- Email: [email protected]
Relationship between autonomic function and plasma fibrinogen, viscosity, and elements of fibrinolytic activity in diabetic nephropathy
AlH
1997; 10:4.54-461
Rehtionship Between Autonomic Em.cti.sn and Plasma l3brins en, Viscosity, and Elements of Fibrino Bytic Activity in Diabetic Nephropathy Larry A. Weinmuch, Ray E. Gleason, loarzne Keough, and John A. D’Elia
Twentv-three insulin-denendent diabetics with proteikia (3.3 g/day: rkge 0.3 to 8.P) and azotemia (creatinine clearance: 58 ml/mm, range 30 to 1121 were tested for 24-h mean arterial blood pressure; instantaneous heart rate variations to a computerized protocol involving timed ventilation, assumption of upright posture, and Valsalva maneuver; plasma fibrinogen, viscosity, fibrinolytic activity, and plasminogen activator inhibitor. These were to test the hypothesis that autonomic dysfunction is associated with altered concentrations of plasma fibrinogen, fibrinolytic activity, viscosity, and plasminogen activator inhibitor. We have previously shown the absence of a correlation between level of blood pressure, clinical and standard laboratory testing, and the results of the autonomic function testing protocol used in this study. In this group of patients, plasma fIbrinopen concentration was correlated (positively) with mean arterial pressure and (negatively1 with heart rate variation in response to the Valsalva maneuver. The greater the mean arterial pressure or the worse the Valsalva results, the higher the plasma fibrinogen concentration. In
addition, patients with one or no abnormal autonomic function tests had a mean fibrinogen of less than 400 mg/dL compared to thi group of patients with two or more abnormal tests who had a mean fibrinogen of 500 mg/dL. In patients with demonstrated parasympathetic abnormalities, postural heart rate variation testing also discerned a differential in plasma fibrinogen. Lower concentration of plasminogen activator inhibitor throughout the day, and greater fibrinolytic activity in the morning were also noted to be present in patlents with abnormal heart rate response to the Valsalva maneuver. We conclude that there are relationships between high blood pressure, autonomic function, and hemostatic factors favoring thrombogenesis that may be related by common mechanisms and treatments in the diabetic with kidney disease. Q 1997 American Journa! of Hypertension, Ltd. Am J Hypertens 1997;10:454-461
Received March 4, 1996. Accepted September 30, 1996. From the Deparhnents of Medicine, New England Deaconess Hospital (LAW, IAD), and Brigham and Women’s Hospital (REQ. Boston; Mt. Auburn Hospital (LAW), Cambridge; John Cook Rex! Unit (LAW, JK, JAD), Elliott P. @Iin Research Laboratory (JK, JAD), Joslin Diabetes Center; and Harvard Med;cal School (LAW, REG, JAD); Boston, Massachusetts.
Presented in part at the Annual National Meeting of the American Federation for Clinical Research, San Diego, California, May 5-8, 1995. Address correspondence and reprint requests to Dr. John A. D’Elia. John Cook Renal Unit, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215.
ofHyp&km~,
(9 1997 by fhe At&n @ma1 Pnbl&flE%ihJ EislviO S&m-, Inc.
Ltd.
KEY WORDS:
autonomic
Insulin-dependent function, plasma
diabetes fibrinogen.
mellitus,
08957061/9?{$17.00 Pll SOE?.5-7061(9610
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n increased rate of myocardial infarctions in the morning hours has been explained by increased sympathetic nervous system function upon arising, leading to more rapid heart rate, higher systemic blood pressure, and more rapid piatelet aggregation. Decreased parasym.. pathetic stimulation has been associated with a greater number of sudden deaths because of ventricular arrhythmias.le4 In type I diabetes mellitus parasympathetic dysfunction oiten precedes clinical neuropathic symptoms.‘.” It follows that abnormal circadian variation of blood pressure control pi‘oceeds directly from altered autonomic function in diabetics. We have recently begun to document aspects of diabetic peripheral and autonomic neuropathy to correlate these with standard risk factors for cardiovascular complications. At baseline there appears to be no statistically signiiicant relationship between standard risk factors for macrovascular disease and the severity of diabetic autonomic dysfunction, even when age, duration of diabetes, and level of renal dysfunction are taken into account.’ To date there havt been no reports evaluating relationships between dysfunctions observed in the autonomic nervous system oi diabetic? and a fv!! panel of fibrinolytic i procoagulant blood tests now available on a research basis. The interface between atherosclerotic plaque disruption, concentrations of lipids; generation or lysis of fibrin, and the activity of the sympathoadrenal system during early morning hours has been the focus of much cli.dcal research. The majority of studies have focused on large groups of patienta at low risk for cardiovascular events, %>r on postmortem data. The study of a group of patients at high risk for such events may provide useful information regarding trigger mechanisms. The variable timing of atherosclerotic events fmyocardial infarction, sudden death, and stroke) has been the subject of theories regarding the mechanisms that trigger them.“,* There appears to be a circadian distribution of ischemic events, along with some of the markers of risk suggesting :eiationships between autonomic nervous syster. function and variations in blood pressure, heart rate, and blood markers for coagulation / tibrinolysis. In vitro and in vivo testing has suggested that the morning peak in myorardial events may be blunted by b-adrenergic b1ockade.‘“-‘2 The blunting of heart rate increase in the morning and of pressor response upon awakening have usua!!y but not always been sufficient to explain the ben:ficial effect of P-adrenergic b!ocbde.“.‘4 & the risk of plaque rupture because Blockers ” decrease flexability and tensile strength of the fibrous cap are increased when heart rate is diminished.‘5 Once microangiopathy is present (renal), a large percentage of diabetics will have coronary arterial disease that is asymptomatic.‘“‘
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HYPOTHESIS Accelerated atherosclerosis with an increased incidence of cardiovascular events is because of increased concentrations of procoaguldnts, of cholesterol related lipids, and perhaps of other blood constituents (advanced glycosylated end-products, homocysteine) that may increase b1oc.l viscosity or change blood rheology. Conditions in which atherosclerosis and cardiovascular event rate have been shcwn to be increased are often associated with autonomic dysfunction (sudden death after myocardial infarction). We postulate that there is an interrelationship between altered autonomic control of cardiovascular tone fparasympathetic defect ii sym,pathetic dominance) and the concentration of some blood constituents responsible for increased cardiovascular events in diabetics with nephrc+ syndrome. MATERlAG
AND
METHODS
We studied 2? insulin-dependent juvenile onset diabetics (14 men, 7 w,omen) between the ages of 21 and 65 years (mean age 39.5 years) who had: 1. onset of insulin dependence before the age of 35; 2. albuminuria > 0.i g,.‘day 1~1 Pi&e;iiui;a i 0.3 gm/day on two separate 24-h urine collections; 3. creatinine clearance of more than 30 mL/min; 4. ability to be followed for a period of 18 months at the Jos!in Clinic; 5. wiliingness to accrpt randomization; and 6. absence of pregnancy or an acute or chronic illness that would render testing uninterpretable (drug dependence, active hepatitis, recent myocardial infarction, or stroke, etc.). These diabetics were pros~pectively and consecutively enrolled as part of a multicenter study involving seven institutions in the United States. Using an %-month follow-up period, comparisons of a regimen including 3 to 4 injections of insulin per day were made with a similar regimen in which a weekly infusion of intravenous insulin was added.” Enrollment in this study required a workup of several weeks to collect the required urine samples and confirm the adequacy of control of diabetes mellitus and blood pressure. To have interpretable data, we attempted to avoid use of any drug that was, at the time, known to exert major effects on the autonomic nervous system that would interfere with either the patient’s sensatiou of hypoglycemic reactions or with the testing of cardiac autonomic function. The patients at the Joslin Clinic underwent cardiac autonomic function tests that included computerized measurements of heart rate variation (NDX, q Med Inc., Lawrence Harbor, NJ) during a period of timed ventilation, standardized Valsalva maneuver (expiration against a 40 mm Hg mercury column), recumbent to a standing position change, and 24-n ambu!atoiy blood pressure measurements (90207 SpaceLabs, Redmond, WA). In
456 WEINRAUCH
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addition to the autonomic studies, each patient t*nderwent a standardized phlebotomy at 8 AM and 4 PM at baseline and at 3-month intervals for plasma fibrinogen, plasma viscosity, plasminogen activator inhibitor antigen, factor 7, von Willebrand factor, fibrinolytic activity, and aggregation response of,platelets to ADP, epinephrine, and collagenase. For this study, to avoid questions of mixing normals into our abnormal group, we hav& strictly dehned heart rate variations (HRV ) as abnormal only if timed ventilation caused < 10% variation (heart rate ratio < 1.09), Valsalva response resulted in < 20% variation (heart rate ratio < 1.19), or if postural change < 5% (heart rate ratio < 1.04) was observed. These numbers are clearly abnormal for all ages included in this study. The day/night blood pressure ratio was considered to be abnormal if there was < 5% variation. For purposes of this study we defined day blood pressures as those occurring in the 16 h from 6 AM to midnight, and night blood pressures as those recorded in the 8 h from midnight to 8 AM. To further classify autonomic function results we defined several different classifications of autonomic dysfunction: ie, by a) individual test abnormalities; b) number of tests abnormal (0 to 1 v 3 to 4); c) selective sympathetic testing in patients whose parasympathetic tests were aonormal (n = 17) by the criteria so stated; and d) creating groups of parasympathetic test dysfunction (timed ventilation IIRV or Valsalva HRV abnormalities) versus sympathetic dysfunction (postural HRV or day/night mean arteria! pressure variation abnormalities). Hemoglobin Ale (high pressure liquid chromatography, Nichols Institute, Van Nuys, CA) was considered high if > 9.0% for purposes of this study. Frequency data were tested for significance using x2 for independence following the implementation of Yates correction for continuity. In cases where expetted frequencies < 5, Fisher’s exact test was used. For quantitative variables, unpaired t tests were used to test for significance between the means of various classification variables (gender, normal-abnormal stratification of cardiac autonomic function), Becadse,, in some cases, stratificaiion groups differed sign& cantly in mean age,‘the same variables were compared using analyses of covariancc with age as the covariant. Interrelationships among the variables were tested for significance using Pearson’s Product Moment correlations. All data are expressed as frequencies or means with standard deviations as a measure of dispersion. An (Y = 0.05 was considered statistically significant. All analyses were carried out using SAS software (SAS Institute, Gary, NC ) .= RESULTS Demographics This group of 23 patients entered the study with a 24-h mean arterial pressure (MAP) of 99.7
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mm Hg (daytime MAP 100.4 mm Hg, nighttime MAP 98.1 mm Hg). Glycohemoglobin Ale mean was 9.5% (range 6.4 to 11.8), hematocrit mean 40% (range 31 to 53), serum albumin mean 3.7 g/dL (range 3 0 to 4.5), serum cholesterol mean 232 mg idL (range 122 to 402), HDL cholesterol 51 mg / dL (range 32 to 82 ), triglyceride 151 mg/ dL (range 44 to 489), serum uric acid 5.8 mg / dL (rmge 4.6 to 8.4), serum creatinine 1.8 mg / dL (range 1.0 to 3.6), creatinine clearance 58 mL/min (range 30 to 112), and urine albumin 3.3 g / 24 h (range 0.3 to 8.9). There were no significant rorrelations between any of the above and any of the four autonomic function tests described individually cr by groupings. Coagulation Tests Mean plJsma fibrinogen was 424 mg / dL (range 238 to 711), mean plasma viscosity 1.24 centipoise (range 1.10 to 1.43), fibi-inolytlc activity was 166.3 mm’ (range 60 to 264), and pksminogen activator inhibitor was 7.41 ng /ml (range 2.4 to 30.9). A significant positive correlation between plasma iibrinogen and mean arterial pressure for 24 h was noted (Figure 1). Plasma viscosity had a significant positive correlation with both glycohemoglobin and plasma fibrinogen, although there appeared to be no statistically significant relationship between glycohemoglobin and serum fibrinogen. In Figure 2 there is a significant negative correlation between plasma fibrinogen concentration and heart rate variation during the Valsalva maneuver (ie, the more abnormal the Valsalva result, the higher the plasma fibrinogen). In both figures plasma fibrinogen levels (220 to 780 mg / dL) were distributed above 300 Isoa 8 5 :
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test results significantly AU and PM 1 abnormal dL,
IN DIABETIC
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(3 to 4 tests abnormal) have a statistically higher plasma fibrinogen level in both the than their counterparts with normal (0 to resuh) autcnomic test results (AM 511 mg /
363; PM 489, 373 )
In patients with parasympathetic dysfunction, sympathetic testing included both assumption of upright posture HRV and day/night MAP variation., In Figure 5 plasma fibrinogen concentrations were similar throughout the day in both the abnormal and normal postural HRV groups. Plasma fibrinogen concentrations were higher for the abnormal postural HRV group (P < .05 for the PM ody) compared to the normal postural HRV group. Day/night MAP variation again did not correlate with plasma fibrinogen level. For the pqoses of comparison, creating groups of pure parasympathetic versus pure sympathetic dysfunction led to groups that were too small to make meaningful comparisons. D:SCUSSION
mg/dL in 12 of the 14 study patients. No other significant positive or negative correlation between heart rate variation and either plasma fibrinogen, viscosity, elements of fibrinolytic activity, or mean arterial pressure were noted. Autonomic Function Testing Individual test abnormalities were noted in timed respiratory heart rate variation (HRV) in 17/21 patients, assumption of upright posture HRV in 7/20, Valsalva maneuver HRV in 9 / 15, and in day/night MAP in 14/21. Figure 3 relates pIasma fibrinogen concentrations (panel A), plasma fibrinolytic activity (panel B), and plasma plasminogen activator inhibitor concentration (panel C) to Valsalva HRV (normal u abnormal). In panel A, elevated plasma fibrinogen concentrations were not different for individuals with normal Valsalva HRV in AM versus PM or for individuals with abnormal Valsalva HRV in AM versus PM. Plasma fibrinogen concentrations were higher for individuals wrth abnormal Valsalva HRV U’ < .05 for both AM and I’M). In panel B, mean plasma fibrinolytic activity was within the normal range for individuals with both normal and abnormal Vaisalva HRV. In both normal and abnormal Valsalva HRV plasma fibrinolytic activities were higher in the PM than in the AM. Plasma fibrinolytic activity was significantly higher in the AM for individuals with abnormal Valsalva HRV compared to normal Valsalva HRV. In panel C, plasma plasminogen activator inhibitor concentrations for individuals with abnormal Valsalva HRV ‘:gere significantly lower than those for individuals with normal Valsalva HRV ( P < .05 for both ~kl and PM ) . Figure 4 demonstrates that patients with abnormal autonomic
Treated hypertensive diabetics in this study had a high prevalence of abnormal autonomic function tests.’ There appeared to be a relationship between asymptomctic autonomic dysfunction and the conczntrations of intravascular bload constituents thought to be related to thromboembolic events. We observed a correiation between abnormal neart rate variation test results, and plasma fibrinogen concentration. It is unlikely that this is a result merely of hemoconcentration or vasosonstrictr; tone induced by the unopposed sympathetic system. Individuals with nephrotic syndrome from any cause may be expected to have ar increased concentration of plasma fibrinogen, but, to our knowledge, there have been no studies correlating the degree of both hyperfibrinogenemia and increased blood viscositv with autonomic nervous control. The mechanism for hyperlipidemia and hypert%rinogenemia in nephrotic syndrome may hinge on hepatic synthesis of multiple proteins (albumin, fibrinogen, and lipoprotein f in response to hypoalbuminemia with hypoviscosity. We have no information testing the possibility that the autonomic nervous system contributes directly to the mechanism responsible for hyperlipidemia / hyperfibrinogeremia in the nephrotic syndrome. We hypothesized that diabetics with both severe autonomic dysfunction and significantly elevated plasma fibrinogen concentrations were at the highest risk for thromboembolic events when compared with individuals demonstrating only one of these abnormalities. Study patients who were capable of maintaining a Valsalva maneuver with relatively normal results had lower (morning and afternoon) plasma fibrinogen levels, and higher (morning and afternoon) plasminogen activator inhibitor levels than did their counter-
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FIGURE 3. Relationship of Valsalva mam?uver heart rate variation results (normal zlewusabnormal) to plasma fibrinogen roncentration, fibrintfytic activity, and plasminogen activafor inhibitor concentrations during morning and afternoon. Panel A: Significant diflerence in plasma fibrinogen concentration between wnnal and abnormal Valsalva result groups in both morning and afternoon hours fP < .051. Panel B: Significance difircnce in plasma fibrinolytic activity between normal and abnormal Valsalva result groups noted in the morning hours on!y IP < ,051. Panel C: Significant difference in piasma plasminogen activator inhibitor concentration between normal and abnormal Vakafvu result groups in both morning and afternoon hours 0’ < .05).
parts whose Valsalva results were markedly abnormal. Patients whose Valsalva HRV results were markedly abnormal had significantly increased plasma fibrinogen and increased fitirinolytic activity with decreased concentration of plasminogen activator inhibitor. In this patient cohort there was a relationship between an intact heart rate response to Valsalva maneuver and normal control of intrinsic prothrombotic
and thrombolytic activity, as well as a relationship between loss of heart rate variation to the Valsalva maneuver and abnormal prothrombotic and tbrombolytic activity. It is possible that patients who do not vary their heart rates with the increase of intrathoracic pressure engendered by the Valsalva; maneuver are demonstrating a highly stimulated q&pathetic system. These patients may be at relatively higher risks
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i 1
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ADllOl7IlII
Autonomic
Function
FIGURE 4. Relationship of parasympathetic and sympathetic dysfunction (HRV, day/night MAD) to plasmr fibrinogen concentration. Significant difference for normal UPrsus abnormal tesf results in both morning and afternoon hours (P c ,051.
for cardiovascular events than those patients whose sympsthetic tone is less active, and may benefit from efforts to reduce sympathetic stimulation. Follow-up studies will be necessary to elucidate the cardiovascular thromboembolic event rates in these subgroups. Mechanisms for diabetic neuropathy are thought to involve &hernia resulting from low flow in the vasa vas.ora because of a) increased plasma viscosity; b) increased blood clotting; c) impaired red blood cell ar.d platelet flexibility leading to slow capi!lary flowz3; d) hypoxia in tissues that require high flow in capillaries because of an impaired release of oxygen from glycosylated hemoglobin; e) capillary injury at points of bindi.qg of advanced glycosylated end-products to their receptors leading to platelet adhesio,l’*; and f) increased release of endotl.di~r and von Willebrand factor from endothelium in diabetics with small :Fessel complications.“‘ib The severity of vessel wall injury and the prothrombotic milieu within both the vessel and the circulating plasma dekermine the rapidity and severity of thrombosis.*’ Once the vessel has been injured the potent vasoconstrictar endothelin is released. The presence of thrombin further accelerates the release of endothelin, which ind,uces chemotaxis, promotes replication of fibroblasts, accelerates cont&tion of collagen fibroblasts,’ and acts as a stimulator of microvascular platelet thrombi.= Thus e-tdothelin reinforces both the unopposed sympathetic vasoconstrictor risk factor in diabetics, and the atherosclerotic thrombotic process
IN DlABETlC
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resulting from hyperfibrinogcncmia. 1~ the hypertcnsive diabetic, loss of parasympathetic innervation leads to vasoconstriction and platelet aggregation. The hyperlipidemia assnci lted with pvoteinuria contributes to plaque formation. Plaque rupture is most likely potentiated by unopposed sympathetic nerve stimulation. Beta blocker therapy may be justified despite the risks of hyp’g u 1y cemia to prevent plaque rupture. A new antagonist of endothelin-A receptor will be of immediate use when available.” We have observed relationships between injury to the autonomic nervous system and changes in the common pathway of blood coagulation indicating a clustering of risk factors in the azotemic diabetic. Specifically, higher plasma fibrinogen levels were distributed among the group of patients whose VaisdJa tests were more abnormal. Improved glucose control has her n shown to improve elevatnd fibrinogen levels over sever-1 weeks of intensive insulin therapy.-H’ Increased p&ma fiblnogen contributes to more vigorous platelet aggregation. Increased plasma fibrinogen is the main cause of increased plasma viscosity. Thus, improved glucose control with prevention of diabetic neuropathy” and lowering of elevated fibrinogen levels may diminish small blood vessel occlusions. Although elevated levels of plasminogen activator inhibitor in the plasma are associated with an increased risk of recurrent myocardisl infarction,” $hele has been no correlation of risk for initial or subsequent
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460 #VEINRAUCHET AL
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heart attack with a test of global fibrino:ytic activity.” Surprisingly the plasminogen activator inhibitor Ieve!; -were not elevated in our type I diabetic patients with high plasma fibrinogens, To test the predictive accuracy of plasma fibrinogen versus plasminogen activa tor inhibitor, future prospective studies must con-
trol for nolmai versus abnormal autonomic function. We suggest that correlations between clinical events and either the coag:+lation sys;cm or the autonomic system
but not all three
are potentially
flawed.
phropathy-a cross-sectionalanalysis m the presymptomatic phase. Am J Hypertens 1995;8:782-789.
8.
Muller JE, Tofler GH: Circadian variation and cardiovascular disease. N Engl J Msd 1991:325:1038-1039. 9. Tofler GH, Gebara OCE, Mittleman MA, et al, for the CPI Investigators: Morning peak in ventricular tachyarrhythmias detected by time of implantable cardioverter/defibrillator therapy. Circulation 1995;92: 1203-1208. 10.
CONCLUSIONS In hypertensive
of proteinuria,
after
the onset
we observed a relationship
diabetic
nephropathy
between
abnormalities in autonomic function and hemostatic factors favoring thrombogenesis. Because it appears that there may be a relationship between relative sympathetic dominance, vascular tone and the homeostasis of the coagulation cascade, we believe that auto-
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Bernardi L, Ricordi L, Lazzari I’, et al: Impaired circadian modulation of sympathovagal activity in diabetes: a possible explanation for altered temporal onset of cardiovascular disease. Circulation 1992;86:1443-1452. Dougherty CM, Burr RI: Comparison of heart rate variability in survivors and non survivors of sudden cardiac arrest. Am J Cardiol 1992;70:441-448.
of any prospective studies which relate the presence of coronary arterial disease to both prothrombotic and autonomic dysfunction. Conclusions regarding the
Kleiger RE, Miller Jl’, Bigger JT, Moss AJ, and the Multi,.enter Post-Infarction ResearchCroup: Decreased herct r:;e variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987;593256-262. 13. Peters RW, Muiler JE, Goldstein S, et al: Propranolol and the morning increase in frequency of sudde‘~ cardiac death (BHAT study). Am J Cardioll989;63:151B1520. 14. Middlekauff HR. Sontz EM: Morning sympathetic nerve activity is not increased in humans: implications for mechanisms underlying the circadian pattern of cardiac tisk. Circulation 1995;91:2549-2555. 15. Maclsaac Al, Thomas JD, Top01 EJ: Toward the quiescent coronary plaque. J Am Co11 Cardiol 1993;22:12281241.
importance
16.
Muiler JE. Tofler GH, Verrier RL: Sympathetic activity as the cause of the morning increase in cardiac events a likely culprit but the evidence remains circumstantial. Circulation 1995;91:2508-2509.
17.
Weinrauch LA, D’Elia JA, Healy RE, et al: Asympiomatic coronary artery disease: assessment in diabetics evaluated for renal transplantation. Circulation 1978; S&1184-1190.
nomic function testing should be extended to a larger population of diabetics. The appeartince of a sympathetic dominant profile may be an indication for the use of beta blockers in these hypertensive insulin dependent diabetics despite the risk of hypoglycemic reactions.
The use of calcium
channel
blockers
that do
not increase the baseline tachycardia in these patients may be justified on clinical grounds. We are not aware
of these findings are not justified until events are correlated with both procoagulant measures and autonomic function tests.
12.
cardiovascular
REFERENCES
1. Sheps SC;, Pickering
TG, White WB, et al: ACC Position Statement. Ambulatory blood pressure monitoring. j Am Co11 Cardiol 1994;23:1511-1513. 2. Dreifus LS, Agarwal JB, Botvinick EH, et al: ACC PO+ tion Statement. Heart rate variability for risk stratification of life threatening arrhythmias. J Am Co11 Cardiol 1993;22:948-950. 3. Vaishanav S, Stevenson R, Marchant B, et al: Relation between heart rate variability early after myocardial infarction and long-term mortality. Am J Cardioll994; 73:653-657. 4. van Kavenswaaij CMA. Kollee LAA, Hopman JCW, et al: Heart rate variability. Ann Intern Med 1993;118: 425-447. 5. Bellavere F, Bosello G, Cardone C, et al: Evidence of early impairment of parasympathetic reflexes u1 insulin dependent diabetics without autonomic symptoms. Diabete et Metabolisme 1985;11:152-156. 6. Ewing 0, Campbell I, Clarke B: Heart rate changes in diabetes mellitus. Lancet 1981;i:183-184. 7. Weinrauch L, Kennedy F, Gleason RE, et al: Autonomic function in type I diabetes mellitus comp!icated by ne-
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Manske CL, Thomas W, Wang Y, Wilson RF: Screening ? diabetic transplant candidates for coronary artery dis; ease: Identification of a low risk subgroup. Kidney Int 1993;44:617-621. 19. Braun WE, Phillips DF, Vidt DG, et al: Coronary artery disease in 100 diabetics with end-stage renal failure. Transplant Proc 1984;16:603-607. 20.
Philipson JD, Carpenter BJ, Itzkoff J, et al: Evaluation of cardiovascular risk for renal transplantation in diabetic patients. Am J Med 1986;81:630-634.
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Aoki TT, Beirbarka M, Okimura intermittent intravenous insu!in abetes. Lancet 1993;432:515-518.
22.
QAS Institute Inc.: SAS User’s Guide: Statistics, Version 5 ed. Cary, NC, SAS Institute Inc., 1985, pp 529-557. Winocur PD, Watala C, Kinglough-Rathbone RL: Membrane fluidity is related to the extent of glycation of proteins, but not to alterations in the cholesterol to phospholipid molar ration in isolated platelet mem-
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MC, et al: Long-term therapy and type 1 di-
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branes from diabetic and control subjects. Thromb Hemost 1992;67:!?67-571. Schmidt AM, Yan SD, Stem DM: The dark side of glucose. Nature Med 1595; i:icnjL-1004. Morise T, Takeuchi Y, Kawano M, et al: Increased plasma levels of immunoreactive endothelin and van W&brand factor in NIDDM patients. Diabetes Care lY95;8:87-89. Lin J, Dub E, Jiang Z: Expression of preproendothelin1 mRNA in streptozotocin-induced diabetic rats (abst). Diabetes 1996;45:48A. Ambrose JA, Weinrauch M: Thrombosis in ischemic heart disease. Arch Intern Med 1996;156:1382-1394. Verghese M, Hasdai D, Lerman A: The role of endothelin in coronary atherosclerosis. Mayo Clinic Proceedings 19%;71:769-777
PRDCOACULANTS
29.
30. 31,
IN DiARETIC
NEPHROPATHY
461
Bird JE, Moreland S, Wnldron TL, I’ewrll JR: Antihypertensive effects of a novel endothelin-A receptor antagomst in rats. Hypertension lY95;25:!191-1195 Jones RL. Peterson CM: Reduced fibrinogen survival in diabetes mrllitus. j Clin invest 1979;63:485-493. The Diabetes Control and Complicatims Research Croup: The effects of intensive treatment on the dcveiopment and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;342:515-518.
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1997; 10:4.54-461
Rehtionship Between Autonomic Em.cti.sn and Plasma l3brins en, Viscosity, and Elements of Fibrino Bytic Activity in Diabetic Nephropathy Larry A. Weinmuch, Ray E. Gleason, loarzne Keough, and John A. D’Elia
Twentv-three insulin-denendent diabetics with proteikia (3.3 g/day: rkge 0.3 to 8.P) and azotemia (creatinine clearance: 58 ml/mm, range 30 to 1121 were tested for 24-h mean arterial blood pressure; instantaneous heart rate variations to a computerized protocol involving timed ventilation, assumption of upright posture, and Valsalva maneuver; plasma fibrinogen, viscosity, fibrinolytic activity, and plasminogen activator inhibitor. These were to test the hypothesis that autonomic dysfunction is associated with altered concentrations of plasma fibrinogen, fibrinolytic activity, viscosity, and plasminogen activator inhibitor. We have previously shown the absence of a correlation between level of blood pressure, clinical and standard laboratory testing, and the results of the autonomic function testing protocol used in this study. In this group of patients, plasma fIbrinopen concentration was correlated (positively) with mean arterial pressure and (negatively1 with heart rate variation in response to the Valsalva maneuver. The greater the mean arterial pressure or the worse the Valsalva results, the higher the plasma fibrinogen concentration. In
addition, patients with one or no abnormal autonomic function tests had a mean fibrinogen of less than 400 mg/dL compared to thi group of patients with two or more abnormal tests who had a mean fibrinogen of 500 mg/dL. In patients with demonstrated parasympathetic abnormalities, postural heart rate variation testing also discerned a differential in plasma fibrinogen. Lower concentration of plasminogen activator inhibitor throughout the day, and greater fibrinolytic activity in the morning were also noted to be present in patlents with abnormal heart rate response to the Valsalva maneuver. We conclude that there are relationships between high blood pressure, autonomic function, and hemostatic factors favoring thrombogenesis that may be related by common mechanisms and treatments in the diabetic with kidney disease. Q 1997 American Journa! of Hypertension, Ltd. Am J Hypertens 1997;10:454-461
Received March 4, 1996. Accepted September 30, 1996. From the Deparhnents of Medicine, New England Deaconess Hospital (LAW, IAD), and Brigham and Women’s Hospital (REQ. Boston; Mt. Auburn Hospital (LAW), Cambridge; John Cook Rex! Unit (LAW, JK, JAD), Elliott P. @Iin Research Laboratory (JK, JAD), Joslin Diabetes Center; and Harvard Med;cal School (LAW, REG, JAD); Boston, Massachusetts.
Presented in part at the Annual National Meeting of the American Federation for Clinical Research, San Diego, California, May 5-8, 1995. Address correspondence and reprint requests to Dr. John A. D’Elia. John Cook Renal Unit, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215.
ofHyp&km~,
(9 1997 by fhe At&n @ma1 Pnbl&flE%ihJ EislviO S&m-, Inc.
Ltd.
KEY WORDS:
autonomic
Insulin-dependent function, plasma
diabetes fibrinogen.
mellitus,
08957061/9?{$17.00 Pll SOE?.5-7061(9610
AJH-APRIL
1997~VOL. Ill, NO. 4. PAR7 1
n increased rate of myocardial infarctions in the morning hours has been explained by increased sympathetic nervous system function upon arising, leading to more rapid heart rate, higher systemic blood pressure, and more rapid piatelet aggregation. Decreased parasym.. pathetic stimulation has been associated with a greater number of sudden deaths because of ventricular arrhythmias.le4 In type I diabetes mellitus parasympathetic dysfunction oiten precedes clinical neuropathic symptoms.‘.” It follows that abnormal circadian variation of blood pressure control pi‘oceeds directly from altered autonomic function in diabetics. We have recently begun to document aspects of diabetic peripheral and autonomic neuropathy to correlate these with standard risk factors for cardiovascular complications. At baseline there appears to be no statistically signiiicant relationship between standard risk factors for macrovascular disease and the severity of diabetic autonomic dysfunction, even when age, duration of diabetes, and level of renal dysfunction are taken into account.’ To date there havt been no reports evaluating relationships between dysfunctions observed in the autonomic nervous system oi diabetic? and a fv!! panel of fibrinolytic i procoagulant blood tests now available on a research basis. The interface between atherosclerotic plaque disruption, concentrations of lipids; generation or lysis of fibrin, and the activity of the sympathoadrenal system during early morning hours has been the focus of much cli.dcal research. The majority of studies have focused on large groups of patienta at low risk for cardiovascular events, %>r on postmortem data. The study of a group of patients at high risk for such events may provide useful information regarding trigger mechanisms. The variable timing of atherosclerotic events fmyocardial infarction, sudden death, and stroke) has been the subject of theories regarding the mechanisms that trigger them.“,* There appears to be a circadian distribution of ischemic events, along with some of the markers of risk suggesting :eiationships between autonomic nervous syster. function and variations in blood pressure, heart rate, and blood markers for coagulation / tibrinolysis. In vitro and in vivo testing has suggested that the morning peak in myorardial events may be blunted by b-adrenergic b1ockade.‘“-‘2 The blunting of heart rate increase in the morning and of pressor response upon awakening have usua!!y but not always been sufficient to explain the ben:ficial effect of P-adrenergic b!ocbde.“.‘4 & the risk of plaque rupture because Blockers ” decrease flexability and tensile strength of the fibrous cap are increased when heart rate is diminished.‘5 Once microangiopathy is present (renal), a large percentage of diabetics will have coronary arterial disease that is asymptomatic.‘“‘
PROCOAGULANTS
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HYPOTHESIS Accelerated atherosclerosis with an increased incidence of cardiovascular events is because of increased concentrations of procoaguldnts, of cholesterol related lipids, and perhaps of other blood constituents (advanced glycosylated end-products, homocysteine) that may increase b1oc.l viscosity or change blood rheology. Conditions in which atherosclerosis and cardiovascular event rate have been shcwn to be increased are often associated with autonomic dysfunction (sudden death after myocardial infarction). We postulate that there is an interrelationship between altered autonomic control of cardiovascular tone fparasympathetic defect ii sym,pathetic dominance) and the concentration of some blood constituents responsible for increased cardiovascular events in diabetics with nephrc+ syndrome. MATERlAG
AND
METHODS
We studied 2? insulin-dependent juvenile onset diabetics (14 men, 7 w,omen) between the ages of 21 and 65 years (mean age 39.5 years) who had: 1. onset of insulin dependence before the age of 35; 2. albuminuria > 0.i g,.‘day 1~1 Pi&e;iiui;a i 0.3 gm/day on two separate 24-h urine collections; 3. creatinine clearance of more than 30 mL/min; 4. ability to be followed for a period of 18 months at the Jos!in Clinic; 5. wiliingness to accrpt randomization; and 6. absence of pregnancy or an acute or chronic illness that would render testing uninterpretable (drug dependence, active hepatitis, recent myocardial infarction, or stroke, etc.). These diabetics were pros~pectively and consecutively enrolled as part of a multicenter study involving seven institutions in the United States. Using an %-month follow-up period, comparisons of a regimen including 3 to 4 injections of insulin per day were made with a similar regimen in which a weekly infusion of intravenous insulin was added.” Enrollment in this study required a workup of several weeks to collect the required urine samples and confirm the adequacy of control of diabetes mellitus and blood pressure. To have interpretable data, we attempted to avoid use of any drug that was, at the time, known to exert major effects on the autonomic nervous system that would interfere with either the patient’s sensatiou of hypoglycemic reactions or with the testing of cardiac autonomic function. The patients at the Joslin Clinic underwent cardiac autonomic function tests that included computerized measurements of heart rate variation (NDX, q Med Inc., Lawrence Harbor, NJ) during a period of timed ventilation, standardized Valsalva maneuver (expiration against a 40 mm Hg mercury column), recumbent to a standing position change, and 24-n ambu!atoiy blood pressure measurements (90207 SpaceLabs, Redmond, WA). In
456 WEINRAUCH
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addition to the autonomic studies, each patient t*nderwent a standardized phlebotomy at 8 AM and 4 PM at baseline and at 3-month intervals for plasma fibrinogen, plasma viscosity, plasminogen activator inhibitor antigen, factor 7, von Willebrand factor, fibrinolytic activity, and aggregation response of,platelets to ADP, epinephrine, and collagenase. For this study, to avoid questions of mixing normals into our abnormal group, we hav& strictly dehned heart rate variations (HRV ) as abnormal only if timed ventilation caused < 10% variation (heart rate ratio < 1.09), Valsalva response resulted in < 20% variation (heart rate ratio < 1.19), or if postural change < 5% (heart rate ratio < 1.04) was observed. These numbers are clearly abnormal for all ages included in this study. The day/night blood pressure ratio was considered to be abnormal if there was < 5% variation. For purposes of this study we defined day blood pressures as those occurring in the 16 h from 6 AM to midnight, and night blood pressures as those recorded in the 8 h from midnight to 8 AM. To further classify autonomic function results we defined several different classifications of autonomic dysfunction: ie, by a) individual test abnormalities; b) number of tests abnormal (0 to 1 v 3 to 4); c) selective sympathetic testing in patients whose parasympathetic tests were aonormal (n = 17) by the criteria so stated; and d) creating groups of parasympathetic test dysfunction (timed ventilation IIRV or Valsalva HRV abnormalities) versus sympathetic dysfunction (postural HRV or day/night mean arteria! pressure variation abnormalities). Hemoglobin Ale (high pressure liquid chromatography, Nichols Institute, Van Nuys, CA) was considered high if > 9.0% for purposes of this study. Frequency data were tested for significance using x2 for independence following the implementation of Yates correction for continuity. In cases where expetted frequencies < 5, Fisher’s exact test was used. For quantitative variables, unpaired t tests were used to test for significance between the means of various classification variables (gender, normal-abnormal stratification of cardiac autonomic function), Becadse,, in some cases, stratificaiion groups differed sign& cantly in mean age,‘the same variables were compared using analyses of covariancc with age as the covariant. Interrelationships among the variables were tested for significance using Pearson’s Product Moment correlations. All data are expressed as frequencies or means with standard deviations as a measure of dispersion. An (Y = 0.05 was considered statistically significant. All analyses were carried out using SAS software (SAS Institute, Gary, NC ) .= RESULTS Demographics This group of 23 patients entered the study with a 24-h mean arterial pressure (MAP) of 99.7
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mm Hg (daytime MAP 100.4 mm Hg, nighttime MAP 98.1 mm Hg). Glycohemoglobin Ale mean was 9.5% (range 6.4 to 11.8), hematocrit mean 40% (range 31 to 53), serum albumin mean 3.7 g/dL (range 3 0 to 4.5), serum cholesterol mean 232 mg idL (range 122 to 402), HDL cholesterol 51 mg / dL (range 32 to 82 ), triglyceride 151 mg/ dL (range 44 to 489), serum uric acid 5.8 mg / dL (rmge 4.6 to 8.4), serum creatinine 1.8 mg / dL (range 1.0 to 3.6), creatinine clearance 58 mL/min (range 30 to 112), and urine albumin 3.3 g / 24 h (range 0.3 to 8.9). There were no significant rorrelations between any of the above and any of the four autonomic function tests described individually cr by groupings. Coagulation Tests Mean plJsma fibrinogen was 424 mg / dL (range 238 to 711), mean plasma viscosity 1.24 centipoise (range 1.10 to 1.43), fibi-inolytlc activity was 166.3 mm’ (range 60 to 264), and pksminogen activator inhibitor was 7.41 ng /ml (range 2.4 to 30.9). A significant positive correlation between plasma iibrinogen and mean arterial pressure for 24 h was noted (Figure 1). Plasma viscosity had a significant positive correlation with both glycohemoglobin and plasma fibrinogen, although there appeared to be no statistically significant relationship between glycohemoglobin and serum fibrinogen. In Figure 2 there is a significant negative correlation between plasma fibrinogen concentration and heart rate variation during the Valsalva maneuver (ie, the more abnormal the Valsalva result, the higher the plasma fibrinogen). In both figures plasma fibrinogen levels (220 to 780 mg / dL) were distributed above 300 Isoa 8 5 :
‘40 130-
4
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test results significantly AU and PM 1 abnormal dL,
IN DIABETIC
NEPHROPATHY
457
(3 to 4 tests abnormal) have a statistically higher plasma fibrinogen level in both the than their counterparts with normal (0 to resuh) autcnomic test results (AM 511 mg /
363; PM 489, 373 )
In patients with parasympathetic dysfunction, sympathetic testing included both assumption of upright posture HRV and day/night MAP variation., In Figure 5 plasma fibrinogen concentrations were similar throughout the day in both the abnormal and normal postural HRV groups. Plasma fibrinogen concentrations were higher for the abnormal postural HRV group (P < .05 for the PM ody) compared to the normal postural HRV group. Day/night MAP variation again did not correlate with plasma fibrinogen level. For the pqoses of comparison, creating groups of pure parasympathetic versus pure sympathetic dysfunction led to groups that were too small to make meaningful comparisons. D:SCUSSION
mg/dL in 12 of the 14 study patients. No other significant positive or negative correlation between heart rate variation and either plasma fibrinogen, viscosity, elements of fibrinolytic activity, or mean arterial pressure were noted. Autonomic Function Testing Individual test abnormalities were noted in timed respiratory heart rate variation (HRV) in 17/21 patients, assumption of upright posture HRV in 7/20, Valsalva maneuver HRV in 9 / 15, and in day/night MAP in 14/21. Figure 3 relates pIasma fibrinogen concentrations (panel A), plasma fibrinolytic activity (panel B), and plasma plasminogen activator inhibitor concentration (panel C) to Valsalva HRV (normal u abnormal). In panel A, elevated plasma fibrinogen concentrations were not different for individuals with normal Valsalva HRV in AM versus PM or for individuals with abnormal Valsalva HRV in AM versus PM. Plasma fibrinogen concentrations were higher for individuals wrth abnormal Valsalva HRV U’ < .05 for both AM and I’M). In panel B, mean plasma fibrinolytic activity was within the normal range for individuals with both normal and abnormal Vaisalva HRV. In both normal and abnormal Valsalva HRV plasma fibrinolytic activities were higher in the PM than in the AM. Plasma fibrinolytic activity was significantly higher in the AM for individuals with abnormal Valsalva HRV compared to normal Valsalva HRV. In panel C, plasma plasminogen activator inhibitor concentrations for individuals with abnormal Valsalva HRV ‘:gere significantly lower than those for individuals with normal Valsalva HRV ( P < .05 for both ~kl and PM ) . Figure 4 demonstrates that patients with abnormal autonomic
Treated hypertensive diabetics in this study had a high prevalence of abnormal autonomic function tests.’ There appeared to be a relationship between asymptomctic autonomic dysfunction and the conczntrations of intravascular bload constituents thought to be related to thromboembolic events. We observed a correiation between abnormal neart rate variation test results, and plasma fibrinogen concentration. It is unlikely that this is a result merely of hemoconcentration or vasosonstrictr; tone induced by the unopposed sympathetic system. Individuals with nephrotic syndrome from any cause may be expected to have ar increased concentration of plasma fibrinogen, but, to our knowledge, there have been no studies correlating the degree of both hyperfibrinogenemia and increased blood viscositv with autonomic nervous control. The mechanism for hyperlipidemia and hypert%rinogenemia in nephrotic syndrome may hinge on hepatic synthesis of multiple proteins (albumin, fibrinogen, and lipoprotein f in response to hypoalbuminemia with hypoviscosity. We have no information testing the possibility that the autonomic nervous system contributes directly to the mechanism responsible for hyperlipidemia / hyperfibrinogeremia in the nephrotic syndrome. We hypothesized that diabetics with both severe autonomic dysfunction and significantly elevated plasma fibrinogen concentrations were at the highest risk for thromboembolic events when compared with individuals demonstrating only one of these abnormalities. Study patients who were capable of maintaining a Valsalva maneuver with relatively normal results had lower (morning and afternoon) plasma fibrinogen levels, and higher (morning and afternoon) plasminogen activator inhibitor levels than did their counter-
458
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FIGURE 3. Relationship of Valsalva mam?uver heart rate variation results (normal zlewusabnormal) to plasma fibrinogen roncentration, fibrintfytic activity, and plasminogen activafor inhibitor concentrations during morning and afternoon. Panel A: Significant diflerence in plasma fibrinogen concentration between wnnal and abnormal Valsalva result groups in both morning and afternoon hours fP < .051. Panel B: Significance difircnce in plasma fibrinolytic activity between normal and abnormal Valsalva result groups noted in the morning hours on!y IP < ,051. Panel C: Significant difference in piasma plasminogen activator inhibitor concentration between normal and abnormal Vakafvu result groups in both morning and afternoon hours 0’ < .05).
parts whose Valsalva results were markedly abnormal. Patients whose Valsalva HRV results were markedly abnormal had significantly increased plasma fibrinogen and increased fitirinolytic activity with decreased concentration of plasminogen activator inhibitor. In this patient cohort there was a relationship between an intact heart rate response to Valsalva maneuver and normal control of intrinsic prothrombotic
and thrombolytic activity, as well as a relationship between loss of heart rate variation to the Valsalva maneuver and abnormal prothrombotic and tbrombolytic activity. It is possible that patients who do not vary their heart rates with the increase of intrathoracic pressure engendered by the Valsalva; maneuver are demonstrating a highly stimulated q&pathetic system. These patients may be at relatively higher risks
AJH-APRIL
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,
i 1
“NOllllOl” AuQaoolic Functioo
ADllOl7IlII
Autonomic
Function
FIGURE 4. Relationship of parasympathetic and sympathetic dysfunction (HRV, day/night MAD) to plasmr fibrinogen concentration. Significant difference for normal UPrsus abnormal tesf results in both morning and afternoon hours (P c ,051.
for cardiovascular events than those patients whose sympsthetic tone is less active, and may benefit from efforts to reduce sympathetic stimulation. Follow-up studies will be necessary to elucidate the cardiovascular thromboembolic event rates in these subgroups. Mechanisms for diabetic neuropathy are thought to involve &hernia resulting from low flow in the vasa vas.ora because of a) increased plasma viscosity; b) increased blood clotting; c) impaired red blood cell ar.d platelet flexibility leading to slow capi!lary flowz3; d) hypoxia in tissues that require high flow in capillaries because of an impaired release of oxygen from glycosylated hemoglobin; e) capillary injury at points of bindi.qg of advanced glycosylated end-products to their receptors leading to platelet adhesio,l’*; and f) increased release of endotl.di~r and von Willebrand factor from endothelium in diabetics with small :Fessel complications.“‘ib The severity of vessel wall injury and the prothrombotic milieu within both the vessel and the circulating plasma dekermine the rapidity and severity of thrombosis.*’ Once the vessel has been injured the potent vasoconstrictar endothelin is released. The presence of thrombin further accelerates the release of endothelin, which ind,uces chemotaxis, promotes replication of fibroblasts, accelerates cont&tion of collagen fibroblasts,’ and acts as a stimulator of microvascular platelet thrombi.= Thus e-tdothelin reinforces both the unopposed sympathetic vasoconstrictor risk factor in diabetics, and the atherosclerotic thrombotic process
IN DlABETlC
NEPHROPATHY
459
resulting from hyperfibrinogcncmia. 1~ the hypertcnsive diabetic, loss of parasympathetic innervation leads to vasoconstriction and platelet aggregation. The hyperlipidemia assnci lted with pvoteinuria contributes to plaque formation. Plaque rupture is most likely potentiated by unopposed sympathetic nerve stimulation. Beta blocker therapy may be justified despite the risks of hyp’g u 1y cemia to prevent plaque rupture. A new antagonist of endothelin-A receptor will be of immediate use when available.” We have observed relationships between injury to the autonomic nervous system and changes in the common pathway of blood coagulation indicating a clustering of risk factors in the azotemic diabetic. Specifically, higher plasma fibrinogen levels were distributed among the group of patients whose VaisdJa tests were more abnormal. Improved glucose control has her n shown to improve elevatnd fibrinogen levels over sever-1 weeks of intensive insulin therapy.-H’ Increased p&ma fiblnogen contributes to more vigorous platelet aggregation. Increased plasma fibrinogen is the main cause of increased plasma viscosity. Thus, improved glucose control with prevention of diabetic neuropathy” and lowering of elevated fibrinogen levels may diminish small blood vessel occlusions. Although elevated levels of plasminogen activator inhibitor in the plasma are associated with an increased risk of recurrent myocardisl infarction,” $hele has been no correlation of risk for initial or subsequent
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460 #VEINRAUCHET AL
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heart attack with a test of global fibrino:ytic activity.” Surprisingly the plasminogen activator inhibitor Ieve!; -were not elevated in our type I diabetic patients with high plasma fibrinogens, To test the predictive accuracy of plasma fibrinogen versus plasminogen activa tor inhibitor, future prospective studies must con-
trol for nolmai versus abnormal autonomic function. We suggest that correlations between clinical events and either the coag:+lation sys;cm or the autonomic system
but not all three
are potentially
flawed.
phropathy-a cross-sectionalanalysis m the presymptomatic phase. Am J Hypertens 1995;8:782-789.
8.
Muller JE, Tofler GH: Circadian variation and cardiovascular disease. N Engl J Msd 1991:325:1038-1039. 9. Tofler GH, Gebara OCE, Mittleman MA, et al, for the CPI Investigators: Morning peak in ventricular tachyarrhythmias detected by time of implantable cardioverter/defibrillator therapy. Circulation 1995;92: 1203-1208. 10.
CONCLUSIONS In hypertensive
of proteinuria,
after
the onset
we observed a relationship
diabetic
nephropathy
between
abnormalities in autonomic function and hemostatic factors favoring thrombogenesis. Because it appears that there may be a relationship between relative sympathetic dominance, vascular tone and the homeostasis of the coagulation cascade, we believe that auto-
1997~VOL. 10, NO. 4, PART I
Il.
Bernardi L, Ricordi L, Lazzari I’, et al: Impaired circadian modulation of sympathovagal activity in diabetes: a possible explanation for altered temporal onset of cardiovascular disease. Circulation 1992;86:1443-1452. Dougherty CM, Burr RI: Comparison of heart rate variability in survivors and non survivors of sudden cardiac arrest. Am J Cardiol 1992;70:441-448.
of any prospective studies which relate the presence of coronary arterial disease to both prothrombotic and autonomic dysfunction. Conclusions regarding the
Kleiger RE, Miller Jl’, Bigger JT, Moss AJ, and the Multi,.enter Post-Infarction ResearchCroup: Decreased herct r:;e variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987;593256-262. 13. Peters RW, Muiler JE, Goldstein S, et al: Propranolol and the morning increase in frequency of sudde‘~ cardiac death (BHAT study). Am J Cardioll989;63:151B1520. 14. Middlekauff HR. Sontz EM: Morning sympathetic nerve activity is not increased in humans: implications for mechanisms underlying the circadian pattern of cardiac tisk. Circulation 1995;91:2549-2555. 15. Maclsaac Al, Thomas JD, Top01 EJ: Toward the quiescent coronary plaque. J Am Co11 Cardiol 1993;22:12281241.
importance
16.
Muiler JE. Tofler GH, Verrier RL: Sympathetic activity as the cause of the morning increase in cardiac events a likely culprit but the evidence remains circumstantial. Circulation 1995;91:2508-2509.
17.
Weinrauch LA, D’Elia JA, Healy RE, et al: Asympiomatic coronary artery disease: assessment in diabetics evaluated for renal transplantation. Circulation 1978; S&1184-1190.
nomic function testing should be extended to a larger population of diabetics. The appeartince of a sympathetic dominant profile may be an indication for the use of beta blockers in these hypertensive insulin dependent diabetics despite the risk of hypoglycemic reactions.
The use of calcium
channel
blockers
that do
not increase the baseline tachycardia in these patients may be justified on clinical grounds. We are not aware
of these findings are not justified until events are correlated with both procoagulant measures and autonomic function tests.
12.
cardiovascular
REFERENCES
1. Sheps SC;, Pickering
TG, White WB, et al: ACC Position Statement. Ambulatory blood pressure monitoring. j Am Co11 Cardiol 1994;23:1511-1513. 2. Dreifus LS, Agarwal JB, Botvinick EH, et al: ACC PO+ tion Statement. Heart rate variability for risk stratification of life threatening arrhythmias. J Am Co11 Cardiol 1993;22:948-950. 3. Vaishanav S, Stevenson R, Marchant B, et al: Relation between heart rate variability early after myocardial infarction and long-term mortality. Am J Cardioll994; 73:653-657. 4. van Kavenswaaij CMA. Kollee LAA, Hopman JCW, et al: Heart rate variability. Ann Intern Med 1993;118: 425-447. 5. Bellavere F, Bosello G, Cardone C, et al: Evidence of early impairment of parasympathetic reflexes u1 insulin dependent diabetics without autonomic symptoms. Diabete et Metabolisme 1985;11:152-156. 6. Ewing 0, Campbell I, Clarke B: Heart rate changes in diabetes mellitus. Lancet 1981;i:183-184. 7. Weinrauch L, Kennedy F, Gleason RE, et al: Autonomic function in type I diabetes mellitus comp!icated by ne-
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Manske CL, Thomas W, Wang Y, Wilson RF: Screening ? diabetic transplant candidates for coronary artery dis; ease: Identification of a low risk subgroup. Kidney Int 1993;44:617-621. 19. Braun WE, Phillips DF, Vidt DG, et al: Coronary artery disease in 100 diabetics with end-stage renal failure. Transplant Proc 1984;16:603-607. 20.
Philipson JD, Carpenter BJ, Itzkoff J, et al: Evaluation of cardiovascular risk for renal transplantation in diabetic patients. Am J Med 1986;81:630-634.
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Aoki TT, Beirbarka M, Okimura intermittent intravenous insu!in abetes. Lancet 1993;432:515-518.
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QAS Institute Inc.: SAS User’s Guide: Statistics, Version 5 ed. Cary, NC, SAS Institute Inc., 1985, pp 529-557. Winocur PD, Watala C, Kinglough-Rathbone RL: Membrane fluidity is related to the extent of glycation of proteins, but not to alterations in the cholesterol to phospholipid molar ration in isolated platelet mem-
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PRDCOACULANTS
29.
30. 31,
IN DiARETIC
NEPHROPATHY
461
Bird JE, Moreland S, Wnldron TL, I’ewrll JR: Antihypertensive effects of a novel endothelin-A receptor antagomst in rats. Hypertension lY95;25:!191-1195 Jones RL. Peterson CM: Reduced fibrinogen survival in diabetes mrllitus. j Clin invest 1979;63:485-493. The Diabetes Control and Complicatims Research Croup: The effects of intensive treatment on the dcveiopment and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;342:515-518.
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Hamstein A, Waldius G, Szamosi A, et al: Plasminogen activator inhibitor in plasma: risk for recurrent myocardial infarction. Lancet 1987;iu3-8.
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Prins MH, Hirsh J: A critical review of the relationship between impaired fibrinolysis and myocardial infarction. Am Heart J 1991;122:545-551.