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PubMed1996

Autonomic activity assessed by heart rate spectral analysis varies with fat distribution in obese women.

Obesity in humans has been associated with altered autonomic nervous system activity. The objective of this study was to examine the relationship between autonomic function and body fat distribution in 16 obese, postmenopausal women using power spectrum analysis of heart rate variability. Using this technique, a low frequency peak (0.04-0.12 Hz) reflecting mixed sympathetic and parasympathetic activity, and a high frequency peak (0.22-0.28 Hz) reflecting parasympathetic activity, were identified from 5-minute consecutive heart rate data (both supine and standing). Autonomic activity in upper body (UBO) vs. lower body obesity (LBO)(by waist-to-hip ratio) and subcutaneous vs. visceral obesity (by CT scan) was evaluated. Power spectrum data were log transformed to normalize the data. The results showed that standing, low-frequency power (reflecting sympathetic activity) and supine, high-frequency power (reflecting parasympathetic activity) were significantly greater in UBO than in LBO, and in visceral compared to subcutaneous obesity. Women with combined UBO and visceral obesity had significantly higher cardiac sympathetic and parasympathetic activity than any other subgroup. We conclude that cardiac autonomic function as assessed by heart rate spectral analysis varies in women depending on their regional body fat distribution.

Adipose Tissue↗
PubMed1993

Heart rate variability in diabetic children: sensitivity of the time- and frequency-domain methods.

Heart rate variability (HRV) is a noninvasive index of the neural activity of the heart. Although also influenced by the sympathetic activity of the heart, HRV is essentially determined by the vagal stimulation of the heart. Several HRV abnormalities have been described in adults with diabetes mellitus. However, there are few data on HRV in children with diabetes mellitus. In the present study, HRV was assessed in seven healthy children, 10 diabetic children with good glycemic control and 11 diabetic children with poor glycemic control. All had normal standard cardiac autonomic function tests, obtained from 24-h Holter tapes. HRV was measured by calculating six time-domain (mean R-R interval (RR), standard deviation of the R-R interval [SDRR], standard deviation of the mean of 288 R-R intervals [SDANN], the mean of the 288 standard deviations computed for each 5-min period [SD], percentage of differences of adjacent R-R intervals of > 50 msec for the entire 24 h [pNN50], and the root mean square of successive differences [rMSSD]) and four frequency-domain (low frequency [LF], high frequency [HF], total heart rate power spectra, and LF/HF ratio) indexes. SD, pNN50, rMSSD, LF, HF and total heart rate power spectra were markedly and significantly reduced in diabetic children with poor metabolic control. The 24-h variation of low- and high-frequency components of heart rate power spectra of the latter children had a different shape. Thus, diabetic children with poor metabolic control (elevated HbA1c and B2M levels) have a low HRV compared to those diabetic children with good control and healthy children.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2002

Assessment of autonomic nervous system with analysis of heart rate variability in children with spastic cerebral palsy.

The purpose of this study was to investigate the function of the autonomic nervous system in children with spastic cerebral palsy (CP) through an analysis of heart rate variability (HRV) occurring with orthostatic stress. Twelve children with spastic CP and twelve normal children participated in this study. The echocardiogram (ECG) signals were recorded for 3 minutes in both the supine and 70 degrees C head-up tilt positions, and then the HRV signals underwent power spectrum analysis at each position. Two components were measured; a low- frequency (LF) component (0.05 - 0.15 Hz) primarily reflecting sympathetic activity during orthostatic stress and a high-frequency (HF) component (0.15 - 0.4 Hz) reflecting parasympathetic activity. In the supine position, there was no significant difference between any of the HRV components of the two groups. In the head-up tilt position, absolute and normalized LF were significantly increased and absolute HF was significantly decreased in the normal children (p < 0.05), but not in the children with spastic CP. The results of this study suggest that cardiac autonomic functions, such as vagal withdrawal and sympathetic activation which occur during head-up tilt position, are not sufficient to overcome the orthostatic stress arising in spastic CP children.

Autonomic Nervous System↗
PubMed1992

Immunohistochemical measurements of nerves and neuropeptides in diabetic skin: relationship to tests of neurological function.

Image-analysis was used to measure nerves immunoreactive to the general neuronal marker protein gene product 9.5 (PGP 9.5-IR) and the neuropeptides calcitonin gene-related peptide and vasoactive intestinal polypeptide in standardised leg skin biopsies of three age-matched groups of young subjects: non-diabetic (n = 14), diabetic patients with normal small fibre function ("non-neuropathic", (n = 11) and diabetic patients with abnormal small fibre function ("neuropathic", n = 11). Depletion of nerves and neuropeptides was most marked in the epidermis, where calcitonin gene-related peptide-immunoreactivity was more frequently absent than PGP 9.5-IR in diabetic patients. Epidermal PGP 9.5-IR nerve area and counts were reduced in neuropathic compared with normal subjects (p less than 0.001), as were epidermal calcitonin gene-related peptide nerve counts (p = 0.003). Sweat gland PGP 9.5 and vasoactive intestinal polypeptide, which may be involved in sweat production, showed no diminution in diabetic patients (area: p = 0.160, p = 0.372 by ANOVA). Two diabetic patients showed elevated sweat gland PGP 9.5-IR and three had increased sweat gland vasoactive intestinal polypeptide; this may represent nerve proliferation. In local sweat tests, acetylcholine-stimulated sweat output was associated with increased immunoreactivity, while the sympathetic skin response showed inverse correlations with immunoreactivity. There were no consistent changes with other commonly-used neurophysiological tests. HbA1 correlated negatively with immunohistochemical measurements. Neuropeptide changes were seen in the absence of macro- and microvascular disease, and epidermal nerve depletion occurred in patients with normal thermal thresholds and cardiac autonomic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Changes in autonomic function as determined by ECG R-R interval variability in sandal, shoe and leather workers exposed to n-hexane, xylene and toluene.

To clarify if autonomic nervous system effects might be associated with exposure to organic solvents, 30 sandal, shoe and leather workers exposed to n-hexane, xylene, and toluene, and 25 unexposed controls were examined using the coefficient of variation in electrocardiographic R-R intervals (CVRR), combined with the distribution of nerve conduction velocities (DCV). The C-CVRSA and C-CVMWSA (two component CVs of the CVRR reflecting parasympathetic and sympathetic activities, respectively) were also computed from component spectral powers using autoregressive spectral and component analyses. Concentrations of the metabolites of the solvents in urine samples taken in the morning before work were 0-3.18 (mean 1.39) mg/l for 2,5-hexanedione, 0.10-0.43 (mean 0.19) g/g creatinine (Cn) for methylhippuric acid, and 0.05-2.53 (mean 0.41) g/g Cn for hippuric acid. In the solvent workers, the CVRR and C-CVRSA were reduced significantly when compared with the unexposed controls. The faster velocities of the DCV as well as the sensory median nerve conduction velocity (SCV) were significantly slowed in the solvent-exposed workers. The SCV was significantly correlated with the CVRR and C-CVMWSA among the solvent workers. These data suggest that chronic exposure to some organic solvents may affect cardiac autonomic function (mainly, parasympathetic activity) in addition to faster myelinated fibers of the peripheral nerves. However, the absence of significant dose-effect relations among the solvent workers makes it difficult to definitively attribute the differences to specific solvent exposures.

Adult↗
PubMed2002

Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (The Autonomic Tone and Reflexes After Myocardial Infarction substudy).

A previous report on heart rate (HR) turbulence showed its value in postinfarction risk stratification. The present study determines the predictive value of HR turbulence in a low-risk population after acute myocardial infarction and provides insight into its pathophysiologic correlates. With use of the database of the The Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) study, data were obtained from 1,212 survivors with a mean duration of follow-up of 20.3 months. The a priori end point was defined as the combination of fatal cardiac arrest and nonfatal cardiac arrest. HR turbulence characterized by turbulence onset (TO) and turbulence slope (TS) was calculated and correlated with baroreflex sensitivity (BRS) and the SD of the normal-to-normal RR intervals (SDNN). A composite index of cardiac autonomic function was assessed by combining HR turbulence (TO and TS), BRS, and SDNN. Both TO and TS correlated moderately but significantly with BRS and SDNN (r = 0.26 to 0.44, p <0.001 for all correlations). On Cox's univariate regression analysis, the RRs for abnormal values of TO, TS, and the combination of abnormal TO and TS were 1.86 (95% confidence interval [CI] 0.96 to 3.61, p = 0.065), 4.08 (95% CI 2.11 to 7.89, p <0.0001), and 6.87 (95% CI 3.06 to 15.45, p <0.0001), respectively. The composite autonomic index (combined TO, TS, BRS, and SDNN) was the strongest risk predictor: for all 4 abnormal factors, RR 16.79 (95% CI 6.01 to 46.89, p <0.0001). On multivariate analysis, abnormal TO and TS, and left ventricular ejection fraction remained as independent predictors: RRs 4.07 (95% CI 1.70 to 9.77, p = 0.0017) and 3.53 (95% CI 1.76 to 7.06, p = 0.0004), respectively. In a separate model, the composite autonomic index was the strongest multivariate risk predictor: RR 8.67 (95% CI 2.72 to 7.65, p = 0.0003) for all abnormal factors, and adjusted for left ventricular ejection fraction. Thus, this study confirms the independent value of HR turbulence in predicting fatal cardiac arrest and nonfatal cardiac arrest in a low-risk post-acute myocardial infarction population. By combining HR turbulence, BRS, and SDNN, a comprehensive assessment of cardiac autonomic reflexes and modulation can be obtained.

Autonomic Nervous System↗
PubMed1999

Effects of paroxetine on heart period variability in patients with panic disorder: a study of holter ECG records.

We investigated cardiac autonomic function in 16 patients with panic disorder before and after treatment with paroxetine using Holter ECG records. Our previous data suggest a relative increase in sympathetic activity in patients with panic disorder, especially during sleep. Data for 20 h and awake and sleep periods were analyzed using spectral analysis to quantify absolute and relative heart period variability in ultra low (ULF: <0.0033 Hz), very low (VLF: 0.0033-0.04 Hz), low (LF: 0.04-0.15 Hz) and high (HF: 0.15-0.5 Hz) frequency bands. We also obtained fractal dimensions (FD) for the 20-hour, awake and sleep time series of RR intervals. Paroxetine treatment (19.7 +/- 4.7 mg/day for 105 +/- 37 days) resulted in a significant improvement in the frequency and intensity of panic attacks and also on the state anxiety inventory. Paroxetine treatment produced a significant decrease of 20-hour absolute HF power, awake absolute LF power and sleep absolute HF power. There was also a significant decrease of FDs after treatment with paroxetine for the sleep period. The decrease in LF and HF powers, and sleep FD is likely due to the antimuscarinic effect of paroxetine. The decrease in day-time LF power may also be due to a decrease in relative cardiac sympathetic activity after paroxetine treatment.

Adult↗
PubMedDate not supplied

Effects of enalapril maleate on heart rate variability: a pilot study.

The effects of enalapril maleate on heart rate variability, an indicator of cardiac autonomic function, were evaluated by nonspectral analysis in 12 patients with standard deviation in the R-R interval for each 5-minute period for 24 hours (SDANN) of 80 msec or less. A 24-hour electrocardiogram was recorded before treatment and after 2 weeks of treatment with enalapril. No significant difference was observed in the mean R-R interval on 24-hour electrocardiography between the pretreatment and the posttreatment periods (824 +/- 84 msec vs 834 +/- 83 msec). The SDANN increased significantly (P < 0.01) between the pretreatment period (62.8 +/- 13.7 msec) and the posttreatment period (87.1 +/- 31.2 msec), as did the standard deviation of the R-R interval during the two monitoring periods (P < 0.001). However, no significant difference was observed in the mean value of the standard deviations of the R-R interval for 5 minutes; the proportion of adjacent R-Rs with a difference of more than 50 msec; or the root-mean square of the difference in successive R-Rs in the pretreatment period as compared with the posttreatment period. Causal blood pressure at rest decreased significantly (P < 0.05) after treatment with enalapril (124 +/- 17/66 +/- 7 mmHg) as compared with the pretreatment period (140 +/- 24/75 +/- 13 mmHg). Enalapril may be useful for maintaining normal autonomic nerve activity, preventing sudden cardiac death, and enhancing quality of life in our stressful society.

Aged↗
PubMedDate not supplied

Effects of sevoflurane on QT dispersion and heart rate variability.

The purpose of this study was to use estimates of corrected QT dispersion (QTcd) and heart rate variability (HRV) to assess the effects of sevoflurane, an inhalation agent used frequently in clinical practice, on autonomic cardiac function. This study was conducted prospectively and in a blind manner on 20 women between 38 and 51 y of age who were classified as American Society of Anesthesiologists stage I-II and whose treatment required total abdominal hysterectomy. Electrocardiograms were recorded by 12-lead Holter monitor for 5 min before sevoflurane induction and again for 5 min at 10 min after tracheal intubation. Data on the first recording were considered as baseline; those on the second recording were viewed as final data. The study was terminated at this point, and surgery was allowed to proceed. QTcd and HRV values were assessed by a cardiologist, who was blinded to all data. All parameters were expressed as a mean value +/- standard deviation. Wilcoxon's test was used to compare baseline and final data. Statistical significance was considered as P<.05. No significant changes were observed between baseline and final QTcd values and between low- and high-frequency components (LF and HF) of HRV; nor were changes seen in the LF/HF ratio. With the patient under sevoflurane/ nitrous oxide anesthesia, no significant changes were detected in QTcd, LF, and HF values, and in the LF/HF ratio, whereas a significant increase (P=.001) was seen in standard deviation of the R-R interval, which was used as a measure of cardiac autonomic tone.

Adult↗
PubMed2002

Effects of menstrual cycle on cardiac autonomic innervation as assessed by heart rate variability.

OBJECTIVE: The aim of the study was to investigate the effects of menstrual cycle on cardiac autonomic function parameters in young healthy women by means of heart rate variability (HRV). METHODS: Forty-three nonobese regularly cycling women (age 29 +/- 6, range 20-38) were enrolled. Recordings for HRV analysis were obtained during the two phases of the menstrual cycle when the estrogen and progesterone levels peaked (follicular phase 11 +/- 1 days and luteal phase 21 +/- 1 days from the start of bleeding). Power spectral analysis of HRV was performed to calculate the low frequency peak (LF, 0.04-0.15 Hz), high frequency peak (HF, 0.15-0.40 Hz), LF in normalized unit (LF nU), HF in normalized unit (HF nU), and LF/HF ratio during the two phases of menstrual cycle. RESULTS: The heart rates, LF and HF, were similar in both phases (P > 0.05). A significant increase was noted in the LF NU in the luteal phase compared to follicular phase of the menstrual cycle (P = 0.014), whereas a tendency for increased HF NU was observed in the follicular phase (P = 0.053). Furthermore, LF/HF ratio was significantly higher in the luteal phase compared to follicular phase (2.1 +/- 1.5 vs 1.6 +/- 0.9, P = 0.002), suggesting increased sympathetic activity in the luteal phase. CONCLUSION: We concluded that regulation of autonomic tone is modified during menstrual cycle. The alteration in the balance of ovarian hormones might be responsible for these changes in the cardiac autonomic innervation.

Adult↗
PubMed1996

Heart rate and heart rate variability in acute coronary heart disease.

The parameters of cardiac autonomic function, heart period length and heart period length variability were investigated in 70 patients, 50 males and 20 females, mean age 54.8 +/- 9.6 years, admitted to coronary care unit. There were 15 unstable angina patients, 21 anterior wall infarction patients, 20 posterior wall infarction patients, and 14 non-Q-wave infarction patients, who survived to discharge. Heart period length and heart period length variability for each patient were manually measured on the basis of 30 consecutive sinus normal-to-normal RR intervals in ECG every 20 minutes during the initial 24 hours of their stay at the coronary care unit and in the third week after admission. For each interval analyzed, the mean duration of RR interval was computed. RR interval variations were expressed as coefficient of variation (CV). On admission, heart rate was significantly slower (848 +/- 173 ms vs. 837 +/- 163 ms) and CV significantly lower (4.8 +/- 4.2 vs. 5.0 +/- 3.4%) than on discharge (p < 0.01). The significant difference in the mean RR interval between anterior wall infarction patients (802 +/- 186 ms) and inferior wall infarction patients (879 +/- 181 ms) recorded on admission disappeared on discharge from hospital (806 +/- 144 vs. 783 +/- 100 ms). CV was lower in acute myocardial infarction patients (4.7 +/- 3.6; 4.1 +/- 3.2) than in unstable angina patients (5.3 +/- 5.6) on admission (p < 0.05). Heart rate variability was greater in anterior wall infarction patients and unstable angina patients (CV = 5.3 +/- 3.1; 5.2 +/- 3.6%) than in posterior wall infarction patients and non-Q-wave infarction patients (CV = 4.7 +/- 3.5; 4.8 +/- 3.6%). The findings showed that different degrees of cardiac sympathovagal activity may occur in acute coronary heart disease patients during the first 24 hours of their stay at coronary care unit and on discharge from hospital.

Adult↗
PubMed2006

Differences in heart rate variability between depressed and non-depressed elderly.

OBJECTIVE: To determine whether older primary care patients with a Major Depressive Disorder (MDD) have lower heart rate variability (HRV) compared to non-depressed patients. HRV is a measure of cardiac autonomic functioning. METHOD: A cross-sectional comparison of 136 elderly persons with MDD and 136 non-depressed controls (matched for age and gender) recruited in family practices in the Netherlands. Depression was determined according to the DSM-IV criteria using the PRIME-MD. HRV was measured with an electrocardiogram (ECG) during a 5-minute supine rest. RESULTS: Multivariate analyses showed statistically significant decrease in HRV in MDD patients compared with controls. CONCLUSION: Older primary care patients with MDD have a reduced HRV. This may explain why depression is a risk factor for cardiovascular disease and mortality.

Aged↗
PubMed1998

Relationship Between Components of Heart Rate Variability and Doppler Echocardiographic Indices of Left Ventricular Systolic Performance in Patients with Coronary Artery Disease

Decreased heart rate variability (HRV) has been reported as prognostic predictor in coronary artery disease population. The aim of the study was to assess the relationship between cardiac autonomic tone disturbances and the degree of left ventricular dysfunction, estimated by 2-dimensional and Doppler echocardiography, in patients with coronary artery disease. Forty patients with angiographically proven coronary artery disease and 15 age-and sex-matched healthy subjects were included into the study (Group I and II, respectively). Routine clinical examinations, electrocardiography, coronary angiography, and 2-dimensional and Doppler echocardiography with assessment of LV systolic performance were done in all the patients and control subjects. Cardiac autonomic function was assessed by means of frequency-domain analysis of heart rate variability. The powers of LF and HF bands (P1 and P2), their ratio (P1/P2), and the logarithmic expression of powers were measured. The patients (Group I) had lower values of parasympathetic band of HRV and higher sympathetic activity than the healthy population (Group II) (p < 0.0002 for P2 and p < 0.04 for P1/P2 ratio). A positive significant correlation was seen between parasympathetic band of HRV and ejection fraction (r = 0.61, p < 0.0001), and mean acceleration of aortal flow (r = 0.56, p < 0.0001), whereas P1/P2 ratio inversely and significantly correlated with the same parameters (r = -0.46, p < 0.002 and r = -0.41, p < 0.008).

Journal Article↗
PubMed1998

A prospective study of orthostatic blood pressure in diabetic patients.

To clarify whether orthostatic blood pressure is affected by the type of diabetes, cardiac autonomic neuropathy, and the duration of diabetes, orthostatic blood pressure (passive 90 degrees tilt) was evaluated in 102 patients with insulin dependent diabetes mellitus (IDDM), 51 patients with non-insulin dependent diabetes mellitus (NIDDM), and in 238 control subjects in a first study followed up after 8 to 17 years. The heart rate reaction during deep breathing (E/I ratio) and to tilt (acceleration and brake indices) assessed cardiac autonomic function. In the first study, the lowest systolic blood pressure (LSBP) and the lowest diastolic blood pressure (LDBP) after tilt were significantly lower in IDDM patients compared with NIDDM patients (p < 0.001 for LSBP and p < 0.05 for LDBP) and controls (p < 0.001). LDBP was, however, also significantly lower (p < 0.05) in NIDDM patients than in controls. Hence, although most severe in IDDM, LDBP was disturbed in both types of diabetes. In IDDM, a low E/I ratio was associated with disturbed orthostatic blood pressure. At follow-up examinations, orthostatic blood pressure deteriorated in NIDDM but not in IDDM patients. In conclusion, LSBP and LDBP were impaired in IDDM patients compared with NIDDM and control subjects; however, LDBP was also impaired in NIDDM patients compared with controls. When the duration of diabetes increased, orthostatic blood pressure deteriorated in NIDDM but not in IDDM patients.

Adult↗
PubMed2001

Standardized tests of heart rate variability: normal ranges obtained from 309 healthy humans, and effects of age, gender, and heart rate.

The authors undertook this study to determine the effects of age, gender, and heart rate (HR) on the results of cardiac autonomic function tests for measuring heart rate variability (HRV) in a large sample of healthy subjects (n = 309). Conventional tests (deep breathing, maximum/minimum 30:15 ratio), and a standardized 5-minute resting study, including spectral analysis of HR, were used. The main findings included (1) the indices of all tests, except for the ratio of the low- (LF) to high-frequency (HF) spectral power (LF/HF ratio) and HR itself, are inversely related to age in both sexes; (2) the 5-minute spectral bands (except for the LF/HF ratio), the variation coefficient, expiratory-inspiratory ratio during deep breathing, and the maximum/minimum 30:15 ratio are independent of HR; (3) women up to the age of 55 years have a higher resting HR compared with men; (4) young and middle-aged women show a significantly lower LF power and LF/HF ratio compared with age-matched men, whereas no significant gender differences are observed in the absolute HF power. The authors computed age- and gender-dependent normal values for each of the HRV indices studied here and discuss the clinical consequences arising from gender differences in HRV.

Adolescent↗
PubMed2001

Spectral analysis of heart rate variability using the integral pulse frequency modulation model.

Spectral analysis of heart rate variability (HRV) is a widely accepted approach for assessment of cardiac autonomic function and its relationship to numerous disorders and diseases. As a rule, the non-parametric methods for HRV spectral analysis are tested using the integral pulse frequency modulation (IPFM) model. However, published results with simulated HRV signals show differences requiring further development of the existing methods. With the aim of improving estimation accuracy, an entirely IPFM-based method for HRV analysis is investigated. According to this method, the spectra are computed by finding the least squares solution of two matrix equations that are derived using the IPFM model and involve irregular samples of a signal representing the HRV. The method is validated with various synthesised signals (in all tests, the relative errors of the power estimates at the modulating frequencies are within 3%, and the relative power of the spurious terms is less than 0.8% only) and is furthermore applied to the spectral analysis of R-R interval series obtained from diabetic children. The results, with simulated and real HRV signals, show that the developed method yields very accurate estimations of the spectral region below half the mean heart rate. Moreover, it allows the detection and assessment of certain genuine modulating components beyond the traditional frequency limit of the HRV spectra.

Child↗
PubMed1998

Comparison of heart rate variability spectra using generic relationships of their input signals.

Spectral analysis of heart rate variability (HRV) is an accepted method for assessment of cardiac autonomic function and its relationship to numerous disorders and diseases. Various non-parametric methods for HRV estimation have been developed. The spectrum of counts, the instantaneous heart rate spectrum and the interval spectrum are mostly practised. Although extensive literature on their respective properties is available, there seems to be a need for a more complete comparison, eventually resulting in recommendations for applicability. The methods for HRV spectral analysis use their specific transforms of the primary R-R interval series into input signals for spectral computation. This is, in fact, the reason for obtaining different spectra. A basis for comparison is established, revealing the generic relationships of these HRV input signals. It allows for a more systematic evaluation and for further development of the considered methods. The results with simulated and real HRV data show better performance by the spectrum of counts and by a proposed instantaneous heart rate spectrum, obtained using a cubic spline interpolated input signal. The modulation depth of the primary signal can influence the accuracy of the HRV analysis methods.

Electrocardiography↗
PubMed2005

Sural nerve pathology in diabetic patients with minimal but progressive neuropathy.

AIMS/HYPOTHESIS: The early pathological features of human diabetic neuropathy are not clearly defined. Therefore we quantified nerve fibre and microvascular pathology in sural nerve biopsies from diabetic patients with minimal neuropathy. METHODS: Twelve diabetic patients underwent detailed assessment of neuropathy and fascicular sural nerve biopsy at baseline, with repeat assessment of neuropathy 8.7+/-0.6 years later. RESULTS: At baseline, neuropathic symptoms, neurological deficits, quantitative sensory testing, cardiac autonomic function and peripheral nerve electrophysiology showed minimal abnormality, which deteriorated at follow-up. Myelinated fibre density, fibre and axonal area, and g-ratio were normal but teased fibre studies showed paranodal abnormalities (p<0.001), segmental demyelination (p<0.01) and remyelination (p<0.01) without axonal degeneration. Unassociated Schwann cell profile density (p<0.04) and unmyelinated axon density (p<0.001) were increased and axon diameter was decreased (p<0.007). Endoneurial capillaries demonstrated basement membrane thickening (p<0.006), endothelial cell hyperplasia (p<0.004) and a reduction in luminal area (p<0.007). CONCLUSIONS/INTERPRETATION: The early pathological features of human diabetic neuropathy include an abnormality of the myelinated fibre Schwann cell and unmyelinated fibre degeneration with regeneration. These changes are accompanied by a significant endoneurial microangiopathy.

Axons↗