjects remained supine. A teflon cannula (Viggo Venflon, 18 gauge) was inserted in an antecubital vein and blood was drawn either every 2 minutes for 90 minutes or every 4 minutes for 180 minutes. Plasma ANP was measured by radioimmunoassay after extraction (’RIAcid,’ Henning, Berlin). To detect pulsatile behaviour spectral analysis, a computer-based method of time-series analysis was used to analyse the data from individual experiments. Mean plasma concentrations varied from 4,0 pg/ml (SEM 0’ 1) to 24-6 pg/ml (0-8). Baseline ANP secretion showed regular pulses every 9 minutes (SEM 1) (figure). In addition we found long-term oscillations with a duration of 34 minutes (4). Pulsatility has been described for insulin,33 glucagon,33 thyrotropin,4and several other hormones. Our data suggest that under basal conditions ANP is also secreted in a pulsatile fashion. Regular oscillations of ANP concentrations can both mimic and conceal ultradian rhythms of ANP secretion if blood is sampled at longer intervals. Therefore, in studies of ANP rhythmicity blood should be sampled at sufficiently short intervals to allow clear-cut demonstration of a normal 24-hour variation of ANP, independently of the pulsatility of plasma hANP. were
Department of Endocrinology, Centre of Internal Medicine, Johann Wolfgang Goethe-University Clinic, D6000 Frankfurt am Main, West Germany
THOMAS HAAK ECKART JUNGMANN KARL SCHÖFFLING
1. Ehlenz K, Schneider H, Tremmel P, Schmidt P, Kaffarnik H. Circadian rhythm of atrial natriuretic peptide in normal subjects. In: Kaufmann W, Wambach G, eds. Endocrinology of the heart. Berlin: Springer-Verlag, 1989: 181-83. 2. Richards AM, Tonolo G, Fraser R, et al. Diurnal change in plasma atrial natriuretic peptide concentrations. Clin Sci 1987; 73: 489-95. 3. Lang DA, Matthews DR, Burnett M, Ward GM, Turner RC. Pulsatile, synchronous basal insulin and glucagon secretion in man. Diabetes 1982; 31: 22-26. 4. Brabant GA, Brabant A, Ranft U, et al. Circadian and pulsatile thyrotropin secretion in euthyroid man under the influence of thyroid hormone and glucocorticoid administration. J Clin Endocrinol Metab 1987; 65: 83-88.
CGRP-like immunoreactivity in plasma of patients with AMI and in controls. Data with SEM bars.
*Significantly
(Wilcoxon signed-rank test) test) at p < 01.
greater than admission levels and levels in controls (Mann-Whitney U
and 24 h. At least 2 ml of plasma
was purified on ’SekPak C18’ cartridges (Waters-Mllipore),’ lyophilised, and redissolved in buffer for CGRP assay with antiserum to human CGRP-alpha
(Peninsula, California). This antiserum does
not cross-react
with
any other
neuropeptide tested so far and corroboration for its specificity comes from high performance liquid chromatography analyses. The detection limit of the assay was about 1 finol/m1 plasma. CGRP-like immunoreactivity in twelve healthy controls aged 17-30 (median 23; six male) was 1-53 (SEM 0.44) finol/ml, which was close to the detection limit. In patients with AMI admission levels and activity 24 h after admission were not significantly different from normal, but increased levels were detected in between (figure). The peak CGRP was at 2-75 h (median) after admission, corresponding to 5 h (median) after the onset of pain. The source of circulating CGRP may be various peripheral organs, including the adrenal medulla.2 If CGRP is released from peripheral terminals of sensory neurons of the heart as a consequence of myocardial ischaemia,l this peptide may be acting as a local mediator in the pathophysiology of AMI.
J. MAIR P. LECHLEITNER T. LÄNGLE C. WIEDERMANN F. DIENSTL
Department of Internal Medicine, Medical School, University of Innsbruck, A-6020 Innsbruck, Austria
Neurochemistry Unit, Department of Psychiatry, A. SARIA
University of Innsbruck
A, Saria A, Lundberg JM. Differential release of calcitonin gene-related peptide and neuropeptide Y from isolated heart by capsaicin, ischaemia, nicotine, bradykinin and ouabain. Acta Physiol Scand 1989; 135:
1. Franco-Cereceda
17387. 2. Rosenfeld
Plasma CGRP in acute
myocardial infarction
SiR,-Your Oct 21 editorial on the impact of peptides, including calcitonin-gene-related peptide (CGRP), on the vascular tone of coronary arteries prompts us to report plasma concentrations of CGRP-like immunoreactivity in thirty patients aged 30-83 years (median 60; twenty males) with confirmed acute myocardial infarction (AMI) who were admitted to intensive care within 4 h of the onset of chest pain. Sixteen patients received intravenous streptokinase, ten were given intravenous urokinase, and four received no fibrinolytic treatment. Blood samples, which were centrifuged and stored at 72°C, were taken on admission, after 30 min, and after 1, 2, 3, 6, -
MG, Mermod JJ, Amara SG, et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature 1983; 304: 129-35.
Kaposi’s sarcoma in HIV-negative homosexual
men
SiR,—Kaposi’s sarcoma (KS) was rarely seen in the United States before 1980.’ An aggressive type of KS has become widespread during the HIV/AIDS epidemic, mainly affecting homosexual men.2.3 We suspect that there has also been an increase in the frequency of a more benign form of KS among homosexual men who do not have HIV infection.
CVR BEFORE AND AFTER ENDART-ERECTOMY
*p001 vs patients with negative side-to-side difference. tp < 0,05 vs baseline
intracerebral haemodynamics were not identified, but might have benefited from EC-IC bypass.6A similar claim could arise in the wake of the endarterectomy trials because none of them takes intracerebral haemodynamics into account. We have evidence that
patients with high-grade carotid artery stenosis are heterogeneous in respect of intracerebral haemodynamics and that haemodynamic determine outcome after surgery. 52 patients of average age 65 with unilateral high-grade stenosis of the internal carotid artery (ICA) were studied immediately before md 3 months after endarterectomy. Stenosis and patency of status may
.ontralateral ICA
was
diagnosed by
transcutaneous
doppler
lonography and confirmed at operation. 24 patients were symptomless (stage I); 19 had a reversible ischaemic neurological deficit lasting less than (13 patients, stage II) or more than (stage III) an hour; and 9 had a permanent but mild neurological deficit (stage IV). Transcranial doppler (TCD) studies of the middle cerebral artery were used to determine peak (systolic) and nadir (diastolic) flow velocity (Vmax and V). The TCD transducer (’Sonotron’; VingMed, Garching, West Germany) was placed on the "skull window" above the zygomatic arch, and the middle cerebral artery was studied at a depth of 50-60 mm. Pourcelot’s index (PI) which represents an index of vascular resistance was Vascular resistance can be manipulated calculated as 1 - VV. min max by varying the PaCû2: hypercapnia results in dilatation of the peripheral vascular bed whereas hypocapnia causes vasoconstriction, thereby altering blood and velocity. Vascular resistance in the middle cerebral artery varies inversely with PaC02 and reflects the vascular resistance in peripheral cerebral vessels. The patients were either connected via a mouthpiece with a non-return valve to a tank containing 5% CO2 (hypercapnia) or hyperventilated (hypocapnia). End-expiratory CO2 was monitored
by infrared analyser (’C02 Analysator’; Engstrom, Eliza, Bromma, Sweden). Flow velocity in the middle cerebral artery was recorded when a steady state was reached in end-tidal CO2 and in flow velocity. Cerebral vasomotor reactivity (CVR) was calculated as % change in PI between hypercapnia and hypocapnia divided by change in CO2, At baseline there was no significant difference in CVR between affected and unaffected hemispheres (table). 25 patients had lower CVR ipsilateral to the stenosis than contralaterally and 27 patients had higher CVR at the ipsilateral hemisphere. However, CVR ipsilateral to the stenosis was higher in patients with a positive interhemispheric difference than in those with a negative side-toside difference (table) (p < 0’0001). CVR was not significantly affected by endarterectomy. However, 18 of the 25 patients who had a negative side-to-side difference preoperatively had improved vasomotor reactivity ipsilaterally after surgery (table). For all patients combined preoperative reactivity ipsilaterally correlated with postoperative changes-the lower the CVR was before surgery, the more it was improved by the operation (r=0719; p < 00001, figure). Carotid endarterectomy also improved CVR contralaterally in all 9 patients who had, preoperatively, a positive hemispheric difference and whose contralateral CVR had been paradoxical (below zero). Our findings suggest that measurement of CVR can identify patients with inadequate formation of intracerebral collaterals (negative side-to-side difference) in association with carotid artery disease and predict the effect of carotid endarterectomy. Poor CVR corresponds to an increased intracerebral blood volume due to compensatory vasodilatation. Patients with a negative side-to-side difference in CVR and whose CVR on the side of ICA stenosis is less than 5%/vol % CO2 may benefit significantly from surgery, as may patients with a paradoxical reactivity contralateral to ICA stenosis. This test could be used on a broad basis to screen patients with carotid artery disease. Furthermore, preoperative classification by intracerebral hemodynamic status may be needed in trials of carotid endarterectomy.
Department of Surgery, Klinikum Grosshadern,
Ludwig-Maximilian University of Munich, Marchioninistr 15, D-8000 Munich 70, FRG
HEINRICH FÜRST WOLFGANG H. HARTL INGRID JANSEN THOMAS SUTTER LUTZ LAUTERJUNG FRIEDRICH W. SCHILDBERG
1. Hertzer NR. Presidential address: carotid endarterectomy—a crisis in confidence. J Vasc Surg 1988; 7: 611-19. 2. Winslow CM, Solomon DH, Chassin MR, Kosecoff J, Merrick NJ, Brook RH. The appropriateness of carotid endarterectomy. N Engl J Med 1988; 318: 721-27. 3. Wilson SE, Mayberg MR, Yatsu FM. Defining the indications for carotid
endarterectomy. Surgery 1988; 104: 932-36. 4. Cusimano MD. The carotid endarterectomy study. Can J Surg 1988; 31: 3-4. 5. Veterans Administration Cooperative Study. Role of carotid endarterectomy as asymptomatic carotid stenosis. Stroke 1986; 17: 534-39. 6. Grotta JC. Current medical and surgical therapy for cerebrovascular disease. N Engl J Med 1987; 317: 1505-16. 7. Powers WJ, Press GW, Grubb RL, Gado M, Raichle ME. The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. Ann Intern Med 1987; 106: 27-35.
24-hour variation in atrial natriuretic
peptide
Relation between preoperative cerebral vasomotor reactivity ipsilateral to ICA stenosis and postoperative change in reactivity in the same hemisphere.
SIR,-Mr Zhang De Xin and colleagues (Oct 28, p 1046) report 24 h variation of atrial natriuretic peptide (ANP) in healthy subjects, with the highest mean plasma concentration at 2000 h (25 pg/ml) and the lowest at 1200 h (79 pg/rnl). Ehlenzl and Richards2 and their colleagues’ results seem to support an ultradian rhythm of ANP but there is considerable controversy about the time points at which ANP concentrations are lowest or highest. Ehlenz at all showed peak ANP concentration at 1100 and 1800 (day) and at 2200 and 0500 h (night), whereas Richards et al2 found peak ANP at 1100 or 1300 but reported a nadir at 1700 or 1900 and low ANP values at 2200 and 0500 h. Our findings of a pulsatile pattern of ANP secretion could explain these contradictory observations.
168
Computer-assisted demonstration of pulsatilefluctuations of plasma atrial natriu retic peptide under resting conditions in a healthy subject. 8 healthy men (age 21-26 years, mm
systolic blood pressure 105-125
Hg, diastolic 75-80 mm Hg) were investigated. The volunteers
asked not to smoke or to drink caffeinated or alcoholic drinks for 12 hours before the study which was started at 0800 with a run-in period of 1 h. Throughout the study the subjects remained supine. A teflon cannula (Viggo Venflon, 18 gauge) was inserted in an antecubital vein and blood was drawn either every 2 minutes for 90 minutes or every 4 minutes for 180 minutes. Plasma ANP was measured by radioimmunoassay after extraction (’RIAcid,’ Henning, Berlin). To detect pulsatile behaviour spectral analysis, a computer-based method of time-series analysis was used to analyse the data from individual experiments. Mean plasma concentrations varied from 4,0 pg/ml (SEM 0’ 1) to 24-6 pg/ml (0-8). Baseline ANP secretion showed regular pulses every 9 minutes (SEM 1) (figure). In addition we found long-term oscillations with a duration of 34 minutes (4). Pulsatility has been described for insulin,33 glucagon,33 thyrotropin,4and several other hormones. Our data suggest that under basal conditions ANP is also secreted in a pulsatile fashion. Regular oscillations of ANP concentrations can both mimic and conceal ultradian rhythms of ANP secretion if blood is sampled at longer intervals. Therefore, in studies of ANP rhythmicity blood should be sampled at sufficiently short intervals to allow clear-cut demonstration of a normal 24-hour variation of ANP, independently of the pulsatility of plasma hANP. were
Department of Endocrinology, Centre of Internal Medicine, Johann Wolfgang Goethe-University Clinic, D6000 Frankfurt am Main, West Germany
THOMAS HAAK ECKART JUNGMANN KARL SCHÖFFLING
1. Ehlenz K, Schneider H, Tremmel P, Schmidt P, Kaffarnik H. Circadian rhythm of atrial natriuretic peptide in normal subjects. In: Kaufmann W, Wambach G, eds. Endocrinology of the heart. Berlin: Springer-Verlag, 1989: 181-83. 2. Richards AM, Tonolo G, Fraser R, et al. Diurnal change in plasma atrial natriuretic peptide concentrations. Clin Sci 1987; 73: 489-95. 3. Lang DA, Matthews DR, Burnett M, Ward GM, Turner RC. Pulsatile, synchronous basal insulin and glucagon secretion in man. Diabetes 1982; 31: 22-26. 4. Brabant GA, Brabant A, Ranft U, et al. Circadian and pulsatile thyrotropin secretion in euthyroid man under the influence of thyroid hormone and glucocorticoid administration. J Clin Endocrinol Metab 1987; 65: 83-88.
CGRP-like immunoreactivity in plasma of patients with AMI and in controls. Data with SEM bars.
*Significantly
(Wilcoxon signed-rank test) test) at p < 01.
greater than admission levels and levels in controls (Mann-Whitney U
and 24 h. At least 2 ml of plasma
was purified on ’SekPak C18’ cartridges (Waters-Mllipore),’ lyophilised, and redissolved in buffer for CGRP assay with antiserum to human CGRP-alpha
(Peninsula, California). This antiserum does
not cross-react
with
any other
neuropeptide tested so far and corroboration for its specificity comes from high performance liquid chromatography analyses. The detection limit of the assay was about 1 finol/m1 plasma. CGRP-like immunoreactivity in twelve healthy controls aged 17-30 (median 23; six male) was 1-53 (SEM 0.44) finol/ml, which was close to the detection limit. In patients with AMI admission levels and activity 24 h after admission were not significantly different from normal, but increased levels were detected in between (figure). The peak CGRP was at 2-75 h (median) after admission, corresponding to 5 h (median) after the onset of pain. The source of circulating CGRP may be various peripheral organs, including the adrenal medulla.2 If CGRP is released from peripheral terminals of sensory neurons of the heart as a consequence of myocardial ischaemia,l this peptide may be acting as a local mediator in the pathophysiology of AMI.
J. MAIR P. LECHLEITNER T. LÄNGLE C. WIEDERMANN F. DIENSTL
Department of Internal Medicine, Medical School, University of Innsbruck, A-6020 Innsbruck, Austria
Neurochemistry Unit, Department of Psychiatry, A. SARIA
University of Innsbruck
A, Saria A, Lundberg JM. Differential release of calcitonin gene-related peptide and neuropeptide Y from isolated heart by capsaicin, ischaemia, nicotine, bradykinin and ouabain. Acta Physiol Scand 1989; 135:
1. Franco-Cereceda
17387. 2. Rosenfeld
Plasma CGRP in acute
myocardial infarction
SiR,-Your Oct 21 editorial on the impact of peptides, including calcitonin-gene-related peptide (CGRP), on the vascular tone of coronary arteries prompts us to report plasma concentrations of CGRP-like immunoreactivity in thirty patients aged 30-83 years (median 60; twenty males) with confirmed acute myocardial infarction (AMI) who were admitted to intensive care within 4 h of the onset of chest pain. Sixteen patients received intravenous streptokinase, ten were given intravenous urokinase, and four received no fibrinolytic treatment. Blood samples, which were centrifuged and stored at 72°C, were taken on admission, after 30 min, and after 1, 2, 3, 6, -
MG, Mermod JJ, Amara SG, et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature 1983; 304: 129-35.
Kaposi’s sarcoma in HIV-negative homosexual
men
SiR,—Kaposi’s sarcoma (KS) was rarely seen in the United States before 1980.’ An aggressive type of KS has become widespread during the HIV/AIDS epidemic, mainly affecting homosexual men.2.3 We suspect that there has also been an increase in the frequency of a more benign form of KS among homosexual men who do not have HIV infection.
