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Peripheral hemodynamics in patients with Fabry's disease
Peripheral hemodynamics Fabry’s disease
in patients
with
Altered vasomotor activity has been reported as a clinically prominent feature of Fabry’s disease (angiokeratoma corporis diffusum universale). While symptomatic cardiovascular involvement occurs eventually in most patients with this disorder, little is known concerning the effect of Fabry’s disease on peripheral hemodynamics. Peripheral hemodynamics in the extremities and digits were studied in eight patients with Fabry’s disease by means of segmental and venous occlusion pneumoplethysmography and thermal probes, and the results obtained were compared with those of 10 normal subjects. Forearm vascular resistance in Fabry’s disease patients was significantly higher (p < 0.01) than that in normal subjects. Forearm venous capacitance in Fabry’s disease was significantly lower (p < 0.01). Segmental pulse volume amplitudes showed no significant difference in any segments (upper arm, wrist, thigh, above and below knee, and the calf) between the two groups. Finger and toe blood flow, finger and toe pulse volume, and temperature in the resting state were all significantly less (p < 0.01, p < 0.05: p < 0.01, p < 0.01: p < 0.05, p < 0.05, respectively) than those in normal subjects. Finger and toe blood flow and pulse volume after vasodilation procedures were significantly less (p < 0.05, p < 0.01: p < 0.05, p < 0.01, respectively) than those in normal subjects despite equal elevation of digital temperature obtained after vasodilation in both groups. These findings indicate the presence of vasoconstrictive process in both resistance vessels and capacitances vessels in cutaneous and skeletal muscular beds. A limited response in the cutaneous circulation to vasodilation procedures also was seen. These data suggest the possibility that latent enhanced sympathoadrenal discharge as well as the accumulation of glycolipid in the autonomic nervous system and vessel walls plays an important role in the disturbed pathophysiology of this disorder. (AM HEART J 105783, 1983.)
Yoshihiko Seino, M.D., John K. Vyden, M.B.,
Harold
B. Rose, Sc.D., and Koichi
Michel Philippart, M.D., Nagasawa, M.D. Los Angeles, Calif.
Fabry’s disease (angiokeratoma corporis diffusum universale) is an X-linked disorder of glycosphingolipid metabolism, related to the defective activity of alpha-galactosidase. In Fabry’s disease the lipid ceramide trihexoside accumulates in the blood and tissues such as the skin, blood vessels, myocardium, conducting tissues in the heart, central nervous system, and kidneys.‘m5 Symptomatic cardiovascular involvements such as myocardial ischemia or infarction, cardiomegaly, hypertension, and renal failure often occur eventually in this disorder.2,6-g Altered vasomotor activity has been reported as a clinically prominent feature of this disorder10-14; severe pain, paresthesia, or Raynaud-like vasospasm From the Division of Cardiology, Department of Medicine, Medical Center, and the Departments of Medicine, Psychiatry, and Neurology, UCLA School of Medicine. Received
for publication
Reprint requests: John Division of Cardiology, Los Angeles, CA 90048.
Jan.
13, 1982;
K. Vyden, Cedars-Sinai
accepted
Feb.
M.B., Publications Medical Center,
Cedars-Sinai Pediatrics,
12, 1982. Office, Halper 321, 8700 Beverly Blvd.,
being induced by changes in temperature. However, there is no detailed information regarding the changes in peripheral hemodynamics in these patients. The purpose of this study is to investigate the peripheral hemodynamics systematically in eight patients with Fabry’s disease followed in our
university. METHODS Patients. Eight patients between the agesof 9 and 46 years (mean age 35.8 years) with Fabry’s disease(including two hemizygous and six heterozygous patients) confirmed at the Neuropsychiatric Institute of the University of California, Los Angeles, were studied in the Vascular Diagnostic Service at Cedars-Sinai Medical Center. The diagnosisof hemizygosity and heterozygosity for Fabry’s disease was made by physical examination, corneal changes, skin biopsy, and biochemical studies which included measurementof trihexosyl ceramide concentration in plasma and urine and the determination of ceramide alpha-galactosidase activity in p1asma.4”6Ten healthy staff members with a mean age of 36.2 years (range 24 to 54 years) acted as control subjects.They had 783
may, 1903 784
Seine
et al.
hnerican
Table I. Forearm hemodynamics in eight patients with Fabry’s diseaseand 10 normal subjects Mensurement
Mean blood pressure (mm Hg) Forearm blood flow (ml/100 ml/min) Forearm vascular resistance (mm Hg/ml/lOO ml/min) Forearm venous capacitance (ml/ lOOmI) Mean
Fa Dry 2 disease
Normal
P
88.4
+ 8.53
85.7
+ 6.98
NS
0.82
+ 0.61
1.21
+ 0.31
NS
148.6 I_ 71.49
0.62
+ 0.47
86.4 +- 35.54 p < 0.01
1.32
I!z 0.47
p < 0.01
__~-
i- SI).
the sameperipheral hemodynamic studies asthe patients with Fabry’s diseasedescribed below. Extremity pulse volumes. Peripheral hemodynamic studieswere performed with patients postcibal and supine in a quiet room at 68” F with the use of a pneumatic plethysmograph as previously described.17-I9 After the patients rested for 20 minutes segmental pulse volume studies were performed above the elbow, at the wrist, the upper thigh, above and below the knee, and at the ankle. The greatest pulsation amplitude in a given area was compared to that produced by a 1.0 cc standard injection of air into a cuff. The accepted reading was the greatest pulsation amplitude in a given area upon 10 mm Hg decrements of arterial blood pressure determined by sphygmomanometer. Forearm arterial and venous dynamics. Venous occlusion plethysmography was used for the measurementof forearm blood flow, vascular resistance,and venouscapacitance. The detecting cuff wasplaced around the midforearm to measureforearm blood flow, the secondcuff being connected to a cylinder of compressedair which was placed around the arm just above the elbow which allowed immediate pressureincreaseby suddeninflation of 30 mm Hg. Forearm blood flow was calculated from a change in volume during venousocclusionexpressedin ml/100 ml of tissue/min. During the recording, blood flow to the hand was occluded by the use of a third cuff inflated to suprasystolic levels of blood pressure. Forearm venous capacitance was determined by an equilibration method described by Mason and Braunwald.” The venous occlusion cuff was suddenly inflated to 30 mm Hg, and venous pressureand limb circumference were permitted to equilibrate for more than 2 minutes. Forearm venous capacitance was calculated from the increments in volume expressedin ml/100 ml. During these measurementsthe forearm was elevated above the level of the heart. Repeated determinations of forearm blood flow and venous capacitancewere undertaken to insure a relatively steady state. When a steady state was consideredto be present, three successivemeasurementswere undertaken, averaged, and utilized as the true measurement. Forearm
Heart Journa!
vascular resistancewasdefined asthe mean arterial blood pressuremeasuredin the arm by the ausculatory method divided by the forearm blood flow. Mean arterial blood pressure was calculated by using the formula: mean arterial blood pressure= diastolic blood pressurei im, (systolic - diastolic blood pressure). Digital blood flow. Digital blood flow wasmeasuredin a similar fashion with the use of a digital recording cup of appropriate size sealed with plethysmographic sealing compound. The digits usedwere the index finger and the second toe. Venous occlusion was achieved by a forearm pressure cuff set, at 30 mm Hg. Calibrations were performed by injecting 10 mm” of air into the system. Oscillometric evaluation of digital pulsation wasperformed with digital cups in the position described above, the largest digital pulsation was performed with digital cups in the position described above, the largest digital pulsation amplitude measured was accepted as the reading. Skin temperatures of the digit were measuredby meansof 24-channel temperature measurementsby tape application of thermal probes. Vasodilator stimulation. Digital blood flows, pulsation amplitudes, and skin temperatures were all recorded at rest and after the useof standard vasodilation technique which consistedof having the patients ingest 30 cc of 4340 ethanol and at the sametime surrounding the patient by an electric blanket to produce body heating. Statistics. All data were expressedas mean values rk standard deviation (mean -1 SD) and statistical analyses were carried out. by means of the Student’s t test for unpaired data. RESULTS Forearm hemodynamics (Table I). Mean forearm venous capacitance in Fabry’s disease patients was 0.62 +- 0.47 ml/100 ml which was significantly lower (p < 0.01) than that of 1.32 + 0.47 ml/l00 ml found in normal control subjects. Fabry’s disease patients had a mean forearm vascular resistance of 148.61 + 71.49 mm Hg/ml/lOO ml/min which was significantly higher (p < 0.01) than that of 86.4 +- 35.54 mm Hg/ml/lOO ml/min found in normal control subjects. However, there were no significant differences in the mean blood pressure and forearm blood flow between the two groups. Segmental pulse volume studies (Table II). Individual measures of the oscillometric examination in the arms, forearms, thighs, and legs of all Fabry’s disease patients and normal subjects showed no evidence of any major stenotic process in these limbs. Also there were no significant differences in each pulse volume amplitude between the two groups. Digital hemodynamic studies (Table Ill). Finger and toe pulse volumes in the control state were both significantly less (p < 0.01 and p < 0.01, respectively) than those in normal subjects. After vasodilation procedures, these differences were still present
Volume
105
Number
5
Abnormal peripheral
II. Segmental pulse volume study in eight patients with Fabry’s diseaseand 10 normal subjects Table
Measurement (ml) Above Wrist Groin Above Below Ankle Mean
elbow
knee knee
FabryS disease 0.52 0.21 1.10 0.92 0.84 0.32
-t r ” -t 1 -t
0.18 0.69 0.35 0.26 0.35 0.10
Normal 0.45 0.26 0.93 0.84 0.83 0.37
+ +r k k +-
P 0.06 0.06 2.21 0.16 1.90 0.03
NS NS NS NS NS NS
+ SD.
(p > 0.05 and p > 0.01, respectively). Similarly, finger and toe blood flows in the control state were significantly lower (p < 0.01 and p < 0.05, respectively) than those in normal subjects, with the difference still being present after the application of vasodilating procedures (p < 0.05 and p < 0.01, respectively). Finger and toe temperatures in the control state were significantly lower in Fabry’s disease Cp < 0.05 and p < 0.05, respectively) compared to those in normal subjects. However, vasodilation procedures abolished this difference.
hemodynamics
785
in Fabry’s disease
Ill. Digital hemodynamic studies in eight patients with Fabry’s diseaseand 10 normal subjects Table
Measurement
Fabry’s disease
Finger pulse volume (mm’) 0.41 & 0.38 Before vasodilation After vasodilation 3.12 r 1.27 Toe pulse volume (mm’) Before vasodilation 0.23 f 0.22 2.25 + 0.87 After vasodilation Finger blood flow (mm’hec) 0.26 k 0.31 Before vasodilation After vasodilation 9.81 + 3.23 Toe blood flow (mm3/sec) Before vasodilation 0.15 k 0.13 After vasodilation 4.07 k 2.17 Finger temperature (” C) Before vasodilation 27.7 k 1.65 35.5 + 0.46 After vasodilation Toe temperature (” C) Before vasodilation 23.1 r 2.41 31.4 ? 4.19 After vasodilation
Normal
P
2.02 + 1.08 4.53 * 1.20
p < 0.01 p < 0.05
1.00 AZ 0.35 4.77 t 1.61
p < 0.01 p < 0.01
3.97 It 2.88 14.70 + 6.07
p < 0.01 P < 0.05
1.65 t- 1.87 9.35 r 2.88
p < 0.05 p < 0.01
29.7 2 2.31 35.3 * 0.54
p < 0.05 NS
25.9 5 2.53 33.7 k 1.39
p < 0.05 NS
Mean rt SD.
DISCUSSION
Fabry’s disease is characterized by the accumulation of glycolipid (ceramide trihexoside) in the vascular smooth muscle, myocardium, cells of sympathetic ganglions and the central nervous system, and epithelial cells of the renal glomeruli.1-5 Although several studies regarding complicated heart disease, histochemical findings of the heart muscle or ECG abnormalities, and the conduction system in the heart have been reported in Fabry’s disease,6mg there is little information regarding peripheral vascular hemodynamics in this disorder. Previous reports. In previous case reports of Fabry’s disease, this disorder sometimes manifested itself with attacks of deep burning pains and paresthesia of the extremities which were precipitated by exposure to cold. lo-l4 In the report of Dempsey et aLlo it is stated that a patient was hospitalized frequently over a period of more than 10 years with the diagnosis of Raynaud’s disease before the diagnosis of Fabry’s disease was made. They provoked Raynaud-like phenomenon in the patient’s fingers by electrical stimulation on the arm; digital blood flow and digital temperature promptly dropped, and this phenomenon continued for a long time. This provoked phenomenon was similar to that seen in true Raynaud’s disease. lo This report is the first and only demonstration of an abnormal vasomotor response in Fabry’s disease. Some investigators have sug-
gested that episodes of pain or paresthesia in extremities in Fabry’s disease were related to such vasospastic phenomenon,2t”g while others have stated that these episodes were due to direct impairment of peripheral nerves such as the deposition of lipids in the perineural cells, unmyelinated and myelinated axons, Schwann cell cytoplasm, or the loss of the number of neurofibers.3’21 The principal object of the present study was to investigate if, and subsequently how, peripheral hemodynamics were affected in Fabry’s disease. Forearm hemodynamics. When a plethysmograph is placed on the forearm, 85% of the tissue enclosed is muscle and the remainder is skin and bone. It is thus accepted that forearm blood flow usually is taken to be an approximate indicator of skeletal muscle blood flo~.*~ Similarly, digital blood flow, since there is very little muscle involved, is thought to approximate skin blood flow.‘* In the present study mean forearm vascular resistance was significantly increased in Fabry’s disease, while mean forearm venous capacitance was significantly dimin-
ished. These findings suggest the presence of vasoconstrictive processes in both resistance vessels and capacitance vessels in the muscular beds. Segmental pulse volume studies. Puke volume amplitude is known to express the time course of difference between the volume of inflow and volume
786
Seino et al.
of outflow in a given area, and the form of the propagating wave on vessels.23-27The present results suggest there was no significant difference in the physiologic properties of major limb vessels between Fabry’s disease patients and normal subjects, and also they were free of major stenotic processes in the limbs. Changes in skin blood flow. Digital hemodynamics demonstrated significantly lower control and postvasodilation digital blood flow and digital pulse volume in Fabry’s disease patients compared to normal subjects. The lack of a significant difference in digital temperature after vasodilation procedures had been employed suggests that capillary blood flow in the two groups was similar with vasodilation. Mechanism of peripheral hemodynamic changes in Fabry’s disease. The peripheral hemodynamic
changes seen in the present study resemble those reported in congestive heart failure, which are characterized by markedly reduced skin blood flow and the presence of vasoconstriction in skeletal muscular vascular beds.28-“2 Zelis et a1.28-30have shown that peripheral resistance vessels and capacitance vessels constrict to reduce the blood flow to limbs and to increase peripheral venous tone in congestive heart failure. These vasoconstrictions are largely due to two mechanisms. First, the capacity of the skeletal muscle resistance vessels to respond to metabolic vasodilator stimuli is limited, and second, enhanced sympathoadrenal discharge is present.28-33 The findings of diminished digital hemodynamic response to vasodilation procedures in the present study also resemble the situation of reduced reactive hyperemia response in congestive heart failure secondary to vascular stiffness, namely, increasing content of NaCl and water retention in the vessel wa11s.28~2g~33 Previous reports of histopathologic studies in Fabry’s disease showed widespread involvement of vascular smooth muscle and endothelium with glyof such colipid deposits. 34,35 The development changes in the blood vessels of skeletal muscle is thought to account for the ischemic type of pain experienced by some patients with Fabry’s disease.:j6 Conclusions. Although no patients had clinical symptoms and signs of congestive heart failure or hypertension in the present study, a latent enhanced sympathoadrenal discharge might be present in Fabry’s disease, as in congestive heart failure. The first describers of this disorder, Scribat7 Ohnishi the presand Dyck,38 and other,3g,40 demonstrated ence of stored lipid material in peripheral autonomic
ganglia and suggested that the episodic pains or diminished sweating might be due to involvement of autonomic nerves. Altered vasomotor activity which presents clinically as Raynaud’s phenomenon in Fabry’s disease”1-‘4 and the fact that alpha-receptor blocking agents can sometimes be partially effective in the management of the episodic pains or paresthesias in this disorder also suggest this possibility. Further investigations of the altered peripheral vascular circulation in Fabry’s disease may offer new insights into the disturbed pathophysiology seen in this disorder. REFERENCES
1. Kolodyn EH: Current concepts in genetics: L,ysosomal storage disease. N Engl J Med 294:1217, 1976. ‘2. Becker AE, Schoorl R, Blak AG, Heide RM: Cardiac manifestation of Fabry’s disease. Am ,J Cardiol 36:829, 197.5. :i. Sima AA, Robertson DM: Involvement of peripheral nerve and muscle in Fabry’s disease. Arch Neurol 35:‘291, 1978. 4. Urbain G, Philippart M, Peremans J: Fabry’s disease with hypogammaglobulinemia and without angiokerat.oma. Arch Int Med 124:72, 1969. 5. Burbank MK, Spittel .JA Jr: Tumors of blood and lymph vessels: Angiokeratoma corporis diffusum (Fabry’s disease). in ,Juergeris JL, Spittel JA, Painbaim JF, editors: Peripheral vascular disease. Philadelphia, 1980, W B Saunders Company, p 684. DG: Accerelated atrioventricular conduc6. Rowe JW, Caralis tion in Fabry’s disease. Angiology 29:562, 1978. 7. Ferrano V,J, Hibbs RG, Burda CD: The heart in Fabry’s disease. A histochemical and electron microsipic study. Am .J Cardiol 24:95, 1969. 8. Desnick RJ, Blieden LC, Sharp HL, Hofschire PJ, Moller JH: Cardiac valvular anomalies in Fabry’s disease. Circulation 54:818, 1976. 9. Mehta .I, Tuna N, Moller JH, Desnick RJ: Electrocardiographic and vectorcardiographic abnormalities in Fabry’s disease. AM HEART J 93:699, 1977. H, Murtley MW, Carroll J, Balint J, Miller RE, 10. Dempsey Frommeyer WB Jr: Fabry’s disease (angiokeratoma corporis diffusum) case report on a rare disease. Ann Intern Med 63:1059, 1965. 11 Kahkle W: Angiokeratoma corporis diffusum universale (Fabry’s disease,. In Schettler G, editor: Lipids and lipidosis. New York, 1967, Springer-Verlag, p 332. 12. Wise D. Wallace HJ. Jellinek GH: Angiokeratoma corporis diffusum. A clinical study of eight affected families. Q JMed 31:177, 196’. 13 Groot WP: Angiokeratoma corporis diffusum Fabry. Dermatologica 128:321, 1964. 14. Leder AA, Bosworth WC: Angiokeratoma corporis diffusum universale (Fabry’s disease) with mitral stenosis. Am .I Med 38:814, 1965. 15. Desnick Rd. Allen KY, Desnick SJ: Fabry’s disease: Enzymatic diagnosis of hemizygotes and heterozygotes. J Lab Clin Med 81:157. 1973. 16. Philippart M: Glycolipid, mucopolysaccharide and carbohydrate distribution in tissues, plasma and urine from glycolipidosis and other disorders: Complex nature of the accumulated substances. Adv Exp Med Biol 25:231, 1972. 17. Vyden .JK, Nagasawa K, Graettinger W, Marcus HS, GroSeth-Dittrich M, Swan HJC: The effects of transfemoral catheterization on blood flow in the extremities. Circulation 50:741. 1974. JK, Sellers A, Nagasawa K, Takano T, Groseth18. Vyden. Dittrich M, Swan HJC: Peripheral hemodynamics in anephric patients with hypertension. AM HEART J 96:2(1X 1978.
Volume Number
105 5
Abnormal
19. Ogawa T, Vyden JK, Rose HB, Kanazawa M, Seino Y, Swan HJC: Peripheral circulatory changes after physical conditioning in coronary artery disease patients. J Cardiac Rehab 1:269, 1981. 20. Mason DT, Braunwald E: The effects of nitroglycerin and amyl nitrite on arteriolar and venous tone in the human forearm. Circulation 32:755, 1965. 21. LeBodic MF, LeBodic L, Buzelin F, Bureau B, MussiniMontpellier J: Les lesions vasculaires de la maladie de Fabry. Ann Anat Path01 (Paris) 23:23, 1978. 22. Grant RT, Pearson RSB: The blood circulation in the human limbs: Observations on the differences between the proximal and distal parts and remarks on the regulation of body temperature. Clin Sci 3:119, 1938. 23. Beuch GE: Method for recording simultaneously the time course of digital rate and of digital volume of inflow, outflow and the difference between inflow and outflow during a single pulse cycle in man. J Appl Physiol 7:99, 1954. 24. Nakayama R, Kobayashi T, Kimura K, Azuma T: A theoretical approach to the volume pulse wave. AM HEART J 86:96, 1973. 25. Lippman HL, Winsor T: Medical instrumentation in peripheral vascular disease. Circulation 45:A285, 1972. Part I: An improved 26. Winsor T: Clinical plethysmography, direct writing plethysmography, Angiology 4:134, 1953. Part II: Plethysmographic procedures of clinical importance. Angiology 4:149, 1953. 27. Winsor T: The segmental plethysmography. A description of the instrument. Angiology 8:87, 1957. 28. Zelis R, Longhurst J, Capone RJ, Lee G: Peripheral circulatory control mechanisms in congestive heart failure. Am J Cardiol 32:481, 1973. 29. Zelis R, Hellis SH, Longhurst J, Mason DT: Abnormalities in the regional circulation accompanying congestive heart failure. Prog Cardiovasc Dis 18:181, 1975.
30.
31.
32.
33.
34.
35.
36. 37.
38. 39. 40.
peripheral
h>emodynamics
in Fabry’s
disease
787
Zelis R, Mason DT, Braunwald E: A comparison of effects of vasodilators stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 47:960, 1968. Takano T, Vyden JK, Ogawa T, Seino Y, Rose HB, Marcus HS, Swan HJC: Observation on the relationship between digital heat loss and systemic hemodynamics in patients with heart disease. AM HEART J 105:830, 1983. Zelis R, Mason DT, Braunwald E: Partition of blood flow to the cutaneous and muscular beds of the forearm rest and during leg exercise in normal subjects and in patients with heart failure. Circ Res 24:711, 1969. Zellis R, Mason DT: Diminished forearm and arteriolar dilator capacity produced by mineral corticoid induced salt retention in man. Circulation 41:589, 1970. Kahlke, W: Angiokeratoma corporis diffusum universale. In Shettler G, editor: Lipids and lipidosis. New York, 1967, Springer-Verlag, p 332. Sweeley CC, Klionsky P: Glycolipid lipidosis: Fabry’s disease. In Stanbury JR, Wyngaarden JB, Fredrickson D, editors: The metabolic basis of inherited disease. New York, 1966, McGraw-Hill Book Company, Inc, p 618. Frost P, Tanaka Y, Spaeth GL: Fabry’s disease-glycolipid lipidosis. Am J Med 40:618, 1966. Scriba K: Zur pathogenese des angioberatoma corporis diffusum Fabry mit cardiovasorenalem symptomenkomplex. Verh Dtsch Ges Path01 34:221, 1950. Ohnishi A, Dyck PJ: Loss of small peripheral sensory neurons in Fabry’s disease. Arch Neurol 31:120,1974, Rahman AN, Lindenberg R: The neuropathology of hereditary dystrophic lipidosis. Arch Neurol 9:373, 1963. Steward VW, Hitchock C: Fabry’s disease: A report of five cases with pain in the extremities as the chief symptom. Path01 Eur 3:377, 1968.
in patients
with
Altered vasomotor activity has been reported as a clinically prominent feature of Fabry’s disease (angiokeratoma corporis diffusum universale). While symptomatic cardiovascular involvement occurs eventually in most patients with this disorder, little is known concerning the effect of Fabry’s disease on peripheral hemodynamics. Peripheral hemodynamics in the extremities and digits were studied in eight patients with Fabry’s disease by means of segmental and venous occlusion pneumoplethysmography and thermal probes, and the results obtained were compared with those of 10 normal subjects. Forearm vascular resistance in Fabry’s disease patients was significantly higher (p < 0.01) than that in normal subjects. Forearm venous capacitance in Fabry’s disease was significantly lower (p < 0.01). Segmental pulse volume amplitudes showed no significant difference in any segments (upper arm, wrist, thigh, above and below knee, and the calf) between the two groups. Finger and toe blood flow, finger and toe pulse volume, and temperature in the resting state were all significantly less (p < 0.01, p < 0.05: p < 0.01, p < 0.01: p < 0.05, p < 0.05, respectively) than those in normal subjects. Finger and toe blood flow and pulse volume after vasodilation procedures were significantly less (p < 0.05, p < 0.01: p < 0.05, p < 0.01, respectively) than those in normal subjects despite equal elevation of digital temperature obtained after vasodilation in both groups. These findings indicate the presence of vasoconstrictive process in both resistance vessels and capacitances vessels in cutaneous and skeletal muscular beds. A limited response in the cutaneous circulation to vasodilation procedures also was seen. These data suggest the possibility that latent enhanced sympathoadrenal discharge as well as the accumulation of glycolipid in the autonomic nervous system and vessel walls plays an important role in the disturbed pathophysiology of this disorder. (AM HEART J 105783, 1983.)
Yoshihiko Seino, M.D., John K. Vyden, M.B.,
Harold
B. Rose, Sc.D., and Koichi
Michel Philippart, M.D., Nagasawa, M.D. Los Angeles, Calif.
Fabry’s disease (angiokeratoma corporis diffusum universale) is an X-linked disorder of glycosphingolipid metabolism, related to the defective activity of alpha-galactosidase. In Fabry’s disease the lipid ceramide trihexoside accumulates in the blood and tissues such as the skin, blood vessels, myocardium, conducting tissues in the heart, central nervous system, and kidneys.‘m5 Symptomatic cardiovascular involvements such as myocardial ischemia or infarction, cardiomegaly, hypertension, and renal failure often occur eventually in this disorder.2,6-g Altered vasomotor activity has been reported as a clinically prominent feature of this disorder10-14; severe pain, paresthesia, or Raynaud-like vasospasm From the Division of Cardiology, Department of Medicine, Medical Center, and the Departments of Medicine, Psychiatry, and Neurology, UCLA School of Medicine. Received
for publication
Reprint requests: John Division of Cardiology, Los Angeles, CA 90048.
Jan.
13, 1982;
K. Vyden, Cedars-Sinai
accepted
Feb.
M.B., Publications Medical Center,
Cedars-Sinai Pediatrics,
12, 1982. Office, Halper 321, 8700 Beverly Blvd.,
being induced by changes in temperature. However, there is no detailed information regarding the changes in peripheral hemodynamics in these patients. The purpose of this study is to investigate the peripheral hemodynamics systematically in eight patients with Fabry’s disease followed in our
university. METHODS Patients. Eight patients between the agesof 9 and 46 years (mean age 35.8 years) with Fabry’s disease(including two hemizygous and six heterozygous patients) confirmed at the Neuropsychiatric Institute of the University of California, Los Angeles, were studied in the Vascular Diagnostic Service at Cedars-Sinai Medical Center. The diagnosisof hemizygosity and heterozygosity for Fabry’s disease was made by physical examination, corneal changes, skin biopsy, and biochemical studies which included measurementof trihexosyl ceramide concentration in plasma and urine and the determination of ceramide alpha-galactosidase activity in p1asma.4”6Ten healthy staff members with a mean age of 36.2 years (range 24 to 54 years) acted as control subjects.They had 783
may, 1903 784
Seine
et al.
hnerican
Table I. Forearm hemodynamics in eight patients with Fabry’s diseaseand 10 normal subjects Mensurement
Mean blood pressure (mm Hg) Forearm blood flow (ml/100 ml/min) Forearm vascular resistance (mm Hg/ml/lOO ml/min) Forearm venous capacitance (ml/ lOOmI) Mean
Fa Dry 2 disease
Normal
P
88.4
+ 8.53
85.7
+ 6.98
NS
0.82
+ 0.61
1.21
+ 0.31
NS
148.6 I_ 71.49
0.62
+ 0.47
86.4 +- 35.54 p < 0.01
1.32
I!z 0.47
p < 0.01
__~-
i- SI).
the sameperipheral hemodynamic studies asthe patients with Fabry’s diseasedescribed below. Extremity pulse volumes. Peripheral hemodynamic studieswere performed with patients postcibal and supine in a quiet room at 68” F with the use of a pneumatic plethysmograph as previously described.17-I9 After the patients rested for 20 minutes segmental pulse volume studies were performed above the elbow, at the wrist, the upper thigh, above and below the knee, and at the ankle. The greatest pulsation amplitude in a given area was compared to that produced by a 1.0 cc standard injection of air into a cuff. The accepted reading was the greatest pulsation amplitude in a given area upon 10 mm Hg decrements of arterial blood pressure determined by sphygmomanometer. Forearm arterial and venous dynamics. Venous occlusion plethysmography was used for the measurementof forearm blood flow, vascular resistance,and venouscapacitance. The detecting cuff wasplaced around the midforearm to measureforearm blood flow, the secondcuff being connected to a cylinder of compressedair which was placed around the arm just above the elbow which allowed immediate pressureincreaseby suddeninflation of 30 mm Hg. Forearm blood flow was calculated from a change in volume during venousocclusionexpressedin ml/100 ml of tissue/min. During the recording, blood flow to the hand was occluded by the use of a third cuff inflated to suprasystolic levels of blood pressure. Forearm venous capacitance was determined by an equilibration method described by Mason and Braunwald.” The venous occlusion cuff was suddenly inflated to 30 mm Hg, and venous pressureand limb circumference were permitted to equilibrate for more than 2 minutes. Forearm venous capacitance was calculated from the increments in volume expressedin ml/100 ml. During these measurementsthe forearm was elevated above the level of the heart. Repeated determinations of forearm blood flow and venous capacitancewere undertaken to insure a relatively steady state. When a steady state was consideredto be present, three successivemeasurementswere undertaken, averaged, and utilized as the true measurement. Forearm
Heart Journa!
vascular resistancewasdefined asthe mean arterial blood pressuremeasuredin the arm by the ausculatory method divided by the forearm blood flow. Mean arterial blood pressure was calculated by using the formula: mean arterial blood pressure= diastolic blood pressurei im, (systolic - diastolic blood pressure). Digital blood flow. Digital blood flow wasmeasuredin a similar fashion with the use of a digital recording cup of appropriate size sealed with plethysmographic sealing compound. The digits usedwere the index finger and the second toe. Venous occlusion was achieved by a forearm pressure cuff set, at 30 mm Hg. Calibrations were performed by injecting 10 mm” of air into the system. Oscillometric evaluation of digital pulsation wasperformed with digital cups in the position described above, the largest digital pulsation was performed with digital cups in the position described above, the largest digital pulsation amplitude measured was accepted as the reading. Skin temperatures of the digit were measuredby meansof 24-channel temperature measurementsby tape application of thermal probes. Vasodilator stimulation. Digital blood flows, pulsation amplitudes, and skin temperatures were all recorded at rest and after the useof standard vasodilation technique which consistedof having the patients ingest 30 cc of 4340 ethanol and at the sametime surrounding the patient by an electric blanket to produce body heating. Statistics. All data were expressedas mean values rk standard deviation (mean -1 SD) and statistical analyses were carried out. by means of the Student’s t test for unpaired data. RESULTS Forearm hemodynamics (Table I). Mean forearm venous capacitance in Fabry’s disease patients was 0.62 +- 0.47 ml/100 ml which was significantly lower (p < 0.01) than that of 1.32 + 0.47 ml/l00 ml found in normal control subjects. Fabry’s disease patients had a mean forearm vascular resistance of 148.61 + 71.49 mm Hg/ml/lOO ml/min which was significantly higher (p < 0.01) than that of 86.4 +- 35.54 mm Hg/ml/lOO ml/min found in normal control subjects. However, there were no significant differences in the mean blood pressure and forearm blood flow between the two groups. Segmental pulse volume studies (Table II). Individual measures of the oscillometric examination in the arms, forearms, thighs, and legs of all Fabry’s disease patients and normal subjects showed no evidence of any major stenotic process in these limbs. Also there were no significant differences in each pulse volume amplitude between the two groups. Digital hemodynamic studies (Table Ill). Finger and toe pulse volumes in the control state were both significantly less (p < 0.01 and p < 0.01, respectively) than those in normal subjects. After vasodilation procedures, these differences were still present
Volume
105
Number
5
Abnormal peripheral
II. Segmental pulse volume study in eight patients with Fabry’s diseaseand 10 normal subjects Table
Measurement (ml) Above Wrist Groin Above Below Ankle Mean
elbow
knee knee
FabryS disease 0.52 0.21 1.10 0.92 0.84 0.32
-t r ” -t 1 -t
0.18 0.69 0.35 0.26 0.35 0.10
Normal 0.45 0.26 0.93 0.84 0.83 0.37
+ +r k k +-
P 0.06 0.06 2.21 0.16 1.90 0.03
NS NS NS NS NS NS
+ SD.
(p > 0.05 and p > 0.01, respectively). Similarly, finger and toe blood flows in the control state were significantly lower (p < 0.01 and p < 0.05, respectively) than those in normal subjects, with the difference still being present after the application of vasodilating procedures (p < 0.05 and p < 0.01, respectively). Finger and toe temperatures in the control state were significantly lower in Fabry’s disease Cp < 0.05 and p < 0.05, respectively) compared to those in normal subjects. However, vasodilation procedures abolished this difference.
hemodynamics
785
in Fabry’s disease
Ill. Digital hemodynamic studies in eight patients with Fabry’s diseaseand 10 normal subjects Table
Measurement
Fabry’s disease
Finger pulse volume (mm’) 0.41 & 0.38 Before vasodilation After vasodilation 3.12 r 1.27 Toe pulse volume (mm’) Before vasodilation 0.23 f 0.22 2.25 + 0.87 After vasodilation Finger blood flow (mm’hec) 0.26 k 0.31 Before vasodilation After vasodilation 9.81 + 3.23 Toe blood flow (mm3/sec) Before vasodilation 0.15 k 0.13 After vasodilation 4.07 k 2.17 Finger temperature (” C) Before vasodilation 27.7 k 1.65 35.5 + 0.46 After vasodilation Toe temperature (” C) Before vasodilation 23.1 r 2.41 31.4 ? 4.19 After vasodilation
Normal
P
2.02 + 1.08 4.53 * 1.20
p < 0.01 p < 0.05
1.00 AZ 0.35 4.77 t 1.61
p < 0.01 p < 0.01
3.97 It 2.88 14.70 + 6.07
p < 0.01 P < 0.05
1.65 t- 1.87 9.35 r 2.88
p < 0.05 p < 0.01
29.7 2 2.31 35.3 * 0.54
p < 0.05 NS
25.9 5 2.53 33.7 k 1.39
p < 0.05 NS
Mean rt SD.
DISCUSSION
Fabry’s disease is characterized by the accumulation of glycolipid (ceramide trihexoside) in the vascular smooth muscle, myocardium, cells of sympathetic ganglions and the central nervous system, and epithelial cells of the renal glomeruli.1-5 Although several studies regarding complicated heart disease, histochemical findings of the heart muscle or ECG abnormalities, and the conduction system in the heart have been reported in Fabry’s disease,6mg there is little information regarding peripheral vascular hemodynamics in this disorder. Previous reports. In previous case reports of Fabry’s disease, this disorder sometimes manifested itself with attacks of deep burning pains and paresthesia of the extremities which were precipitated by exposure to cold. lo-l4 In the report of Dempsey et aLlo it is stated that a patient was hospitalized frequently over a period of more than 10 years with the diagnosis of Raynaud’s disease before the diagnosis of Fabry’s disease was made. They provoked Raynaud-like phenomenon in the patient’s fingers by electrical stimulation on the arm; digital blood flow and digital temperature promptly dropped, and this phenomenon continued for a long time. This provoked phenomenon was similar to that seen in true Raynaud’s disease. lo This report is the first and only demonstration of an abnormal vasomotor response in Fabry’s disease. Some investigators have sug-
gested that episodes of pain or paresthesia in extremities in Fabry’s disease were related to such vasospastic phenomenon,2t”g while others have stated that these episodes were due to direct impairment of peripheral nerves such as the deposition of lipids in the perineural cells, unmyelinated and myelinated axons, Schwann cell cytoplasm, or the loss of the number of neurofibers.3’21 The principal object of the present study was to investigate if, and subsequently how, peripheral hemodynamics were affected in Fabry’s disease. Forearm hemodynamics. When a plethysmograph is placed on the forearm, 85% of the tissue enclosed is muscle and the remainder is skin and bone. It is thus accepted that forearm blood flow usually is taken to be an approximate indicator of skeletal muscle blood flo~.*~ Similarly, digital blood flow, since there is very little muscle involved, is thought to approximate skin blood flow.‘* In the present study mean forearm vascular resistance was significantly increased in Fabry’s disease, while mean forearm venous capacitance was significantly dimin-
ished. These findings suggest the presence of vasoconstrictive processes in both resistance vessels and capacitance vessels in the muscular beds. Segmental pulse volume studies. Puke volume amplitude is known to express the time course of difference between the volume of inflow and volume
786
Seino et al.
of outflow in a given area, and the form of the propagating wave on vessels.23-27The present results suggest there was no significant difference in the physiologic properties of major limb vessels between Fabry’s disease patients and normal subjects, and also they were free of major stenotic processes in the limbs. Changes in skin blood flow. Digital hemodynamics demonstrated significantly lower control and postvasodilation digital blood flow and digital pulse volume in Fabry’s disease patients compared to normal subjects. The lack of a significant difference in digital temperature after vasodilation procedures had been employed suggests that capillary blood flow in the two groups was similar with vasodilation. Mechanism of peripheral hemodynamic changes in Fabry’s disease. The peripheral hemodynamic
changes seen in the present study resemble those reported in congestive heart failure, which are characterized by markedly reduced skin blood flow and the presence of vasoconstriction in skeletal muscular vascular beds.28-“2 Zelis et a1.28-30have shown that peripheral resistance vessels and capacitance vessels constrict to reduce the blood flow to limbs and to increase peripheral venous tone in congestive heart failure. These vasoconstrictions are largely due to two mechanisms. First, the capacity of the skeletal muscle resistance vessels to respond to metabolic vasodilator stimuli is limited, and second, enhanced sympathoadrenal discharge is present.28-33 The findings of diminished digital hemodynamic response to vasodilation procedures in the present study also resemble the situation of reduced reactive hyperemia response in congestive heart failure secondary to vascular stiffness, namely, increasing content of NaCl and water retention in the vessel wa11s.28~2g~33 Previous reports of histopathologic studies in Fabry’s disease showed widespread involvement of vascular smooth muscle and endothelium with glyof such colipid deposits. 34,35 The development changes in the blood vessels of skeletal muscle is thought to account for the ischemic type of pain experienced by some patients with Fabry’s disease.:j6 Conclusions. Although no patients had clinical symptoms and signs of congestive heart failure or hypertension in the present study, a latent enhanced sympathoadrenal discharge might be present in Fabry’s disease, as in congestive heart failure. The first describers of this disorder, Scribat7 Ohnishi the presand Dyck,38 and other,3g,40 demonstrated ence of stored lipid material in peripheral autonomic
ganglia and suggested that the episodic pains or diminished sweating might be due to involvement of autonomic nerves. Altered vasomotor activity which presents clinically as Raynaud’s phenomenon in Fabry’s disease”1-‘4 and the fact that alpha-receptor blocking agents can sometimes be partially effective in the management of the episodic pains or paresthesias in this disorder also suggest this possibility. Further investigations of the altered peripheral vascular circulation in Fabry’s disease may offer new insights into the disturbed pathophysiology seen in this disorder. REFERENCES
1. Kolodyn EH: Current concepts in genetics: L,ysosomal storage disease. N Engl J Med 294:1217, 1976. ‘2. Becker AE, Schoorl R, Blak AG, Heide RM: Cardiac manifestation of Fabry’s disease. Am ,J Cardiol 36:829, 197.5. :i. Sima AA, Robertson DM: Involvement of peripheral nerve and muscle in Fabry’s disease. Arch Neurol 35:‘291, 1978. 4. Urbain G, Philippart M, Peremans J: Fabry’s disease with hypogammaglobulinemia and without angiokerat.oma. Arch Int Med 124:72, 1969. 5. Burbank MK, Spittel .JA Jr: Tumors of blood and lymph vessels: Angiokeratoma corporis diffusum (Fabry’s disease). in ,Juergeris JL, Spittel JA, Painbaim JF, editors: Peripheral vascular disease. Philadelphia, 1980, W B Saunders Company, p 684. DG: Accerelated atrioventricular conduc6. Rowe JW, Caralis tion in Fabry’s disease. Angiology 29:562, 1978. 7. Ferrano V,J, Hibbs RG, Burda CD: The heart in Fabry’s disease. A histochemical and electron microsipic study. Am .J Cardiol 24:95, 1969. 8. Desnick RJ, Blieden LC, Sharp HL, Hofschire PJ, Moller JH: Cardiac valvular anomalies in Fabry’s disease. Circulation 54:818, 1976. 9. Mehta .I, Tuna N, Moller JH, Desnick RJ: Electrocardiographic and vectorcardiographic abnormalities in Fabry’s disease. AM HEART J 93:699, 1977. H, Murtley MW, Carroll J, Balint J, Miller RE, 10. Dempsey Frommeyer WB Jr: Fabry’s disease (angiokeratoma corporis diffusum) case report on a rare disease. Ann Intern Med 63:1059, 1965. 11 Kahkle W: Angiokeratoma corporis diffusum universale (Fabry’s disease,. In Schettler G, editor: Lipids and lipidosis. New York, 1967, Springer-Verlag, p 332. 12. Wise D. Wallace HJ. Jellinek GH: Angiokeratoma corporis diffusum. A clinical study of eight affected families. Q JMed 31:177, 196’. 13 Groot WP: Angiokeratoma corporis diffusum Fabry. Dermatologica 128:321, 1964. 14. Leder AA, Bosworth WC: Angiokeratoma corporis diffusum universale (Fabry’s disease) with mitral stenosis. Am .I Med 38:814, 1965. 15. Desnick Rd. Allen KY, Desnick SJ: Fabry’s disease: Enzymatic diagnosis of hemizygotes and heterozygotes. J Lab Clin Med 81:157. 1973. 16. Philippart M: Glycolipid, mucopolysaccharide and carbohydrate distribution in tissues, plasma and urine from glycolipidosis and other disorders: Complex nature of the accumulated substances. Adv Exp Med Biol 25:231, 1972. 17. Vyden .JK, Nagasawa K, Graettinger W, Marcus HS, GroSeth-Dittrich M, Swan HJC: The effects of transfemoral catheterization on blood flow in the extremities. Circulation 50:741. 1974. JK, Sellers A, Nagasawa K, Takano T, Groseth18. Vyden. Dittrich M, Swan HJC: Peripheral hemodynamics in anephric patients with hypertension. AM HEART J 96:2(1X 1978.
Volume Number
105 5
Abnormal
19. Ogawa T, Vyden JK, Rose HB, Kanazawa M, Seino Y, Swan HJC: Peripheral circulatory changes after physical conditioning in coronary artery disease patients. J Cardiac Rehab 1:269, 1981. 20. Mason DT, Braunwald E: The effects of nitroglycerin and amyl nitrite on arteriolar and venous tone in the human forearm. Circulation 32:755, 1965. 21. LeBodic MF, LeBodic L, Buzelin F, Bureau B, MussiniMontpellier J: Les lesions vasculaires de la maladie de Fabry. Ann Anat Path01 (Paris) 23:23, 1978. 22. Grant RT, Pearson RSB: The blood circulation in the human limbs: Observations on the differences between the proximal and distal parts and remarks on the regulation of body temperature. Clin Sci 3:119, 1938. 23. Beuch GE: Method for recording simultaneously the time course of digital rate and of digital volume of inflow, outflow and the difference between inflow and outflow during a single pulse cycle in man. J Appl Physiol 7:99, 1954. 24. Nakayama R, Kobayashi T, Kimura K, Azuma T: A theoretical approach to the volume pulse wave. AM HEART J 86:96, 1973. 25. Lippman HL, Winsor T: Medical instrumentation in peripheral vascular disease. Circulation 45:A285, 1972. Part I: An improved 26. Winsor T: Clinical plethysmography, direct writing plethysmography, Angiology 4:134, 1953. Part II: Plethysmographic procedures of clinical importance. Angiology 4:149, 1953. 27. Winsor T: The segmental plethysmography. A description of the instrument. Angiology 8:87, 1957. 28. Zelis R, Longhurst J, Capone RJ, Lee G: Peripheral circulatory control mechanisms in congestive heart failure. Am J Cardiol 32:481, 1973. 29. Zelis R, Hellis SH, Longhurst J, Mason DT: Abnormalities in the regional circulation accompanying congestive heart failure. Prog Cardiovasc Dis 18:181, 1975.
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