561
180 mg/dl (220, 25), and patients were aged 43-76 years (56, 10). Exclusion criteria were severe, systemic, or infectious diseases and disorders of the kidney and liver. None of the patients with over
Immunofluorescent staining of muscle-biopsy specimen from patient with inclusion-body myositis. Transverse sections, showing positive &bgr;-amyloid protein deposits (white regions) in two abnormal muscle fibres Muscle fibre on left is more atrophic and vacuolated than that right x 1094, reduced by a factor of 1 4.
on
right. Leftx 1281,
Previously, &bgr;-AP had not been localised in human muscle. The deposits of &bgr;-AP we describe in muscle-biopsy specimens from patients with inclusion-body myositis and the co-localisation with ubiquitin raise the possibility that &bgr;-AP deposits in muscle in inclusion-body myositis, and the brain findings in Alzheimer’s disease may follow similar cellular events. The easily accessible muscle tissue may provide a good source for future molecular studies of &bgr;-AP to help to elucidate the pathogenesis of these two diseases.
Supported in part by the Muscular Dystrophy Association and the Vemon B. Link Research Fund. USC Neuromuscular Center, University of Southern California School of Medicine, Los Angeles, California 90017, USA
VALERIE ASKANAS W. KING ENGEL RENATE B. ALVAREZ
University of California San School of Medicine, La Jolla
GEORGE G. GLENNER
hypercholesterolaemia had received lipid-lowering therapy in the 6 months before this study. The diagnoses of group I and II, respectively, were coronary artery disease (9/9), dilated cardiomyopathy (1/0), valvular heart disease (1/2), essential hypertension (2/2), peripheral vascular disease (1/2), and diabetes mellitus (2/3). Drug treatment was similar in the two groups. Blood samples were taken under standardised conditions-at 0800 h after 15 min rest, in the supine position, and 12 h after the last meal. L-arginine plasma concentrations were measured by high-performance liquid chromatography. Double control measurements showed an accuracy of 4-2% (SD 3). In patients with hypercholesterolaemia, L-arginine plasma values were significantly lower than in age-matched patients with normal cholesterol: (mean [SD]) 78-2 (21) vs 111-2 (22-8) µmol/1; p < 0-001). As far
as we are aware
there
are no
other reports of reduced
plasma L-arginine in patients with hypercholesterolaemia. These data suggest that impairment of endothelium-dependent relaxation in patients with hypercholesterolaemia may be, in part, due to a deficiency of L-arginine, the precursor of NO. The underlying mechanisms for reduced
L-arginine
remain
to
be elucidated.
However, hypercholesterolaemia might be associated with diminished dietary L-arginine uptake (ie, food rich in lipids may contain less L-arginine) or altered L-arginine metabolism, such as increased arginase activity in the liver. If our findings are confirmed by investigations in a large patient population, L-arginine supplements may indeed represent a useful adjunctive and preventive treatment in patients with hypercholesterolaemia. Department of Cardiology, Medical Klinik III, University of Freiburg, 7800 Freiburg, Germany
MICHAEL JESERICH THOMAS MÜNZEL
HANJÖRG JUST HELMUT DREXLER
Diego
1. Dalakas MC Polymyositis, dermatomyositis and inclusion body myositis. N Engl J Med 1991; 325: 1487-98. 2. Carpenter S, Karpati G, Heller I, Eisen A. Inclusion-body myositis: a distinct variety of idiopathic inflammatory myopathy. Neurology 1978; 28: 8-17. 3. Askanas V, Serdaroglu P, Engel WK, Alvarez RB. Immunocytochemical localization of ubiquitin in muscle biopsies of patients with inclusion-body myositis and oculopharyngeal muscular dystrophy. Neurosci Lett 1991; 130: 73-76. 4. Mendell JR, Sahenk Z, Gales T, Paul L. Amyloid filaments in inclusion body myositis. Arch Neurol 1991; 48: 1229-34. 5 Wong CW, Quaranta V, Glenner GG. Neuritic plaques and cerebrovascular amyloid m Alzheimer’s disease are antigenically related. Proc Natl Acad Sci USA 1985; 82: 8729-32. 6. Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characteristics of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885-90. 7 Yankiner BA, Mesulam MM. &bgr;-amyloid and the pathogenesis of Alzheimer’s disease. N Engl J Med 1991; 325: 1849-57.
plasma L-arginine in hypercholesterolaemia
Reduced
SIR,-L-arginine is the precursor for nitric oxide (NO) synthase in vascular endothelial cells,l and NO is an important regulator of vascular tone in man.2 Hypercholesterolaemia impairs endothelial function-manifested as an attenuation of endothelial-dependent relaxation-before the formation of artherosclerotic lesions.3-5
Experimentalb
and clinicaF data have shown that impaired endothelial function in hypercholesterolaemia subjects could be corrected by L-arginine. This dysfunction might be due to substrate (L-arginine) deficiency, impairment of NO production or release, or inactivation of L-arginine. To test the first hypothesis, we have examined in a prospective
age-matched study plasma L-arginine concentrations in 13 patients with normal serum cholesterol and low-density lipoprotein (LDL) (group 1), and in 13 patients with hypercholesterolaemia type IIa (group II). In group I, cholesterol was less than 220 mg/dl (mean 182, SD 22) and LDL was less than 140 mg/dl (123, 14), and patients were aged 30-76 years (mean 56, SD 13). In group II, cholesterol was over 270 mg/dl (mean 301, SD 27), and LDL was
RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesise nitric oxide from L-arginine. Nature 1988, 333: 664-66. 2. Vallance P, Collier J, Moncada S. Effects of endothehum-denved nitric oxide on peripheral arteriolar tone in man. Lancet 1989; ii: 997-1000. 3. Cohen RA, Zitnay KM, Haudenschild CC, Cunningham LD. Loss of selective endothelial cell vasoactive functions caused by hyperdiolesterolemia in pig coronary arteries. Circ Res 1988, 63: 903-10. 4. Drexler H, Zeiher AM. Endothelial function in human coronary arteries in vivo. Focus 1. Palmer
on
hypercholesterolemia. Hypertension 1991; 18 (suppl II): 1-10.
5. Zeiher AM, Drexler H, Wollschlaeger H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991; 83: 391-401. 6. Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine restores cholineric relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation 1991; 83: 1057-62. 7. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculanon of hypercholesterolaemic patients by L-arginine. Lancet
1991; 338: 1546-60.
The J-curve
hypothesis
SIR,-Dr Cruickshank (Jan 18, p 187) reminds us that, despite the stake driven through its heart by your Nov 23 editorial (p 1299), the J-curve hypothesis continues to stalk during dark moonless nights. But in what guise? Initially, we were warned that reduction in blood pressure might be hazardous but only in hypertensive patients with pre-existing coronary heart disease; normotensive patients would be spared. Most recently, we find that even subjects who had mostly never been hypertensive let alone treated are at risk.2 Few would disagree that there must be a J-relation between diastolic blood pressure and coronary heart disease events. The critical question is, what is the level of the J-point? Here too, the goalposts are shifting; first 85-90 mm Hg,l now 75-79 mm Hg.2 Is it time to lower the limit further? In studies of left ventricular dysfunction (SOLVD), patients with symptomatic left ventricular (LV) dysfunction (heart failure) and symptomless LV dysfunction were randomised to treatment with the angiotensin-converting-enzyme (ACE) inhibitor enalapril or matching placebo. Most patients enrolled had LV dysfunction due to coronary artery disease (usually previous myocardial infarction) and those with heart failure had fairly low arterial pressures (mean diastolic pressure 77 mm Hg). Despite receiving
562
that lowered blood pressure (systolic/diastolic) by 5/4 Hg, the enalapril-treated patients had a substantially and significantly reduced incidence of unstable angina and myocardial infarction. The patients in these studies are exactly those who should be especially at risk in the J-curve hypothesis which seems to operate independent of LV function.2 Yet reducing diastolic blood pressure to around 73 mm Hg did these patients no harm. Perhaps the critical diastolic pressure in the J-curve mechanism needs further downward adjustment, or perhaps the J-curve might be best forgotten? treatment
mm
Department of Cardiology and University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK
JOHN MCMURRAY GORDON T. MCINNES
1. Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet 1987; i: 581-84. 2. D’Agostino RB, Belanger AJ, Kannell WB, Cruickshank JM. Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study. Br Med J 1991; 303: 385-89. 3. The SOLVD Investigators. Studies of left ventricular dysfunction (SOLVD), rationale, design and methods: two trials that evaluate the effect of enalapril in patients with reduced ejection fraction. Am J Cardiol 1990; 66: 315-22 4. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293-302. 5. The SOLVD Investigators. Initial blood pressure response to enalapril in hospitalised patients. (Studies of Left Ventricular Dysfunction [SOLVD]). Am J Cardiol 1991; 68: 1465-67. 6. SOLVD Prevention Arm: unpublished results presented to American Heart Association. November, 1991.
Does thrombolysis produce cholesterol embolisation? SIR,-Microembolisation of cholesterol crystals from ruptured atherosclerotic aortic plaques may produce a multisystem disease with variable clinical manifestations and high mortality.1 Cholesterol embolisation can occur spontaneously, or after aortic surgery or major vessel angiography in severely atherosclerotic aorta.In some cases anticoagulants are involved in this process, but only few are related to thrombolysis.2-4 We report a 64-year-old white man, with a recent history of non-Q-wave anterior myocardial infarction. He was treated with intravenous streptokinase 1500 000 IU for enduring chest pain with electrocardiographic signs of acute transmural anterior ischaemia. Thrombolysis was successful and no signs of new myocardial infarction developed. Coronary angiography showed critical stenosis of three vessels of the left main coronary artery. He was referred for elective aortocoronary bypass graft and discharged on treatment with verapamil 240 mg per day, transdermal nitroglycerine disc 15 mg per day, heparin 5000 units per day subcutaneously. 1 month later he was readmitted because of acute renal failure. He had an arterial blood pressure of 180/110 mm Hg with grade 3 hypertensive retinopathy. Peripheral arterial pulses were bilaterally decreased, and he had cyanosis of the distal phalanx of the left-hand fingers and of the 4th and 5th toe of the left foot. Limbs were cool and the skin of the left leg had a livedo reticularis pattern. Lungs were clear to auscultation and cardiac examination was normal. Abdominal and aortic sonography was unremarkable. Left gastrocnemius muscle and skin biopsy demonstrated cholesterol embolisation and concentric fibrosis of a small artery of the skin. The patient’s status further deteriorated; he was successfully treated with intermittent haemodialysis. The diagnosis of atheroembolic renal disease was based on the appearance of clinical features such as livedo reticularis, peripheral ischaemia, hypertension, leucocytosis and progressive renal failure after thrombolysis, coronary angiography, and anticoagulation with heparin, in the recorded sequence. Unlike major vessel angiography, the role of anticoagulant or thrombolytic therapy in cholesterol embolisation is controversial. Some workers postulated that anticoagulants’ and thrombolytic agents3,4 might promote embolisation, by preventing thrombus formation or destabilising a thrombus over ulcerating atheromatous plaques and favouring continous dissemination of atheromatous fragments into the peripheral circulation.
Atheroembolisation is a cause of major clinical complications," but it has not been mentioned in reports of major thrombolytic trials.5 In these trials, at least some of the reported cases of renal vasculitis and glomerulonephritis could also be related to unrecognised cholesterol embolisation. This has been described as a .6 direct cause of necrotising glomerulonephritis As Smith et all suggested, the clinical manifestations of atheroembolism are fortunately far less frequent than expected on the base of the histological findings. We suggest that thrombolysis should be included in the causative factors or cholesterol embolisation. Because of the long time course of renal cholesterol embolisation after angiography and/or thrombolysis, which we have also seen, it seems advisable to check renal function one to six weeks after thrombolysis and coronary angiography, or during anticoagulation. Equally important, the clinical status of the patient should be carefully observed for 1-2 months after treatment. Departments of Cardiology, Nephrology, and Pathology, Fatebenefratelli and Oftalmico Hospitals, 20123 Milan, Italy
R. MENDIA G. CAVALIERE F. SPARACIO F. M. TURAZZA
G. D’ALOYA M. G. PALMERI
G. SORGATO G. P. SANNA
1. Smith MC, Ghose MK, Henry AR. The clinical spectrum of renal cholesterol embolization. Am J Med 1981; 71: 174-80. 2. Ikram S, Lewis S, Bucknall C, et al. Treatment of acute myocardial infarction with anisoylated plasminogen streptokinase activator complex. Br Med J 1986, 293: 786-89. 3. Shapiro LS. Cholesterol embolisation after treatment with tissue plasminogen activator. N Engl J Med 1989; 321: 1270. 4. Pochmalicki G, Feldman L, Meunier P, Rougeot C, Weschler J, Jan F Cholesterol embolisation syndrome after thrombolytic therapy for myocardial infarction Lancet 1992; 339: 58-59. 5. Gruppo Italiano per lo Studio Della Streptokinasi nell’infarto Miocardico Acuto (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 397-402. 6. Goldman M, Thoua Y, Dhaene M, Toussaint C. Necrotising glomerulonephntis associated with cholesterol microemboli. Br MedJ 1985; 290: 205-06.
Fragmentation of pulmonary embolus SIR,-Dr Brady and colleagues’ technique (Nov 9, p 1186) opens successful, and they are to be commended. However, some points need clarification. Brady et al state that "pressure monitoring and contrast angiography are ’luxuries’". How else can we determine the success of the procedure? We do not think that we can be certain of localising and crossing the obstruction without the help of a simple initial angiogram at least.2 Specificity of diagnosis of pulmonary embolism by clinical examination, electrocardiography, and chest radiography is poorand in the absence of classic features, which were present in Brady and colleagues’ 3 patients (tablet taking, surgery, immobilisation, smoking), and without angiography can one blindly catheterise sick, shocked patients ?2,3 Use of an arm vein does not really obviate the need for a venesection since percutaneous procedure may be difficult in obese sick individuals (those most susceptible to pulmonary embolism) who have already had intravenous lines. The risk of cannulating the subclavian vein in a severely tachypnoeic patient needs to be carefully considered. Do Brady et al suggest that this method totally obviates the need for thrombolysis? What if pulmonary embolism were to recur in the acute setting? Should we repeat the same procedure or thrombolysis? Can this method be used for emboli in the main pulmonary trunk? Lastly, with respect to availability of catheters, even established centres occasionally have difficulties in emergencies. Thrombolysis seems less expensive for the general population. up many options, if it is
Department of Cardiology, SGPGIMS, PO Box 375,
K. PRASAD S. RADHAKRISHNAN
Lucknow 226 001, India
1. Brady AJB, Crake T, Oakley CM. Percutaneous fragmentation and distal dispersion of pulmonary embolus. Lancet 1991; 338: 1186-89. 2 Goldhaber SR, Braunwald E. Pulmonary embolism. In. Braunwald E, ed. Heart disease. Philadelphia: Saunders, 1988: 1577-96. 3. Bell
WR, Simon TL, DeMets DL The clinical features of submassive and massive
pulmonary emboli Am J Med 1977; 62:
355-61.
180 mg/dl (220, 25), and patients were aged 43-76 years (56, 10). Exclusion criteria were severe, systemic, or infectious diseases and disorders of the kidney and liver. None of the patients with over
Immunofluorescent staining of muscle-biopsy specimen from patient with inclusion-body myositis. Transverse sections, showing positive &bgr;-amyloid protein deposits (white regions) in two abnormal muscle fibres Muscle fibre on left is more atrophic and vacuolated than that right x 1094, reduced by a factor of 1 4.
on
right. Leftx 1281,
Previously, &bgr;-AP had not been localised in human muscle. The deposits of &bgr;-AP we describe in muscle-biopsy specimens from patients with inclusion-body myositis and the co-localisation with ubiquitin raise the possibility that &bgr;-AP deposits in muscle in inclusion-body myositis, and the brain findings in Alzheimer’s disease may follow similar cellular events. The easily accessible muscle tissue may provide a good source for future molecular studies of &bgr;-AP to help to elucidate the pathogenesis of these two diseases.
Supported in part by the Muscular Dystrophy Association and the Vemon B. Link Research Fund. USC Neuromuscular Center, University of Southern California School of Medicine, Los Angeles, California 90017, USA
VALERIE ASKANAS W. KING ENGEL RENATE B. ALVAREZ
University of California San School of Medicine, La Jolla
GEORGE G. GLENNER
hypercholesterolaemia had received lipid-lowering therapy in the 6 months before this study. The diagnoses of group I and II, respectively, were coronary artery disease (9/9), dilated cardiomyopathy (1/0), valvular heart disease (1/2), essential hypertension (2/2), peripheral vascular disease (1/2), and diabetes mellitus (2/3). Drug treatment was similar in the two groups. Blood samples were taken under standardised conditions-at 0800 h after 15 min rest, in the supine position, and 12 h after the last meal. L-arginine plasma concentrations were measured by high-performance liquid chromatography. Double control measurements showed an accuracy of 4-2% (SD 3). In patients with hypercholesterolaemia, L-arginine plasma values were significantly lower than in age-matched patients with normal cholesterol: (mean [SD]) 78-2 (21) vs 111-2 (22-8) µmol/1; p < 0-001). As far
as we are aware
there
are no
other reports of reduced
plasma L-arginine in patients with hypercholesterolaemia. These data suggest that impairment of endothelium-dependent relaxation in patients with hypercholesterolaemia may be, in part, due to a deficiency of L-arginine, the precursor of NO. The underlying mechanisms for reduced
L-arginine
remain
to
be elucidated.
However, hypercholesterolaemia might be associated with diminished dietary L-arginine uptake (ie, food rich in lipids may contain less L-arginine) or altered L-arginine metabolism, such as increased arginase activity in the liver. If our findings are confirmed by investigations in a large patient population, L-arginine supplements may indeed represent a useful adjunctive and preventive treatment in patients with hypercholesterolaemia. Department of Cardiology, Medical Klinik III, University of Freiburg, 7800 Freiburg, Germany
MICHAEL JESERICH THOMAS MÜNZEL
HANJÖRG JUST HELMUT DREXLER
Diego
1. Dalakas MC Polymyositis, dermatomyositis and inclusion body myositis. N Engl J Med 1991; 325: 1487-98. 2. Carpenter S, Karpati G, Heller I, Eisen A. Inclusion-body myositis: a distinct variety of idiopathic inflammatory myopathy. Neurology 1978; 28: 8-17. 3. Askanas V, Serdaroglu P, Engel WK, Alvarez RB. Immunocytochemical localization of ubiquitin in muscle biopsies of patients with inclusion-body myositis and oculopharyngeal muscular dystrophy. Neurosci Lett 1991; 130: 73-76. 4. Mendell JR, Sahenk Z, Gales T, Paul L. Amyloid filaments in inclusion body myositis. Arch Neurol 1991; 48: 1229-34. 5 Wong CW, Quaranta V, Glenner GG. Neuritic plaques and cerebrovascular amyloid m Alzheimer’s disease are antigenically related. Proc Natl Acad Sci USA 1985; 82: 8729-32. 6. Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characteristics of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885-90. 7 Yankiner BA, Mesulam MM. &bgr;-amyloid and the pathogenesis of Alzheimer’s disease. N Engl J Med 1991; 325: 1849-57.
plasma L-arginine in hypercholesterolaemia
Reduced
SIR,-L-arginine is the precursor for nitric oxide (NO) synthase in vascular endothelial cells,l and NO is an important regulator of vascular tone in man.2 Hypercholesterolaemia impairs endothelial function-manifested as an attenuation of endothelial-dependent relaxation-before the formation of artherosclerotic lesions.3-5
Experimentalb
and clinicaF data have shown that impaired endothelial function in hypercholesterolaemia subjects could be corrected by L-arginine. This dysfunction might be due to substrate (L-arginine) deficiency, impairment of NO production or release, or inactivation of L-arginine. To test the first hypothesis, we have examined in a prospective
age-matched study plasma L-arginine concentrations in 13 patients with normal serum cholesterol and low-density lipoprotein (LDL) (group 1), and in 13 patients with hypercholesterolaemia type IIa (group II). In group I, cholesterol was less than 220 mg/dl (mean 182, SD 22) and LDL was less than 140 mg/dl (123, 14), and patients were aged 30-76 years (mean 56, SD 13). In group II, cholesterol was over 270 mg/dl (mean 301, SD 27), and LDL was
RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesise nitric oxide from L-arginine. Nature 1988, 333: 664-66. 2. Vallance P, Collier J, Moncada S. Effects of endothehum-denved nitric oxide on peripheral arteriolar tone in man. Lancet 1989; ii: 997-1000. 3. Cohen RA, Zitnay KM, Haudenschild CC, Cunningham LD. Loss of selective endothelial cell vasoactive functions caused by hyperdiolesterolemia in pig coronary arteries. Circ Res 1988, 63: 903-10. 4. Drexler H, Zeiher AM. Endothelial function in human coronary arteries in vivo. Focus 1. Palmer
on
hypercholesterolemia. Hypertension 1991; 18 (suppl II): 1-10.
5. Zeiher AM, Drexler H, Wollschlaeger H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991; 83: 391-401. 6. Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine restores cholineric relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation 1991; 83: 1057-62. 7. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculanon of hypercholesterolaemic patients by L-arginine. Lancet
1991; 338: 1546-60.
The J-curve
hypothesis
SIR,-Dr Cruickshank (Jan 18, p 187) reminds us that, despite the stake driven through its heart by your Nov 23 editorial (p 1299), the J-curve hypothesis continues to stalk during dark moonless nights. But in what guise? Initially, we were warned that reduction in blood pressure might be hazardous but only in hypertensive patients with pre-existing coronary heart disease; normotensive patients would be spared. Most recently, we find that even subjects who had mostly never been hypertensive let alone treated are at risk.2 Few would disagree that there must be a J-relation between diastolic blood pressure and coronary heart disease events. The critical question is, what is the level of the J-point? Here too, the goalposts are shifting; first 85-90 mm Hg,l now 75-79 mm Hg.2 Is it time to lower the limit further? In studies of left ventricular dysfunction (SOLVD), patients with symptomatic left ventricular (LV) dysfunction (heart failure) and symptomless LV dysfunction were randomised to treatment with the angiotensin-converting-enzyme (ACE) inhibitor enalapril or matching placebo. Most patients enrolled had LV dysfunction due to coronary artery disease (usually previous myocardial infarction) and those with heart failure had fairly low arterial pressures (mean diastolic pressure 77 mm Hg). Despite receiving
562
that lowered blood pressure (systolic/diastolic) by 5/4 Hg, the enalapril-treated patients had a substantially and significantly reduced incidence of unstable angina and myocardial infarction. The patients in these studies are exactly those who should be especially at risk in the J-curve hypothesis which seems to operate independent of LV function.2 Yet reducing diastolic blood pressure to around 73 mm Hg did these patients no harm. Perhaps the critical diastolic pressure in the J-curve mechanism needs further downward adjustment, or perhaps the J-curve might be best forgotten? treatment
mm
Department of Cardiology and University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK
JOHN MCMURRAY GORDON T. MCINNES
1. Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet 1987; i: 581-84. 2. D’Agostino RB, Belanger AJ, Kannell WB, Cruickshank JM. Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study. Br Med J 1991; 303: 385-89. 3. The SOLVD Investigators. Studies of left ventricular dysfunction (SOLVD), rationale, design and methods: two trials that evaluate the effect of enalapril in patients with reduced ejection fraction. Am J Cardiol 1990; 66: 315-22 4. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293-302. 5. The SOLVD Investigators. Initial blood pressure response to enalapril in hospitalised patients. (Studies of Left Ventricular Dysfunction [SOLVD]). Am J Cardiol 1991; 68: 1465-67. 6. SOLVD Prevention Arm: unpublished results presented to American Heart Association. November, 1991.
Does thrombolysis produce cholesterol embolisation? SIR,-Microembolisation of cholesterol crystals from ruptured atherosclerotic aortic plaques may produce a multisystem disease with variable clinical manifestations and high mortality.1 Cholesterol embolisation can occur spontaneously, or after aortic surgery or major vessel angiography in severely atherosclerotic aorta.In some cases anticoagulants are involved in this process, but only few are related to thrombolysis.2-4 We report a 64-year-old white man, with a recent history of non-Q-wave anterior myocardial infarction. He was treated with intravenous streptokinase 1500 000 IU for enduring chest pain with electrocardiographic signs of acute transmural anterior ischaemia. Thrombolysis was successful and no signs of new myocardial infarction developed. Coronary angiography showed critical stenosis of three vessels of the left main coronary artery. He was referred for elective aortocoronary bypass graft and discharged on treatment with verapamil 240 mg per day, transdermal nitroglycerine disc 15 mg per day, heparin 5000 units per day subcutaneously. 1 month later he was readmitted because of acute renal failure. He had an arterial blood pressure of 180/110 mm Hg with grade 3 hypertensive retinopathy. Peripheral arterial pulses were bilaterally decreased, and he had cyanosis of the distal phalanx of the left-hand fingers and of the 4th and 5th toe of the left foot. Limbs were cool and the skin of the left leg had a livedo reticularis pattern. Lungs were clear to auscultation and cardiac examination was normal. Abdominal and aortic sonography was unremarkable. Left gastrocnemius muscle and skin biopsy demonstrated cholesterol embolisation and concentric fibrosis of a small artery of the skin. The patient’s status further deteriorated; he was successfully treated with intermittent haemodialysis. The diagnosis of atheroembolic renal disease was based on the appearance of clinical features such as livedo reticularis, peripheral ischaemia, hypertension, leucocytosis and progressive renal failure after thrombolysis, coronary angiography, and anticoagulation with heparin, in the recorded sequence. Unlike major vessel angiography, the role of anticoagulant or thrombolytic therapy in cholesterol embolisation is controversial. Some workers postulated that anticoagulants’ and thrombolytic agents3,4 might promote embolisation, by preventing thrombus formation or destabilising a thrombus over ulcerating atheromatous plaques and favouring continous dissemination of atheromatous fragments into the peripheral circulation.
Atheroembolisation is a cause of major clinical complications," but it has not been mentioned in reports of major thrombolytic trials.5 In these trials, at least some of the reported cases of renal vasculitis and glomerulonephritis could also be related to unrecognised cholesterol embolisation. This has been described as a .6 direct cause of necrotising glomerulonephritis As Smith et all suggested, the clinical manifestations of atheroembolism are fortunately far less frequent than expected on the base of the histological findings. We suggest that thrombolysis should be included in the causative factors or cholesterol embolisation. Because of the long time course of renal cholesterol embolisation after angiography and/or thrombolysis, which we have also seen, it seems advisable to check renal function one to six weeks after thrombolysis and coronary angiography, or during anticoagulation. Equally important, the clinical status of the patient should be carefully observed for 1-2 months after treatment. Departments of Cardiology, Nephrology, and Pathology, Fatebenefratelli and Oftalmico Hospitals, 20123 Milan, Italy
R. MENDIA G. CAVALIERE F. SPARACIO F. M. TURAZZA
G. D’ALOYA M. G. PALMERI
G. SORGATO G. P. SANNA
1. Smith MC, Ghose MK, Henry AR. The clinical spectrum of renal cholesterol embolization. Am J Med 1981; 71: 174-80. 2. Ikram S, Lewis S, Bucknall C, et al. Treatment of acute myocardial infarction with anisoylated plasminogen streptokinase activator complex. Br Med J 1986, 293: 786-89. 3. Shapiro LS. Cholesterol embolisation after treatment with tissue plasminogen activator. N Engl J Med 1989; 321: 1270. 4. Pochmalicki G, Feldman L, Meunier P, Rougeot C, Weschler J, Jan F Cholesterol embolisation syndrome after thrombolytic therapy for myocardial infarction Lancet 1992; 339: 58-59. 5. Gruppo Italiano per lo Studio Della Streptokinasi nell’infarto Miocardico Acuto (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 397-402. 6. Goldman M, Thoua Y, Dhaene M, Toussaint C. Necrotising glomerulonephntis associated with cholesterol microemboli. Br MedJ 1985; 290: 205-06.
Fragmentation of pulmonary embolus SIR,-Dr Brady and colleagues’ technique (Nov 9, p 1186) opens successful, and they are to be commended. However, some points need clarification. Brady et al state that "pressure monitoring and contrast angiography are ’luxuries’". How else can we determine the success of the procedure? We do not think that we can be certain of localising and crossing the obstruction without the help of a simple initial angiogram at least.2 Specificity of diagnosis of pulmonary embolism by clinical examination, electrocardiography, and chest radiography is poorand in the absence of classic features, which were present in Brady and colleagues’ 3 patients (tablet taking, surgery, immobilisation, smoking), and without angiography can one blindly catheterise sick, shocked patients ?2,3 Use of an arm vein does not really obviate the need for a venesection since percutaneous procedure may be difficult in obese sick individuals (those most susceptible to pulmonary embolism) who have already had intravenous lines. The risk of cannulating the subclavian vein in a severely tachypnoeic patient needs to be carefully considered. Do Brady et al suggest that this method totally obviates the need for thrombolysis? What if pulmonary embolism were to recur in the acute setting? Should we repeat the same procedure or thrombolysis? Can this method be used for emboli in the main pulmonary trunk? Lastly, with respect to availability of catheters, even established centres occasionally have difficulties in emergencies. Thrombolysis seems less expensive for the general population. up many options, if it is
Department of Cardiology, SGPGIMS, PO Box 375,
K. PRASAD S. RADHAKRISHNAN
Lucknow 226 001, India
1. Brady AJB, Crake T, Oakley CM. Percutaneous fragmentation and distal dispersion of pulmonary embolus. Lancet 1991; 338: 1186-89. 2 Goldhaber SR, Braunwald E. Pulmonary embolism. In. Braunwald E, ed. Heart disease. Philadelphia: Saunders, 1988: 1577-96. 3. Bell
WR, Simon TL, DeMets DL The clinical features of submassive and massive
pulmonary emboli Am J Med 1977; 62:
355-61.
