AJP - Endo Information on EB 2010
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 293: E1274-E1279, 2007. First published August 28, 2007; doi:10.1152/ajpendo.00114.2007
0193-1849/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/5/E1274    most recent
00114.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sommerfield, A. J.
Right arrow Articles by Frier, B. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sommerfield, A. J.
Right arrow Articles by Frier, B. M.

Vessel wall stiffness in type 1 diabetes and the central hemodynamic effects of acute hypoglycemia

Andrew J. Sommerfield,1 Ian B. Wilkinson,2 David J. Webb,3 and Brian M. Frier1

1Department of Diabetes, Royal Infirmary, Edinburgh; 2Department of Clinical Pharmacology, Addenbrooke's Hospital, Cambridge; and 3Department of Clinical Pharmacology, Western General Hospital, Edinburgh, United Kingdom

Submitted 20 February 2007 ; accepted in final form 21 August 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Objective: To examine the effects of intravenous insulin and acute hypoglycemia on arterial wall stiffness and central hemodynamic responses in adults with and without type 1 diabetes. Research Design and Methods: In 30 young male volunteers [10 nondiabetic (Group 1); 10 with type 1 diabetes, <5 yr duration (Group 2); 10 with type 1 diabetes, >15 yr duration (Group 3)], intravenous insulin was administered to provoke an acute autonomic reaction (R) to hypoglycemia. Heart rate, peripheral blood pressure, and pulse wave analysis (radial artery) were monitored. Augmentation index (AIx), a measure of arterial wall stiffness and wave reflection, and central arterial pressure were recorded. Results: At baseline, no significant differences were observed between Groups 1 and 2 in either AIx or in central arterial pressure, but in Group 3, both measures were significantly higher. All three groups exhibited similar responses to intravenous infusion of insulin and to hypoglycemia: AIx fell progressively from baseline to R, peripheral systolic blood pressure increased, and central systolic pressure decreased. Conclusion: Compared with age- and sex-matched nondiabetic controls, people who had type 1 diabetes for a long duration had increased stiffness of vessel walls. The opposing responses in peripheral and central systolic pressures during hypoglycemia may be related to the reduction in AIx, which causes diminished amplification of the systolic pressure wave. Changes in AIx are probably mediated by a direct action of insulin on arterial endothelium, or changes in heart rate. These functional changes may contribute to the increased cardiovascular morbidity that is associated with type 1 diabetes of long duration.

arterial wall stiffness; central arterial pressure; insulin

PEOPLE WITH TYPE 1 DIABETES are frequently exposed to acute hypoglycemia, which, in humans, is associated with profound hemodynamic changes, including an increase in heart rate and stroke volume, increased myocardial contractility, and a rise in cardiac output (14, 15). Changes in peripheral blood pressure include an increase in systolic and a decrease in diastolic pressure, with no change in mean arterial pressure. The effects on central arterial pressure are not known. Acute hypoglycemia also has significant, albeit transient, effects on peripheral blood that encourage hemostasis and increase blood viscosity (15). These changes influence capillary blood flow and in some tissues may predispose to intravascular stasis during hypoglycemia. The hemodynamic and hematological changes that occur during acute hypoglycemia do not appear to compromise vascular perfusion in the normal healthy vasculature, but they may have potentially adverse effects in people with diabetes, in whom endothelial dysfunction and vascular disease are common, and in whom premature atherosclerosis and cardiovascular disease are often present. Indeed, acute hypoglycemia may precipitate an acute vascular event or a dysrhythmia in people who have preexisting coronary heart disease (15). Angina and acute myocardial infarction have been documented, albeit infrequently and anecdotally, as the direct consequences of acute hypoglycemia (35).

Arterial blood pressure is usually recorded noninvasively at the brachial artery by sphygmomanometry. It is assumed that the pressure is the same throughout the arterial tree, and that it represents an accurate index of aortic peak pressure and of left ventricular systolic pressure, and so of left ventricular afterload. However, blood pressure measured in the peripheral circulation is not an accurate estimate of central pressure because of amplification of the pressure pulse between central and peripheral arteries (34, 43). Normally, there is amplification of the pulse pressure between the aorta and brachial artery (24). It is the aortic, rather than the brachial, pressure that determines left ventricular workload (42, 47).

Central arterial pressure and arterial wall stiffness, which are independent predictors of cardiovascular morbidity (1, 3, 20, 25, 31), can be studied noninvasively using pulse wave analysis (30, 32, 44, 51), which requires the external application of a micromanometer-tipped probe over a peripheral artery (6, 8). Pulse wave analysis allows the measurement of central arterial pressure, and the degree of its augmentation by pulse wave reflection, to be studied reliably and noninvasively (32). The system utilizes applanation tonometry, with the external application of a micromanometer-tipped probe to record peripheral pulse waveforms. The radial artery is usually used for these measurements because of its close proximity to and the support provided by nearby bony structures (6, 8). Changes occur in the pressure contour as it travels from the aorta to more peripheral sites, so that pressures at the radial artery cannot be used directly as a surrogate to predict central pressure in the aorta. However, it is possible to estimate the central aortic pressure wave from measurements of radial artery tonometry with the use of a mathematical transformation (8). Several studies have validated the accuracy and reliability of pulse wave analysis (44, 51). Contraction of the left ventricle generates a pressure wave that travels along the major arteries until it meets sites of resistance (high-resistance arterioles), and then the wave is reflected back to the heart (29). The stiffness of the arterial wall influences the velocity of the reflected wave. In healthy young people, the reflected wave reaches the heart during diastole and, by increasing diastolic pressure, enhances coronary perfusion. However, when arterial stiffening has developed, the increased pulse wave velocity of the stiffened arteries leads to earlier reflection of the wave, so that it returns to the heart during late systole (31, 33). The increase in systolic pressure that results from this earlier reflection of the pressure wave is known as "augmentation," with augmentation index (AIx) measured as the augmented pressure expressed as a percentage of the pulse pressure. AIx increases with age and in disease states such as hypertension (28) and hypercholesterolemia (49). It is also influenced by heart rate; a decrease in AIx is observed with an increase in heart rate (45). Central arterial pressure and waveform convey important information about cardiovascular status (21, 27, 31).

In view of the frequency of exposure to acute hypoglycemia in people with diabetes and the potential effects of acute hypoglycemia on the cardiovascular system, it is valuable to establish the effects of acute hypoglycemia on central arterial pressure and left ventricular load. The present study sought to measure arterial wall stiffness and the central hemodynamic responses to the administration of intravenous insulin and the induction of acute hypoglycemia in people with type 1 diabetes of varying duration and in nondiabetic subjects.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. To avoid potential gender differences in the counterregulatory hormonal responses to hypoglycemia (10), three groups of male subjects, matched for age, body mass index (BMI), and peripheral blood pressure, were studied: 10 nondiabetic volunteers (Group 1), 10 subjects with type 1 diabetes of short duration (<5 yr) (Group 2), and 10 subjects with type 1 diabetes of longer duration (>15 yr) (Group 3). Subjects with diabetes were matched for glycated hemoglobin (HbA1c) and were recruited from the outpatient clinic at the Department of Diabetes at the Royal Infirmary of Edinburgh. All patients were receiving treatment with a basal-bolus insulin regimen consisting of a preprandial short-acting insulin analog and a long-acting insulin analog, administered once daily. Blood pressure and plasma cholesterol concentration were measured before inclusion in the study. HbA1c was measured by HPLC (Variant II Hemoglobin Testing System; Bio-Rad Diagnostics Group, Hercules, CA), with a local Diabetes Control and Complications Trial-adjusted nondiabetic reference range of 4.3–6.5%. Subjects were excluded from the study if there was a history of hypertension (blood pressure >140/80 mmHg), hypercholesterolemia (total cholesterol >5.0 mmol/l), or other chronic disease or a history of a previous head injury, alcohol or drug abuse, seizures, or blackouts. All of the subjects were nonsmokers, had no intercurrent illness, and were not taking any regular medication (other than insulin for diabetes). Subjects with diabetes were excluded if they had any evidence of microvascular disease other than background diabetic retinopathy (2 subjects in Group 2 and 5 subjects in Group 3). The presence of retinopathy was determined by direct ophthalmoscopy, peripheral neuropathy by clinical examination, and nephropathy by the presence of microalbuminuria (albumin-to-creatinine ratio >2.5 mg/mmol for women and >3.5 mg/mmol for men). All potential participants underwent standard autonomic function testing (13) before inclusion in the study, and any with autonomic dysfunction were excluded. Subjects were also excluded if they had a history of impaired awareness of hypoglycemia.

Studies were postponed if a subject had experienced hypoglycemia in the preceding 48 h, and subjects were required to measure their blood glucose frequently during this period, including bedtime tests on the evening before the study to identify biochemical hypoglycemia. Ethical permission for the study was given by the Lothian Research Ethics Committee. All subjects gave their written, informed consent.

Procedure. Each study session began at 0800 after a 10- to 12-h overnight fast. The subjects with type 1 diabetes omitted their insulin on the morning of the study. A hyperinsulinemic glucose clamp (12) was used initially to maintain euglycemia (blood glucose concentration 4.0–7.0 mmol/l) for 20 min before the induction of acute hypoglycemia. Because of the variable fasting blood glucose level in people with diabetes, it took a variable time to achieve euglycemia (usually between 20 and 30 min). An intravenous cannula was inserted retrogradely into a vein on the dorsum of the nondominant hand for regular blood sampling. The hand was placed in a heated blanket to arterialize the venous blood. A second intravenous cannula was inserted into a vein in the antecubital fossa of the same arm for infusion of human soluble insulin (Humulin S; Eli Lilly) and 20% dextrose. Intradermal lignocaine (1%) was used for insertion of each cannula. Insulin was infused at a constant rate of 60 mU·m–2·min–1 using an IMED Gemini PCI pump (Alaris Medical Systems, San Diego, CA). A variable intravenous infusion of 20% dextrose was given simultaneously. The rate of dextrose infusion was varied according to the arterialized blood glucose concentration. This was measured at the bedside using the glucose oxidase method (Yellow Springs Instrument 2300 Stat, Yellow Springs, OH). Blood glucose concentration was measured every 3 min initially and then every 5 min once a stable level had been achieved.

Because the purpose of inducing acute hypoglycemia was to provoke an acute autonomic reaction with profound activation of the sympathoadrenal system, a rapid fall in blood glucose was then induced by infusing insulin intravenously at a rate of 2 mU·kg–1·min–1. This caused a controlled decline in blood glucose to a level that triggered the autonomic reaction associated with hypoglycemia. This method of inducing hypoglycemia simulates the development of hypoglycemia under everyday conditions and cannot be induced using the hyperinsulinemic glucose clamp technique. Any variability among subjects in the rate of fall in blood glucose and the depth of the hypoglycemia achieved is inconsequential, as the intention is to lower blood glucose to the blood glucose threshold at which autonomic activation is stimulated.

The autonomic reaction (designated as R) was identified by an abrupt rise in heart rate (15% above baseline), the rapid onset of autonomic symptoms, such as sweating and tremor, and a rapid rise in peripheral systolic blood pressure. When the R occurred, the clock timer was reset to zero, and all subsequent measurements were timed relative to this point. This accommodates the variable time interval that occurs among individuals in the development of the R using the insulin infusion technique (9). As soon as R had occurred, the insulin infusion was discontinued, and hypoglycemia was reversed using an intravenous infusion of 20% dextrose to restore normoglycemia. All subjects consumed a meal on completion of the study.

Measurements. During the study, arterialized blood glucose was measured at the bedside (Yellow Springs Instrument 2300 Stat) every 5 min until R and every 15 min thereafter until R+30 min. The maximal hemodynamic changes in response to hypoglycemia occur in the 30 min following the onset of the R (14). Pulse wave analysis at the radial artery was therefore performed every 5 min until R and every 5 min thereafter until R+30 min. Heart rate was monitored continuously using a pulse oximetry probe. Peripheral blood pressure was recorded every 5 min using a digital automated sphygmomanometer.

The Edinburgh Hypoglycemia Scale (11), a validated subjective self-rating questionnaire, was used to document the symptoms of hypoglycemia experienced by the subjects during the study. The symptoms of hypoglycemia were classified as autonomic (hunger, palpitations, sweating, shaking), neuroglycopenic (drowsiness, confusion, inability to concentrate, speech difficulty, blurred vision), and nonspecific (malaise, nausea, headache). Each symptom was graded on a Likert scale of 1 to 7 (1 = not present, 7 = very intense). The questionnaire was applied at baseline and at 5-min intervals thereafter until the onset of the R. It was repeated at R+30 min.

Statistics. A general linear model (repeated-measures ANOVA) was used to compare means within individual groups. Between groups, an ANOVA with post hoc t-tests was used. Correlation analyses for changes in AIx and insulin dose and duration of the study were performed using the Pearson correlation. A P value <0.05 was considered to be significant. All analyses were performed using SPSS version 11.0 for Windows. All results are expressed as means ± SD.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
The clinical characteristics of the subjects in the study are shown in Table 1.


View this table:
[in this window]
[in a new window]

  		Table 1. Characteristics of participants in the study

 
Changes in blood glucose concentration. The blood glucose concentrations (means ± SD) at baseline were 4.3 ± 0.5 mmol/l in Group 1 (nondiabetic) and 8.4 ± 2.1 and 8.9 ± 3.1 mmol/l in Groups 2 and 3 (diabetic), respectively. Following application of the euglycemic clamp, the blood glucose concentrations were stabilized at 4.2 ± 0.1 mmol/l (Group 1), 4.3 ± 0.2 mmol/l (Group 2), and 4.3 ± 0.2 mmol/l (Group 3). The nadir blood glucose concentrations at R were 2.9 ± 0.3 mmol/l (Group 1), 2.8 ± 0.3 mmol/l (Group 2), and 2.6 ± 0.3 mmol/l (Group 3) (P = 0.2).

Peripheral blood pressure. No significant differences were observed in the peripheral systolic, diastolic, and mean arterial pressures among the three groups at baseline. In all three groups of subjects, an increase in peripheral systolic blood pressure and a decrease in peripheral diastolic pressure occurred at R compared with baseline (Table 2). Systolic and diastolic pressures had returned to baseline levels by R+30 min in all three groups (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2. Hemodynamic measurements in study participants

 
Central arterial pressure. Central systolic blood pressure at baseline was significantly higher in Group 3 compared with Groups 1 and 2 (Table 1). A small, but significant, reduction in central systolic pressure was observed at R in all three groups compared with the respective baseline levels (Table 2). No change in central diastolic blood pressure was observed throughout the study in any of the three groups (Table 2).

Heart rate and autonomic symptom score. The induction of hypoglycemia and the onset of the R were associated with significant increments of heart rate and autonomic symptom score in all three groups compared with baseline levels (Table 2). In all groups, the heart rate and the autonomic symptom score had returned to baseline values at R+30 min.

AIx. At baseline, no difference in AIx was discernible between Group 1 and Group 2, whereas the AIx in Group 3 was higher than in either of these groups (Table 1).

All three groups exhibited a progressive decline in AIx between baseline and the development of hypoglycemia at R (Fig. 1). The fall in AIx from baseline to R was significantly less in Group 3 compared with the reduction in AIx from baseline to R in Groups 1 (P < 0.01) and 2 (P < 0.01). At R+30 min, AIx had risen to approach baseline levels in all three groups.


Figure 1
View larger version (9K):
[in this window]
[in a new window]

  		Fig. 1. Mean change in augmentation index (AIx). Group 1, nondiabetic subjects; Group 2, type 1 diabetes, <5 yr duration; Group 3, type 1 diabetes, >15 yr duration. EC, euglycemic clamp commenced; 0, start of insulin infusion to induce hypoglycemia; R, autonomic reaction; R–20, R–15, R–10, and R–5, 20, 15, 10, and 5 min before R, respectively; R+30, 30 min after R. *P < 0.0001 compared with values at 0.

 
Changes in AIx, duration of insulin exposure, and insulin dose. There was no significant difference in the duration of the euglycemic clamp procedure or the time taken to induce hypoglycemia among the three groups. The duration of the euglycemic clamp [means (SD)] measured 37.3 (11.1) min in Group 1, 44.2 (8.5) min in Group 2, and 46.9 (10.0) min in Group 3 (P = 0.3). The time taken to induce the R measured 18.1 (6.4) min in Group 1, 22.4 (5.2) min in Group 2, and 20.7 (6.9) min in Group 3 (P = 0.5). However, among individuals within the separate groups, a correlation was observed between the time taken to induce hypoglycemia and changes in AIx, with a longer duration being associated with a greater reduction in AIx (Group 1, r = 0.25, P = 0.04; Group 2, r = 0.38, P = 0.3; Group 3, r = 0.28, P = 0.04). Similarly, no significant difference was found in the amount of insulin infused during the studies among the three different groups. The total insulin dose administered was 14.6 (4.4) U in Group 1, 12.7 (3.1) U in Group 2, and 15.7 (4.8) U in Group 3 (P = 0.6). However, within the separate groups, a significant correlation was present between changes in AIx and insulin exposure. A greater decrement in AIx was associated with greater insulin exposure (Group 1, r = 0.30, P = 0.05; Group 2, r = 0.34, P = 0.04; Group 3, r = 0.3, P = 0.03).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Arterial stiffness is increased in people with type 2 diabetes (5, 7, 16, 17), in their nondiabetic relatives (19), and in people with impaired glucose tolerance (37). In people with type 1 diabetes, discrepant results have been reported. Some studies have demonstrated greater arterial stiffness compared with nondiabetic controls (4, 36, 46), whereas others have shown either no difference (23) or lower arterial stiffness (26). These differences may relate to the methodologies used and to patient selection, with participants differing in their duration of diabetes, age and gender, smoking status, peripheral blood pressure, serum cholesterol concentrations, and the presence or absence of microvascular disease.

In the present study, arterial stiffness and central arterial pressure were studied both in nondiabetic adults and in people with type 1 diabetes of differing duration, using radial artery pulse wave analysis and calculation of the AIx, and the subjects, all of whom were nonsmokers, were matched for age, gender, blood pressure, serum cholesterol, and body mass index. The results showed no difference in vessel wall stiffness or central arterial pressure between a group with well-controlled type 1 diabetes of short duration and a matched cohort of healthy nondiabetic volunteers. However, the people with type 1 diabetes of longer duration had greater stiffness of the arterial vessel wall and an elevated central arterial pressure compared with nondiabetic controls. This suggests that the duration of exposure to chronic hyperglycemia influences vessel wall stiffness rather than the presence of type 1 diabetes itself. This may result from structural changes caused by the gradual deposition of advanced glycation end products within the walls of large blood vessels (18). The endothelium (22, 50) and arterial wall smooth muscle bulk and tone (2) (the latter under the control of the endothelium) also influence the elasticity of arteries, and it is also possible, therefore, that increased vessel wall stiffness in people with type 1 diabetes of long duration is the result of functional changes that occur within the endothelium with increasing duration of diabetes.

In the present study, the rise in peripheral systolic blood pressure that is known to accompany acute insulin-induced hypoglycemia was accompanied by a reduction of central systolic blood pressure. These findings highlight the potential for divergent responses of central and peripheral arterial pressures and support the premise that the measurement of peripheral blood pressure by conventional methods does not provide an accurate measure of the central arterial pressure load on the left ventricle. Specifically, the results show how the changes of central and peripheral arterial pressures differ in response to the stress provoked by acute hypoglycemia and mediated by sympathoadrenal stimulation. It could be speculated that the reduction in central arterial pressure that was observed during acute hypoglycemia may lead to a reduction of coronary perfusion, which could potentially precipitate a vascular event in people with vascular disease.

The difference that was observed between the responses of peripheral and central systolic blood pressures to insulin-induced hypoglycemia is indicated by the observed changes in AIx; a reduction in AIx reflects diminished amplification of the systolic pressure wave and so causes a net overall reduction in central arterial systolic blood pressure. It is possible that this observed change in AIx had resulted either from changes in heart rate (45) or from the actions of vasoactive hormones that are secreted in response to hypoglycemia (38), or as a combination of both effects. An increment in heart rate of 10 beats/min causes a fall in AIx of ~4% (45), and the infusion of norepinephrine promotes an increase in AIx (48). However, in the present study, the AIx initially was observed to fall during euglycemia, before any stimulated changes in heart rate, autonomic symptom score, or peripheral blood pressure. Insulin per se may have a direct effect on the functional integrity of large blood vessels. In the present study, no significant differences were observed in the duration of insulin exposure or in the total insulin dose administered, but it was observed that, in individuals within each study group, a significant correlation existed between changes in AIx and the duration of insulin exposure and, consequently, the amount of insulin infused. This would support the suggestion that the early changes in AIx may therefore be a consequence of the direct action of insulin on endothelial function or on smooth muscle tone of large arteries. This interpretation would be consistent with the results of other studies that have demonstrated that the intravenous administration of insulin increases the distensibility of large arteries (39, 40).

The decrement of AIx was less in the group with type 1 diabetes of longer duration compared with that of subjects with diabetes of short duration and nondiabetic subjects. This would be consistent with greater stiffness and diminished elasticity of the vessel walls of large arteries in people with type 1 diabetes of long duration. Consistent with this observation, Westerbacka et al. (41) have shown that the effect of insulin to reduce vessel wall stiffness in large arteries is diminished in people with type 1 diabetes who have no vascular complications. The mean duration of type 1 diabetes in their participants was 18 yr (41), which is similar to the duration of diabetes of Group 3 in the present study. It has to be acknowledged that the algorithm to relate peripheral and central pressures by applanation tonometry was derived in nondiabetic subjects. However, in the present study, the changes in the central hemodynamic responses to insulin infusion and the induction of acute hypoglycemia were similar in both the nondiabetic and the diabetic groups.

Type 1 diabetes is associated with an increased prevalence of cardiovascular disease, and vessel wall stiffness is an independent predictor of cardiovascular morbidity and mortality. The present study has demonstrated that a greater duration of type 1 diabetes was associated with an increase in vessel wall stiffness, before the development of overt macrovascular disease. Central systolic pressure at rest was also greater in people with type 1 diabetes of longer duration, although peripheral blood pressure did not differ among the three study groups. Changes in brachial pressure may therefore underestimate changes in aortic pulse pressure and the response of left ventricular systolic function to hemodynamic stress in people who have had type 1 diabetes for several years. These vascular changes and the attendant rise in central arterial blood pressure may contribute to the increased risk of cardiovascular morbidity in people with type 1 diabetes.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
A. J. Sommerfield was supported by research funding from Eli Lilly and Company.


   ACKNOWLEDGMENTS
 
We wish to acknowledge the expert assistance of the staff of the Wellcome Trust Clinical Research Facility, Western General Hospital, Edinburgh, Scotland.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. M. Frier, Dept. of Diabetes, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, Scotland, UK (e-mail: brian.frier{at}luht.scot.nhs.uk)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Asmar R, Rudnichi A, Blacher J, London GM, Safar ME. Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. Am J Hypertens 14: 91–97, 2001.[CrossRef][Web of Science][Medline]
  2. Bank AJ, Kaiser DR, Rajala S, Cheng A. In vivo human brachial artery elastic mechanics: effects of smooth muscle relaxation. Circulation 100: 41–47, 1999.[Abstract/Free Full Text]
  3. Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 33: 1111–1117, 1999.[Abstract/Free Full Text]
  4. Brooks B, Molyneaux L, Yue DK. Augmentation of central arterial pressure in type 1 diabetes. Diabetes Care 10: 1722–1727, 1999.
  5. Brooks BA, Molyneaux LM, Yue DK. Augmentation of central arterial pressure in type 2 diabetes. Diabet Med 18: 374–380, 2001.[CrossRef][Web of Science][Medline]
  6. Cameron JD, McGrath BP, Dart AM. Use of radial artery applanation tonometry and a generalised transfer function to determine aortic pressure augmentation in subjects with treated hypertension. J Am Coll Cardiol 32: 1214–1220, 1998.[Abstract/Free Full Text]
  7. Cameron JD, Pinto ES, Bulpitt CJ, Rajkumar C. The ageing of elastic and muscular arteries. A comparison of diabetic and non-diabetic subjects. Diabetes Care 26: 2133–2138, 2003.[Abstract/Free Full Text]
  8. Chen CH, Nevo E, Fetics B, Pak PH, Yin FCP, Maughan L, Kass DA. Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure. Circulation 95: 1827–1836, 1997.[Abstract/Free Full Text]
  9. Corrall RJM, Frier BM, Davidson NMcD, French EB. Hormonal and substrate responses during recovery from hypoglycaemia in man during beta1-selective and non-selective beta-adrenergic blockade. Eur J Clin Invest 11: 279–283, 1981.[Web of Science][Medline]
  10. Cryer PE. Glucose counterregulation in man. Diabetes 30: 261–269, 1981.[Web of Science][Medline]
  11. Deary IJ, Hepburn DA, MacLeod KM, Frier BM. Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis. Diabetologia 36: 771–777, 1993.[CrossRef][Web of Science][Medline]
  12. DeFronzo R, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol Endocrinol Metab Gastrointest Physiol 237: E214–E223, 1979.[Abstract/Free Full Text]
  13. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 8: 491–498, 1985.[Abstract]
  14. Fisher BM, Gillen G, Dargie HJ, Inglis GC, Frier BM. The effects of insulin-induced hypoglycaemia on cardiovascular function in normal man: studies using radionuclide ventriculography. Diabetologia 30: 841–845, 1987.[Web of Science][Medline]
  15. Fisher BM, Heller SR. Mortality, cardiovascular morbidity and possible effects of hypoglycaemia on diabetic complications. In: Hypoglycaemia in Clinical Diabetes, edited by Frier BM and Fisher BM. Chichester, UK: John Wiley and Sons, 1999, p. 167–186.
  16. Fukui M, Kitigawa Y, Nakamura M, Mogami S, Ohnishi M, Hirata C, Ichio N, Wada K, Kamiuchi K, Shigeta M, Sawada M, Hasegawa G, Yoshikawa T. Augmentation of central arterial pressure as a marker of atherosclerosis in patients with type 2 diabetes. Diabetes Res Clin Pract 59: 153–161, 2003.[CrossRef][Web of Science][Medline]
  17. Goodfellow J, Ramsay MW, Luddington LA, Jones CJ, Coates PA, Dunstan F, Lewis MJ, Owens DR, Henderson AH. Endothelium and inelastic arteries: an early marker of vascular dysfunction in non-insulin dependent diabetes. Br Med J 312: 744–745, 1996.[Free Full Text]
  18. Grant PJ, Davies JA. Cardiovascular disease and diabetes. In: Textbook of Diabetes (3rd ed.), edited by Pickup JC and Williams G. Oxford: Blackwell Science, 2003, p. 56.1–56.24.
  19. Hopkins KD, Lehmann ED, Jones RL, Turay RC, Gosling RG. A family history of NIDDM is associated with decreased aortic distensibility in normal healthy young adult subjects. Diabetes Care 19: 501–503, 1996.[Abstract]
  20. Kannel WB, Wolf PA, McGee DL, Dawber TR, McNamara P, Castelli WP. Systolic blood pressure, arterial rigidity and risk of stroke. The Framingham study. JAMA 245: 1225–1229, 1981.[Abstract/Free Full Text]
  21. Karamanoglu M, O'Rourke MF, Avolio AP, Kelly RP. An analysis of the relationship between central aortic and peripheral upper limb pressure waves in man. Eur Heart J 14: 160–167, 1993.[Abstract/Free Full Text]
  22. Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, Ganz P. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension 38: 1049–1053, 2001.[Abstract/Free Full Text]
  23. Kool MJ, Lambert J, Stehouwer CD, Hoeks AP, Struijker Boudier HA, Van Bortel LM. Vessel wall properties of large arteries in uncomplicated IDDM. Diabetes Care 18: 618–624, 1995.[Abstract]
  24. Kroeker EJ, Wood EH. Comparison of simultaneously recorded central and peripheral arterial pressure pulses during rest, exercise and tilted position in man. Circ Res 3: 623–632, 1955.[Abstract/Free Full Text]
  25. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetier P, Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37: 1236–1241, 2001.[Abstract/Free Full Text]
  26. Lehmann ED, Gosling RG, Sonksen PH. Arterial wall compliance in diabetes. Diabet Med 9: 114–119, 1992.[Web of Science][Medline]
  27. London GM, Blacher J, Pannier B, Guerin AP, Marchais SJ, Safar ME. Arterial wave reflections and survival in end-stage renal failure. Hypertension 38: 434–438, 2001.[Abstract/Free Full Text]
  28. Megnien JL, Simon A, Valensi P, Flaud P, Merli I, Levenson J. Comparative effects of diabetes mellitus and hypertension on physical properties of human large arteries. J Am Coll Cardiol 20: 1562–1568, 1992.[Abstract]
  29. Nichols WW, O'Rourke MF. Wave reflections. In: McDonalds Blood Flow in Arteries: Theoretic, Experimental and Critical Principles. London: Arnold, 1998.
  30. Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 23: 554–566, 2003.[Abstract/Free Full Text]
  31. O'Rourke MF. Arterial stiffness, systolic blood pressure and logical treatment of arterial hypertension. Hypertension 15: 339–347, 1990.[Abstract/Free Full Text]
  32. O'Rourke MF, Gallagher DE. Pulse wave analysis. J Hypertens 14: S147–S157, 1996.[CrossRef][Web of Science]
  33. O'Rourke MF. Wave travel and reflection in the arterial system. J Hypertens 17, Suppl 5: S45–S47, 1999.
  34. Pauca AL, Wallenhaupt SL, Kon ND, Tucker WY. Does radial artery pressure accurately reflect aortic pressure? Chest 102: 1093–1098, 1992.
  35. Pladziewicz DS, Nesto RW. Hypoglycemia-induced silent myocardial ischemia. Am J Cardiol 63: 1531–1532, 1989.[CrossRef][Web of Science][Medline]
  36. Romney JS, Lewanczuk RZ. Vascular compliance is reduced in the early stages of type 1 diabetes. Diabetes Care 24: 2102–2106, 2001.[Abstract/Free Full Text]
  37. Schram MT, Henry RM, van Dijk RA, Kostense PJ, Dekker JM, Heine RJ, Bouter LM, Westerhof N, Stehouwer CD. Increased central artery stiffness in impaired glucose metabolism and type 2 diabetes: the Hoorn study. Hypertension 43: 176–181, 2004.[Abstract/Free Full Text]
  38. Thompson CJ, Bayliss PH. Endocrine changes during insulin-induced hypoglycaemia. In: Hypoglycaemia and Diabetes: Clinical and Physiological Aspects, edited by Frier BM and Fisher BM. London: Edward Arnold, 1993, p. 116–131.
  39. Westerbacka J, Wilkinson I, Cockcroft J, Utriainen T, Vehkavaara S, Yki-Jarvinen H. Diminished wave reflection in the aorta. A novel physiological action of insulin on large blood vessels. Hypertension 33: 1118–1122, 1999.[Abstract/Free Full Text]
  40. Westerbacka J, Vehkavaara S, Bergholm R, Wilkinson I, Cockcroft J, Yki-Jarvinen H. Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity. Diabetes 428: 821–827, 1999.
  41. Westerbacka J, Uosokainen A, Makimattila S, Sclenzka A, Yki-Jarvinen H. Insulin-induced decrease in large artery stiffness is impaired in uncomplicated type 1 diabetes mellitus. Hypertension 35: 1043–1048, 1999.[Web of Science]
  42. Westerhof N, O'Rourke MF. Haemodynamic basis for the development of left ventricular failure in systolic hypertension and for its logical treatment. J Hypertens 13: 943–952, 1995.[Web of Science][Medline]
  43. Wilkinson IB, Cockcroft JR, Webb DJ. Pulse wave analysis and arterial stiffness. J Cardiovasc Pharmacol 32, Suppl 3: S33–S37, 1998.
  44. Wilkinson IB, Fuchs SA, Jansen IM, Spratt JC, Murray GD, Cockcroft JR, Webb DJ. Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis. J Hypertens 16: 2079–2084, 1998.[CrossRef][Web of Science][Medline]
  45. Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ. The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol 525: 263–270, 2000.[Abstract/Free Full Text]
  46. Wilkinson IB, MacCallum H, Rooijmans DF, Murray GD, Cockcroft JR, McKnight JA, Webb DJ. Increased augmentation index and systolic stress in type 1 diabetes mellitus. QJM 93: 441–448, 2000.[Abstract/Free Full Text]
  47. Wilkinson IB, Franklin SS, Hall IR, Tyrrell S, Cockcroft JR. Pressure amplification explains why pulse pressure is unrelated to risk in young subjects. Hypertension 38: 1461–1466, 2001.[Abstract/Free Full Text]
  48. Wilkinson IB, MacCallum H, Hupperetz PC, van Thoor CJ, Cockcroft JR, Webb DJ. Changes in the derived central pressure waveform and pulse pressure in response to angiotensin II and noradrenaline in man. J Physiol 530: 541–550, 2001.[Abstract/Free Full Text]
  49. Wilkinson IB, Prasad K, Hall IR, Thomas A, MacCallum H, Webb DJ, Frenneaux AP, Cockcroft JR. Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia. J Am Coll Cardiol 39: 1005–1011, 2002.[Abstract/Free Full Text]
  50. Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, Cockcroft JR. Nitric oxide regulates local arterial distensibility in vivo. Circulation 105: 213–217, 2002.[Abstract/Free Full Text]
  51. Yasmin Brown MJ. Similarities and differences between augmentation index and pulse wave velocity in the assessment of arterial stiffness. QJM 92: 595–600, 1999.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/5/E1274    most recent
00114.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sommerfield, A. J.
Right arrow Articles by Frier, B. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sommerfield, A. J.
Right arrow Articles by Frier, B. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.