Impairment of cerebral autoregulation in diabetic patients with cardiovascular autonomic neuropathy and orthostatic hypotension.

AIMS: Impaired cerebrovascular reactivity and autoregulation has been previously reported in patients with diabetes mellitus. However, the contribution of cardiovascular diabetic autonomic neuropathy and orthostatic hypotension to the pathogenesis of such disturbances is not known. The purpose of this study was to evaluate cerebral blood flow velocity in response to standing in patients with diabetes and cardiovascular autonomic neuropathy with or without orthostatic hypotension. METHODS: We studied 27 patients with diabetes--eight had cardiovascular autonomic neuropathy and orthostatic hypotension (age 46.4 +/- 13.5 years, diabetes duration 25.0 +/- 11.0 years), seven had autonomic neuropathy without hypotension (age 47.3 +/- 12.7 years, diabetes duration 26.4 +/- 12.1 years), and 12 had no evidence of autonomic neuropathy (age 44.1 +/- 13.8 years, diabetes duration 17.1 +/- 10.2 years)-and 12 control subjects (age 42.6 +/- 9.7 years). Flow velocity was recorded in the right middle cerebral artery using transcranial Doppler sonography in the supine position and after active standing. RESULTS: Cerebral flow velocity in the supine position was not different between the groups studied. Active standing resulted in a significant drop of mean and diastolic flow velocities in autonomic neuropathy patients with orthostatic hypotension, while there were no such changes in the other groups. The relative changes in mean flow velocity 1 min after standing up were -22.7 +/- 16.25% in patients with neuropathy and orthostatic hypotension, +0.02 +/- 9.8% in those with neuropathy without hypotension, -2.8 +/- 14.05% in patients without neuropathy, and -9.2 +/- 15.1% in controls. CONCLUSIONS: Patients with diabetes and cardiovascular autonomic neuropathy with orthostatic hypotension show instability in cerebral blood flow upon active standing, which suggests impaired cerebral autoregulation.

Platelet activation in diabetic cardiovascular autonomic neuropathy.

AIMS: Platelet activation is known to be associated with arrhythmic effects in myocardial ischaemia. The present study attempts to clarify whether diabetic cardiovascular autonomic neuropathy (CAN) is associated with intravascular platelet activation. METHODS: Platelet activation was assessed by flow cytometry analysis in 30 patients with Type 1 diabetes mellitus screened for diabetic complications. Fifteen patients showed evidence of CAN as assessed by a battery of standard cardiovascular autonomic reflex tests. Fifteen patients without CAN were then selected as a matched control group. Platelet activation was assessed by flow cytometric detection of activation-dependent platelet membrane antigens (P-selectin (CD62), thrombospondin, lysosomal GP53 (CD63) and ligand-induced binding site-1 of GPIIb/IIIa (LIBS-1)). RESULTS: Significantly more activated platelets were detected in the patients with CAN showing 20.9% (coefficient of variation (CV) 44%) CD63+ (vs. 17.2% (CV 19%) in controls, P < or = 0.05), 6.4% (CV 87%) CD62+ (vs. 4.1% (CV 37%), P < or = 0.05), and 6.7% (CV 55%) thrombospondin+ (vs. 4.6% (CV 39%), P < or = 0.01) platelets, respectively. LIBS-1 on platelets was not significantly different between patients with and without CAN. No correlation was found between glucose metabolism and platelet activation. CONCLUSIONS: Cardiovascular autonomic neuropathy is associated with platelet activation in Type 1 diabetes mellitus. The high platelet activation may reflect an increased prothrombotic state in diabetic cardiovascular autonomic dysfunction.

Normal ranges and reproducibility of statistical, geometric, frequency domain, and non-linear measures of 24-hour heart rate variability.

Diabetic cardiovascular autonomic neuropathy (CAN) carries an increased risk of mortality. The early detection and characterization of CAN has traditionally been based on the results of autonomic reflex tests (AFTs). A variety of different measures to quantify 24-hour heart rate variability (HRV) have recently been introduced, but their normal ranges, reliability, and validity in patients with CAN have not been adequately studied. We established the normal ranges of statistical (SDNN index, CV, SNN50, RMSSD), geometric (triangular index (TI), triangular interpolation (TINN), top angle index [TAI]), frequency domain (spectral power in the VLF, LF, and HF bands, LF/HF ratio, LF in normalized units [NU]), and non-linear measures (CV1 and CV2 of the Poincaré plot) of 24-hour HRV in 94 healthy control subjects. Day-to-day reproducibility was evaluated on two occasions in 17 healthy subjects and 9 diabetic patients. The parameters of HRV were computed over time periods representing the day (6:00-24:00 hours), night (00:00-6:00 hours), and 24 hours in total. The results of all indexes, except for the LF/HF ratio and LF-NU, declined significantly with increasing age (p<0.05), but were independent of sex and BMI. The statistical, geometric, and non-linear measures (p<0.05), but not the frequency-domain parameters decreased significantly with increasing heart rate. Since the HRV data showed log normal distribution, log transformation was used to define the age-related lower limits of normal at the 2.5th centile. Intraindividual reproducibility was highest for the geometric measures. The nonlinear and statistical parameters also showed high reliability, except for the SNN50. The repeatability of the frequency domain measures was somewhat lower but still satisfactory. Reproducibility was lower in the diabetic than in the control group, higher during the day than during the night, and better than that reported previously for the AFTs. In conclusion, in healthy subjects the measures of 24-h HRV are not related to sex or BMI, but strongly dependent on age and heart rate, the latter except for the frequency domain measures. The majority of the HRV measures, in particular the geometric parameters, show a relatively high intraindividual reproducibility which underlines their suitability for the use in prospective studies.

Effect of glycaemic control on myocardial sympathetic innervation assessed by [123I]metaiodobenzylguanidine scintigraphy: a 4-year prospective study in IDDM patients.

Diabetic cardiovascular autonomic neuropathy (CAN) has been directly characterized by reduced or absent myocardial [123I]metaiodobenzylguanidine (MIBG) uptake, but there is no information available on the relationship between the myocardial adrenergic innervation defects and long-term glycaemic control. In a prospective study over a mean of 4 years we examined myocardial sympathetic innervation in 12 Type 1 (insulin-dependent) diabetic patients using MIBG scintigraphy (absolute and relative global MIBG uptake at 2 h p.i.) in conjunction with cardiovascular autonomic function tests, QTc interval, and QT dispersion. Six healthy non-diabetic subjects served as controls for the MIBG scintigraphy at baseline. HbA1c was measured twice a year. One patient, in whom MIBG accumulation was reduced maximally, died during follow up. Among the remaining patients 5 had good or borderline glycaemic control (mean HbA1c < 7.6%; Group 1), whereas 6 patients were poorly controlled (mean HbA1c > or = 7.6%; Group 2). Absolute global MIBG uptake increased from baseline to follow-up by 260 (-190-540) [median (range)] cpm/g in Group 1 and decreased by -150 (-450-224) cpm/g in Group 2 (p < 0.05 vs Group 1). Relative global MIBG uptake decreased by -1.7 (-3.4-9.4) % in Group 1 and by -4.7 (-17.4-1.3) % in Group 2 (p < 0.05 vs Group 1). No differences between the groups were noted for the changes in the automatic function tests, QTc interval, and QT dispersion. In conclusion, long-term poor glycaemic control constitutes an essential determinant in the progression of left ventricular adrenergic dysinnervation which may be prevented by near-normoglycaemia. Evaluation of susceptibility to metabolic intervention may be superior when CAN is characterized directly by MIBG scintigraphy rather than by indirect autonomic function testing.

Evaluation of QT interval length, QT dispersion and myocardial m-iodobenzylguanidine uptake in insulin-dependent diabetic patients with and without autonomic neuropathy.

1. An association has been reported between QT interval abnormalities and cardiovascular autonomic neuropathy in diabetic patients. The QT interval abnormalities reflect local inhomogeneities of ventricular recovery time and may be related to an imbalance in cardiac sympathetic innervation. Sympathetic innervation of the heart can be visualized and quantified by single-photon emission-computed tomography with m-[123I]iodobenzylguanidine. In this study we evaluated cardiac sympathetic integrity by m-[123I]iodobenzylguanidine imaging and the relationship between both QT interval prolongation and QT dispersion from standard 12-lead ECG variables and m-[123I]iodobenzylguanidine uptake in insulin-dependent diabetic patients. 2. Three patient groups were studied, comprising six healthy control subjects, nine diabetic patients without cardiovascular autonomic neuropathy (CAN-) and 12 diabetic patients with cardiovascular neuropathy (CAN+). Resting 12-lead ECG was recorded for measurement of maximal QT interval and QT dispersion. The QT interval was heart rate corrected using Bazett's formula (QTc) and the Karjalainen approach (QTk). Quantitative measurement (in counts/min per g) and visual defect pattern of m-[123I]iodobenzylguanidine uptake were performed using m-[123I]iodobenzylguanidine single-photo emission-computed tomography. 3. Global myocardial m-[123I]iodobenzylguanidine uptake was significantly reduced in both diabetic patient groups compared with control subjects. The visual defect score of m-[123I]iodobenzylguanidine uptake was significantly higher in CAN+ diabetic patients than in control subjects and in CAN- patients. This score was not significantly different between control subjects and CAN- patients. QTc interval and QT dispersion were significantly increased in CAN+ diabetic patients as compared with control subjects (QTc: 432 +/- 15 ms versus 404 +/- 19 ms, P < 0.05; QT dispersion: 42 +/- 10 versus 28 +/- 8 ms, P < 0.05). QT dispersion was also significantly longer in CAN- diabetic patients than in control subjects (41 +/- 9 ms versus 28 +/- 8 ms, P < 0.05). QTc interval was significantly related to global myocardial m-[123I]iodobenzylguanidine uptake and defect score in diabetic patients (r = -0.648, P < 0.01, and r = 0.527, P < 0.05, respectively). There was no correlation between QT dispersion and both m-[123I]iodobenzylguanidine uptake measures. 4. In conclusion, these findings suggest that m-[123I]iodobenzylguanidine imaging is a valuable tool for the detection of early alterations in myocardial sympathetic innervation in long-term diabetic patients without cardiovascular autonomic neuropathy. Insulin-dependent diabetic patients with cardiovascular autonomic neuropathy have a delayed cardiac repolarization and increased variability of ventricular refractoriness. The cardiac sympathetic nervous system seems to be one of the determinants of QT interval lengthening, but does not appear to be involved in dispersion of ventricular recovery time. It is assumed that QT dispersion is based on more complex electrophysiological mechanisms which remain to be elucidated.

Application of isotope-selective nondispersive infrared spectrometry (IRIS) for evaluation of [13C]octanoic acid gastric-emptying breath tests: comparison with isotope ratio-mass spectrometry (IRMS).

Suitability of isotope-selective nondispersive infrared spectrometry (IRIS) for evaluation of [13C]octanoic acid gastric-emptying breath test was assessed and compared with standard isotope ratio-mass spectrometry (IRMS). The estimated bias of IRMS and IRIS measurements of baseline-corrected 13CO2 exhalation amounted to +/-0.1 and +/-0.6 delta delta values (n = 360), respectively. In breath tests performed on 60 diabetic patients, the gastric emptying parameters were calculated by nonlinear regression analysis of the time course of 13CO2 exhalation: half-emptying time (t1/2,breath, 90 +/- 39 min), lag phase (tlag,breath, 34 +/- 27 min), and gastric emptying coefficient (GEC, 2.9 +/- 0.5). A reasonable linear correlation was found between the two methods (y = IRIS, x = IRMS) with respect to delta delta values (y = 0.35 + 0.92x, r = 0.985, Sy[symbol: see text]x = +/-0.6, n = 1116) and a rather good agreement of the computed gastric emptying parameters was obtained (t1/2,breath: y = 0.99x + 4.06, Sy[symbol: see text]x = +/- 6.3; tlag, breath: y = 0.97x + 0.96, Sy[symbol: see text]x = +/-3.4; GEC: y = 0.97x - 0.01, Sy[symbol: see text]x = +/-0.09).

[13C]octanoic acid breath test for non-invasive assessment of gastric emptying in diabetic patients: validation and relationship to gastric symptoms and cardiovascular autonomic function.

Since there is a need for a widely applicable non-invasive test to assess gastric emptying in diabetic patients, we evaluated the sensitivity, specificity, and reproducibility of the [13C]octanoic acid breath test as compared with scintigraphy. Moreover, we examined the relationship between the breath test indices and gastric symptoms, cardiovascular autonomic function, and metabolic parameters. Forty healthy control subjects and 34 diabetic patients were studied. Three indices of gastric emptying, assessed by the breath test, were computed: half-emptying time (t1/2breath), gastric emptying coefficient (GEC), and lag phase. Furthermore, the half-emptying time, measured by scintigraphy (t1/2scint), was calculated and gastric symptoms and cardiovascular autonomic neuropathy (CAN) were scored. The coefficients of variation of day-to-day reproducibility in 10 healthy subjects were 29.6% for t1/2breath, 7.4% for GEC, and 46.5% for lag phase. An abnormal delay for t1/2scint (> 100 min) or t1/2breath (> 200 min) was noted in 12 patients. Based on the results for t1/2scint, the sensitivity of t1/2breath and GEC was 75% and the specificity was 86%. Both t1/2breath (rs = 0.523; p < 0.05) and GEC (r2 = -0.594; p < 0.05) were significantly associated with the gastric symptom score. A significant relationship to the CAN score was demonstrated for t1/2breath (rs = 0.448; p < 0.05), GEC (rs = -0.467; p < 0.05), and t1/2scint (rs = 0.602; p < 0.05). There were no significant associations of the breath test indices with the blood glucose levels during the test, HbA1c, age, and duration of diabetes. In patients with abnormal t1/2scint (n = 12) not only was t1/2breath significantly prolonged and GEC reduced, but also the scores of CAN and gastric symptoms were significantly increased as compared with those who had a normal t1/2scint (n = 22). We conclude that the [13C]octanoic acid breath test represents a suitable measure of delayed gastric emptying in diabetic patients which is associated with the severity of gastric symptoms and CAN but not affected by the blood glucose level.