European Heart Journal Advance Access originally published online on March 19, 2007
European Heart Journal 2007 28(7):814-820; doi:10.1093/eurheartj/ehm018
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Association between cardiac autonomic dysfunction and inflammation in type 1 diabetic patients: effect of beta-blockade
1 Istituto di cardiologia, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma, Italy
2 Diabetes Care Unit, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma, Italy
Received 25 September 2006; revised 7 February 2007; accepted 15 February 2007; online publish-ahead-of-print 19 March 2007.
* Corresponding author. Tel: +39 06 3015 4187; fax: +39 06 3055535. E-mail address: g.a.lanza{at}inwind.it
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Aims: To assess the relationship between cardiac autonomic dysfunction and inflammation in patients with type 1 diabetes and whether beta-blocker therapy might improve both abnormalities in these patients.
Methods and results: We studied 49 patients with type 1 diabetes (age 50.5 ± 11 years, 33 men). Serum levels of high-sensitivity C-reactive protein, as a marker of inflammation, and frequency-domain heart rate variability (HRV) on 24 h Holter monitoring, as a measure of cardiac autonomic function, were assessed in all patients. Twenty-one patients with depressed HRV were subsequently randomized to receive atenolol (50 mg daily) or no-beta-blockade. HRV and C-reactive protein were re-assessed after 3–4 weeks from randomization. An inverse correlation was found between C-reactive protein levels and HRV parameters, with the highest r coefficient shown with low-frequency (LF) power (r = –0.38; P = 0.007). Furthermore, C-reactive protein serum levels were significantly higher in patients with bottom quartile values of LF power compared with patients with values in the three top quartiles (4.64 ± 2.8 vs.1.79 ± 1.6 mg/L, respectively; P = 0.003), also after adjustment for potential confounding variables (P = 0.013). HRV parameters improved significantly in patients treated with atenolol, but not in the no-atenolol group. Furthermore, C-reactive protein levels decreased in the beta-blockade group, but not in the no-beta-blockade group (P = 0.04 for changes between groups).
Conclusion: In type 1 diabetic patients, serum C-reactive protein levels are significantly associated with depressed HRV; the favourable effects of beta-blockade on both HRV parameters and C-reactive protein serum levels suggest that autonomic nervous system may have significant modulator effects on inflammation.
Key Words: Type 1 diabetes • Heart rate variability • C-reactive protein
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Abnormal cardiac autonomic function1,2 and increased markers of inflammation3,4 are findings detectable in a sizeable proportion of patients affected by type 1 diabetes mellitus and are both associated with worse clinical conditions and outcome.5–8
|
Recent experimental data suggest that inflammatory reactions can be modulated by the activity of the autonomic nervous system (ANS). Specifically, vagal activity has been shown to have anti-inflammatory effects, which may mainly result from inhibition of macrophage activation through stimulation of macrophage nicotine receptors.9,10 On the other hand, possible effects of products and mediators of inflammation on the ANS activity have also been described.11,12
Accordingly, recent clinical studies have found a significant association between a reduced heart rate variability (HRV) and increased markers of inflammation in several populations, including apparently healthy subjects,13,14 and patients with heart disease.15–18 The exact relationship between cardiac autonomic function and inflammation, however, remains to be elucidated.
This study was aimed at assessing two questions: (i) whether a relationship between impaired cardiac autonomic function and inflammation also exists in patients with type 1 diabetes mellitus in the absence of any clinical evidence of heart disease; (ii) whether an intervention (i.e. beta-blocker therapy) known to have significant favourable effects on cardiac autonomic activity19–21 might also improve low-grade inflammation in these patients.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study consisted of two phases. In the first phase, we assessed the relation between HRV parameters and C-reactive protein serum levels in a group of type 1 diabetic patients. In the second phase, we randomized patients with reduced HRV to beta-blocker therapy or no-beta-blocker therapy. Specifically, we preventively decided to enrol in the second phase of the study patients who showed values below the median of the HRV variable found to have the best correlation with C-reactive protein serum levels.
The study protocol complied with the Declaration of Helsinki and has been approved by institutional research committee. All participants gave written informed consent to both phases of the study.
Study phase I
Patients
About 400 patients with a diagnosis of type 1 diabetes mellitus according to the American Diabetes Association (ADA) guidelines22 are regularly followed at the Diabetes Care Unit of our Hospital. In this study, we enrolled a consecutive group of such patients who fulfilled all the following inclusion criteria: (i) no symptoms suspected for heart disease in clinical history; (ii) normal physical examination; (iii) normal 2D-echocardiographic colour-Doppler exam; (iv) normal symptom-limited exercise stress test (Bruce protocol); (v) no clinical evidence of any acute or chronic inflammatory disease. All patients were treated on a regular basis with three subcutaneous injections of insulin at meal times and an injection of neutral protamine or glargine insulin at bedtime. Of 51 patients screened for the study, two were excluded because of exercise-induced ST-segment depression. Thus, the study group included 49 diabetic type 1 patients, whose main clinical characteristics are summarized in Table 1.
Clinical assessment
For each patient, HbA1c mean values were obtained by high-performance liquid chromatography analysis performed on Diamat BioRad (BioRad, Milan, Italy). The HbA1c reference range for healthy subject was 4.3–5.9%.
The presence of retinopathy was assessed by a trained ophthalmologist according to the criteria of the EURODIAB Prospective Complication Study.23
Albumin excretion rate was also assessed in all patients using a radioimmunoassay method. Microalbuminuria was defined as an albumin excretion rate of 30–300 mg/24 h and macroalbuminuria as an excretion rate >300 mg/24 h in at least two consecutive urine samples, in the absence of a urinary tract infection.24
Heart rate variability
A 24 h electrocardiographic Holter monitoring (HM) was performed in all patients, using 3-channel tape recorders (Oxford Medilog FD5) and monitoring the bipolar chest leads CM5, CM1 and modified aVF lead. All HM tapes were analysed by an expert cardiologist, using the Oxford Medilog Excel 3.0 device (Oxford Instruments, Abingdon, UK).
Cardiac autonomic function was assessed by frequency-domain HRV analysis on the entire 24 h in the frequency range of 0 to 0.5 Hz using a fast Fourier transform spectral analysis algorithm, with a spectral resolution of 0.0005 Hz. Data were analysed in 10 min epochs throughout the 24 h, and results from all epochs were averaged to form a composite spectrum. The power of the RR-interval variations in the whole frequency range of the spectrum (total power frequency 0–0.5 Hz) and in the range of very-low frequency (VLF, 0.0033–0.04 Hz), low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15–0.40 Hz) were obtained. Furthermore, the LF/HF ratio was calculated, and the average RR interval in the 24 h was obtained.
C-reactive protein measures
A venous blood sample was collected in all patients before starting HM. Blood was centrifuged and serum and plasma samples were frozen at –80°C until assayed. C-reactive protein serum levels were measured, using a high-sensitivity immunonephelometric method (Behring Nephelometric 100 Analyzer, Scoppito, Italy), the lowest detection limit of which was 0.05 mg/L.
Study phase II
LF power was the HRV variable that showed the best correlation with C-reactive protein serum levels (given subsequently). Thus, the 24 patients with an LF power value below the median level were invited to participate in the beta-blocker phase of the study. Three patients were excluded, however, because of refusal to participate (n = 1), a referred history of asthma (n = 1), and use of aspirin (100 mg/day, n = 1) prescribed by the patient's physician after the first study phase. Thus, 21 patients, fulfilling the inclusion criteria and confirmed to have a stability of their clinical and diabetic status and absence of any contraindications to beta-blocker agents, were randomized to add atenolol (25 mg od for 3 days, then 50 mg od) to their standard treatment or to continue their standard treatment for 3–4 weeks. Patients were re-studied by HM in the same order in which they were enrolled in the first phase and assigned to either group using the last figure (even or odd) of a computer-generated table of random numbers.
A blood sample and a 24 h HM were repeated in these patients 3–4 weeks after randomization. All other medical therapy was left unchanged throughout the whole period from the first investigation to the end of the trial.
Although patients were obviously not blinded to group assignment, HRV analysis and measurement of C-reactive protein serum levels were performed by an expert cardiologist and an expert technician, respectively, who were blinded to patients' treatment and who were unaware of each other and of the results of the other's test.
Statistics
Between-group comparisons of continuous variables were done by the Mann–Whitney U test, whereas proportions were compared by Fisher's exact test. Correlation analyses were done by the Spearman test. Owing to skewed distribution, C-reactive protein and HRV variables were transformed into natural logarithmic values for parametric analyses.
To better define the relation between impaired HRV and subclinical inflammation, patients were divided into quartile groups according to LF power values, and C-reactive protein levels were compared among these groups by analysis of variance (ANOVA), with multiple comparisons done by the Bonferroni test. As ANOVA showed that C-reactive protein serum levels were significantly lower in the bottom quartile group, but did not differ among the three other quartile groups, the latter were grouped together and C-reactive protein levels were also compared between the bottom LF power quartile group and all other patients, both by unadjusted and adjusted ANOVA, with variables associated with C-reactive protein at univariate analysis (P < 0.1) included as covariates.
The response of HRV variables and C-reactive protein serum levels to atenolol, when compared with the randomized control group (atenolol–C-reactive protein interaction), was assessed by two-way ANOVA with a repeated measure design. Correction for possible intra-group correlation was done by the Greenhouse–Geisser method, and the Bonferroni correction was applied for multiple comparisons.
Statistical analyses were done by the SPSS 12.01 statistical software. Data are reported as mean ± SD, unless differently indicated. All tests were two-sided, and a P < 0.05 was required for statistical significance.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Heart rate variability parameters and C-reactive protein levels
An inverse statistically significant, or just above statistical significant, correlation was found between C-reactive protein levels and HRV variables (Table 2), the most significant association being found with LF power (r = –0.39, P = 0.005, Figure 1). Other variables associated with C-reactive protein serum levels included age, duration of diabetes, body mass index, triglyceride blood levels and microalbuminuria (inverse relation), with active smoking and hypertension being of borderline statistical significance (Table 3).
|
|
|
When assessed according to quartile values of LF power, C-reactive protein serum levels were significantly lower in patients in the bottom quartile (4.64 ± 2.8 mg/L), compared with those in the second (1.76 ± 1.6 mg/L, P < 0.001), third (2.42 ± 1.4 mg/L, P = 0.04), and top (1.20 ± 1.62 mg/L, P < 0.001) quartiles (Figure 2, P = 0.003 by ANOVA), whereas no statistically significant differences were found among the three upper quartile groups. The difference in C-reactive protein levels between the bottom quartile group and the three top quartile groups of LF power combined (1.79 ± 1.6 mg/L) was highly significant (P = 0.001) and persisted after adjustment for potentially confounding variables (i.e. age, duration of diabetes, body mass index, triglyceride blood levels, microalbuminuria, active smoking, and hypertension) (P = 0.013).
|
Effect of beta-blockade
Of the 21 patients enrolled in the beta-blocker trial, 11 were randomized to receive atenolol and 10 to no-beta-blocker therapy. There were no differences in the main clinical and laboratory variables between the two groups of patients (Table 4). Both patients in the treatment group and those in the no-treatment group were re-studied at a median follow-up time of 1 month from the first study (interquartile time intervals 1–8 and 1–9, respectively; P = 1.0).
|
The results of HRV parameters and serum C-reactive protein levels at the end of the trial period in the two groups are shown in Table 5. There were no significant differences in HRV values at the basal evaluation. At follow-up, however, HRV variables were higher in the beta-blocker group when compared with no-beta-blocker patients, with the most significant difference being found for VLF power (P = 0.016).
|
Moreover, HRV variables did not show any significant changes at follow-up in the no-beta-blocker group, whereas they improved, almost all significantly, in patients treated with atenolol (Figure 3).
|
C-reactive protein serum levels at baseline were not significantly different between the two groups. At follow-up, on the other hand, there was a significant reduction of C-reactive protein levels in the atenolol group, but not in the no-beta-blockade group (P = 0.04 by two-way ANOVA) (Figure 3).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In this study, we found a significant association between impaired cardiac autonomic function, as assessed by the HRV analysis, and low-grade inflammation, as assessed by C-reactive protein serum levels, in patients with type 1 diabetes mellitus. Furthermore, patients with low values of LF power showed higher C-reactive protein serum levels also after adjustment for possible confounding variables.
Most important, we found that the significant improvement of HRV in the group of patients with a clear impairment of cardiac autonomic function treated with atenolol was associated with a parallel reduction of C-reactive protein serum levels. In contrast, no significant changes in both HRV variables and C-reactive protein serum levels were detected in patients not treated with atenolol.
Taken together, our data give further support to the evidence that an imbalance of the ANS activity, characterized by a predominance of sympathetic activity, may favour inflammatory reactions and suggest that intervention able to modify the sympatho-vagal balance towards a reduction of adrenergic activity and a relative increase of vagal tone may also modulate the inflammatory state.
Finding interpretation
The frequent impairment of autonomic nervous function in diabetic patients is well known1,2 and it is also associated with worse clinical conditions and outcome.5,6 More recent studies, on the other hand, have shown that inflammation is also increased in diabetic patients3,4 and might also contribute to a bad clinical outcome.7,8 In this study, for the first time, we show a significant association in type 1 diabetic patients between inflammation, as assessed by serum C-reactive protein levels, and impaired cardiac autonomic function, as assessed by frequency-domain HRV parameters.
In a very recent study, diabetic neuropathy, in type 1 diabetic patients, has been shown to be associated with tissue necrosis factor-alpha system, whereas no significant relation with C-reactive protein levels was found.25 However, in this study, only a minority of patients showed abnormalities in cardiac autonomic function, which was also assessed with methods (deep breathing, Valsalva manoeuvre) less sensitive than HRV in detecting early cardiac autonomic impairment.26,27 Our results, on the other hand, confirm some previous findings obtained in other populations, including healthy subjects,13,14 patients with stable or unstable coronary artery disease,15,16 and patients with heart failure.17,18 In particular, by showing significantly increased C-reactive protein serum levels specifically in patients with LF power values in the bottom quartile, the results of this study confirm our previous observation that the relation between cardiac autonomic function and inflammation may become particularly evident when clearly abnormal findings are detectable, whereas it may be less evident when subjects with HRV values and C-reactive protein levels still in the normal or near-normal range are considered.16
The exact relationship between cardiac autonomic dysfunction and inflammation in the clinical setting remains to be elucidated. Indeed, whether impaired autonomic function may be a major causal factor for inflammation or vice versa or even whether both are caused by an independent third factor remains to be established.
Experimental findings suggest that the nervous autonomic system can significantly modulate inflammatory reactions.9,10 Autonomic fibres innervate the lymphoreticular system (e.g. spleen, liver, gut, bone marrow) and may influence tissue inflammatory cells in these organs as well as in inflamed tissues.28 Vagal stimulation, in particular, may reduce inflammatory reactions by inhibiting tissue macrophage activation through stimulation by acetylcholine9,10 of macrophage nicotine receptors. High sympathetic activity, on the other hand, may favour, and sympathectomy thwart, inflammatory reactions.29,30
Products of inflammation, however, have also the potential to influence nervous autonomic activity. Thus, IL-6 and TNF may reach the hypothalamus and the limbic system and stimulate autonomic-related centers.11 Furthermore, inflammatory mediators may stimulate peripheral afferent endings evoking autonomic responses finalized to modulate the inflammatory reaction (inflammatory reflex).28
In this study, for the first time, we give some evidence in man that a causal link may exist between modulation of ANS activity and inflammation. Indeed, the beta-blocker atenolol, as expected,19–21 improved HRV (i.e. sympatho-vagal balance) in our patients, and this was associated with a parallel decrease in C-reactive protein in the absence of any change of the clinical status of patients.
Although we cannot exclude an effect of atenolol on inflammation, we suggest that the C-reactive protein reduction observed in our patients was actually mediated by the improvement of autonomic nervous function. Indeed, the direct effects of beta-blockers on cardiac autonomic activity are well known, and several studies have repeatedly showed its ability to improve HRV in several groups of patients, including type 1 diabetic patients.20
Thus, although several other factors may variably contribute to inflammation and although we cannot exclude that inflammation may influence ANS activity, our data strongly support the hypothesis that short-term variations in ANS activity may significantly influence inflammation in diabetic type 1 patients and that this is likely to occur also in other clinical conditions.
It should be acknowledged that we cannot also exclude the possibility that the reduction in C-reactive protein by atenolol might be related to a local antagonist drug effect on a potential adrenergically stimulated C-reactive protein production by liver cells. To our knowledge, however, there are no clinical or experimental findings supporting a direct effect of adrenergic activity on C-reactive protein release by the liver.
Clinical implications
The possibility to improve simultaneously autonomic nervous function and inflammation may suggest that beta-blockers may be helpful in diabetic patients with cardiac autonomic dysfunction, although our data deserve confirmation in larger studies, and only appropriately designed clinical trials may establish whether beta-blockers may improve clinical outcome in these patients.
Recent data suggested that inflammation may be predictive of sudden death in some groups of patients with severe forms of heart disease.31,32 The association between HRV and C-reactive protein, however, may suggest that this relation may be mediated by the impaired autonomic function, frequently present and predictive of sudden death in these groups of patients.33,34
Limitations of the study
It should be acknowledged that the beta-blocker study included a small group of patients and was not blinded or placebo-controlled. However, HRV variables and C-reactive protein serum levels were assessed independently and in a blinded way, and it is also unlikely that they could be significantly influenced by a subjective placebo effect.
Inflammation was assessed only by serum C-reactive protein measurements, whereas confirmation of the effect of atenolol on inflammatory state by other markers of inflammation might have given further strength to our study. However, C-reactive protein is the most largely used inflammatory biomarker in research studies and in clinical practice, and the large experience accumulated on C-reactive protein suggests that it can be used reliably to assess the inflammatory state.
Conflict of interest: none declared.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Vinik AL, Maser RE, Mitchell BD, Freeman R. (2003) Diabetic autonomic neuropathy. Diabetes Care 26:1553–1559.
[Abstract/Free Full Text] - Ziegler D. (1999) Cardiovascular autonomic neuropathy: clinical manifestations and measurement. Diabetes Rev 7:300–315.
- Schalkwijk CG, Poland DC, van Dijk W, Kok A, Emeis JJ, Drager AM, Doni A, van Hinsbergh VW, Stehouwer CD. (1999) Plasma concentration of C-reactive protein is increased in type 1 diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic infiammation. Diabetologia 42:351–357.[CrossRef][Web of Science][Medline]
- Gomes MB, Piccirillo LJ, Nogueira VG, Matos HJ. (2003) Acute-phase proteins among patients with type 1 diabetes. Diabetes Metab 29:405–411.[Web of Science][Medline]
- Rathmann W, Ziegler D, Jahnke M, Haastert B, Gries FA. (1993) Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med 10:820–824.[Web of Science][Medline]
- Astrup AS, Tarnow L, Rossing P, Hansen BV, Hilsted J, Parving HH. (2006) Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 29:334–339.
[Abstract/Free Full Text] - Schram MT, Chaturvedi N, Schalkwijk CG, Fuller JH, Stehouwer CDA. (2005) Markers of infiammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetologia 48:370–378.[CrossRef][Web of Science][Medline]
- Saraheimo M, Teppo AM, Forsblom C, Fagerudd J, Groop PH. (2003) Diabetic nephropathy is associated with lowgrade inflammation in Type 1 diabetic patients. Diabetologia 46:1402–1407.[CrossRef][Web of Science][Medline]
- Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462.[CrossRef][Medline]
- Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384–388.[CrossRef][Medline]
- Banks WA and Kastin AJ. (1991) Blood to brain transport of interleukin links the immune and central nervous systems. Life Sci 48:PL117–PL121.[CrossRef][Web of Science][Medline]
- Goehler LE, Gaykema RP, Hansen MK, Anderson K, Maier SF, Watkins LR. (2000) Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci 85:49–59.[CrossRef][Web of Science][Medline]
- Jensen-Urstad M, Jensen-Urstad K, Ericson M, Johansson J. (1998) Heart rate variability is related to leucocyte count in men and to blood lipoproteins in women in a healthy population of 35-year-old subjects. J Intern Med 243:33–40.[CrossRef][Web of Science][Medline]
- Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF. (2004) Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J 25:363–370.
[Abstract/Free Full Text] - Janszky I, Ericson M, Lekander M, Blom M, Buhlin K, Georgiades A, Ahnve S. (2004) Inflammatory markers and heart rate variability in women with coronary heart disease. J Intern Med 256:421–428.[CrossRef][Web of Science][Medline]
- Lanza GA, Sgueglia GA, Cianflone D, Rebuzzi AG, Angeloni G, Sestito A, Infusino F, Crea F, Maseri A. (2006) Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 97:1702–1706.[CrossRef][Web of Science][Medline]
- Aronson D, Mittleman MA, Burger AJ. (2001) Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure. J Cardiovasc Electrophysiol 12:294–300.[CrossRef][Web of Science][Medline]
- Malave HA, Taylor AA, Nattama J, Deswal A, Mann DL. (2003) Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: a study in patients with mild-to-moderate heart failure. Chest 123:716–724.[CrossRef][Web of Science][Medline]
- Sandrone G, Mortara A, Torzillo D, La Rovere MT, Malliani A, Lombardi F. (1994) Effects of beta blockers (atenolol or metoprolol) on heart rate variability after acute myocardial infarction. Am J Cardiol 74:340–345.[CrossRef][Web of Science][Medline]
- Ebbehoj E, Poulsen PL, Hansen KW, Knudsen ST, Molgaard H, Mogensen CE. (2002) Effects on heart rate variability of metoprolol supplementary to ongoing ACE-inhibitor treatment in type 1 diabetic patients with abnormal albuminuria. Diabetologia 45:965–975.[CrossRef][Web of Science][Medline]
- Cogliati C, Colombo S, Ruscone TG, Gruosso D, Porta A, Montano N, Malliani A, Furlan R. (2004) Acute beta-blockade increases muscle sympathetic activity and modifies its frequency distribution. Circulation 110:2786–2791.
[Abstract/Free Full Text] - . American Diabetes Association. (2005) Diagnosis and classification of Diabetes. Diabetes Care 28:Suppl. 1S37–S42.
[Free Full Text] - Schram MT, Chaturvedi N, Schalkwijk C, Giorgino F, Ebeling P, Fuller JH, Stehouwer CD. (2003) Vascular risk factors and markers of endothelial function as determinants of inflammatory markers in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care 26:2165–2173.
[Abstract/Free Full Text] - Amin R, Turner C, van Aken S, Bahu TK, Watts A, Lindsell DR, Dalton RN, Dunger DB. (2005) The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects: The Oxford Regional Prospective Study. Kidney Int 68:1740–1749.[CrossRef][Web of Science][Medline]
- Gonzalez-Clemente JM, Mauricio D, Richart C, Broch M, Caixas A, Megia A, Gimenez-Palop O, Simon I, Martinez-Riquelme A, Gimenez-Perez G, Vendrell J. (2005) Diabetic neuropathy is associated with activation of the TNF-alfa system in subjects with type 1 diabetes mellitus. Clin Endocrinol 63:525–529.[CrossRef][Medline]
- Pagani M. (2000) Heart rate variability and autonomic diabetic neuropathy. Diabetes Nutr Metab 13:341–346.[Web of Science][Medline]
- Spallone V and Menzinger G. (1997) Diagnosis of cardiovascular autonomic neuropathy in diabetes. Diabetes 46:S67–S76.[Web of Science][Medline]
- Tracey KJ. (2002) The inflammatory reflex. Nature 420:853–859.[CrossRef][Medline]
- März P, Cheng JG, Gadient RA, Patterson PH, Stoyan T, Otten U, Rose-John S. (1998) Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci USA 95:3251–3256.
[Abstract/Free Full Text] - Madden KS, Felten SY, Felten DL, Hardy CA, Livnat S. (1994) Sympathetic nervous system modulation of the immune system. II. Induction of lymphocyte proliferation and migration in vivo by chemical sympathectomy. J Neuroimmunol 49:67–75.[CrossRef][Web of Science][Medline]
- Burke AP, Tracy RP, Kolodgie F, Malcom GT, Zieske A, Kutys R, Pestaner J, Smialek J, Virmani R. (2002) Elevated C-reactive protein values and atherosclerosis in sudden coronary death: association with different pathologies. Circulation 105:2019–2023.
[Abstract/Free Full Text] - Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. (2002) Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 105:2595–2599.
[Abstract/Free Full Text] - La Rovere MT, Pinna GD, Hohnloser SH, Marcus FI, Mortara A, Nohara R, Bigger JT Jr, Camm AJ, Schwartz PJ. ATRAMI (Autonomic Tone Reflexes After Myocardial Infarction) Investigators. (2001) Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation 103:2072–2077.
[Abstract/Free Full Text] - Lanza GA, Guido V, Galeazzi MM, Mustilli M, Natali R, Ierardi C, Milici C, Burzotta F, Pasceri V, Tomassini F, Lupi A, Maseri A. (1998) Prognostic role of heart rate variability in patients with a recent acute myocardial infarction. Am J Cardiol 82:1323–1328.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Ares-Carrasco, B. Picatoste, A. Benito-Martin, I. Zubiri, A. B. Sanz, M. D. Sanchez-Nino, A. Ortiz, J. Egido, J. Tunon, and O. Lorenzo Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes Am J Physiol Heart Circ Physiol, December 1, 2009; 297(6): H2109 - H2119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Herder, M. Lankisch, D. Ziegler, W. Rathmann, W. Koenig, T. Illig, A. Doring, B. Thorand, R. Holle, G. Giani, et al. Subclinical Inflammation and Diabetic Polyneuropathy: MONICA/KORA Survey F3 (Augsburg, Germany) Diabetes Care, April 1, 2009; 32(4): 680 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Yildiz, R. Yilmaz, R. Demirbag, and M. Gur Cardiac autonomic dysfunction and inflammation in type 1 diabetic patients Eur. Heart J., August 2, 2007; 28(16): 2041 - 2041. [Full Text] [PDF]
|
|
|
|
|
|
G. A. Lanza Cardiac autonomic dysfunction and inflammation in type 1 diabetic patients: reply Eur. Heart J., August 2, 2007; 28(16): 2041 - 2042. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||