Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis.

The functional 5A/6A polymorphism of the stromelysin-1 promoter has been implicated as a potential genetic marker for the progression of angiographically determined atherosclerosis in patients with coronary artery disease. Recently, a novel interleukin-6 (IL-6) gene functional G/C polymorphism at -174 in the promoter has also been reported. In this study, we analyzed the relation of these two polymorphisms with carotid artery atherosclerosis in 109 randomly selected, middle-aged men without exercise-induced ischemia. Atherosclerosis was quantified as intima-media thickness (IMT) by high-resolution ultrasonography. Univariately, stromelysin genotype was significantly (P:=0.015) associated with IMT, and this relation remained (P:=0.033) after adjustments for age, cardiorespiratory fitness, body mass index, smoking, LDL cholesterol, and systolic blood pressure and for sonographers. The 5A/6A polymorphism independently explained 7% of the variance in carotid bifurcation IMT. The IL-6 polymorphism was also significantly associated (P:=0. 036) with increased IMT, with men homozygous for the G allele having IMT that was 11% greater than men homozygous for the C allele. Men who were homozygous for both the 6A and G alleles had an covariate adjusted IMT that was 36% greater than men who were homozygous for neither allele (P:<0.003). These data suggest that genetic factors that predispose to reduced matrix remodeling (stromelysin 6A allele) and to increased inflammation (IL-6 G allele) combine to increase susceptibility for intima-media thickening in the carotid bifurcation, a predilection site for atherosclerosis.

Oral symptoms and signs in elderly patients with type 2 diabetes mellitus. A focus on diabetic neuropathy.

OBJECTIVE: We investigated oral disorders and compared the findings with the occurrence of neuropathy in type 2 diabetes mellitus. STUDY DESIGN: Mucosal diseases, tooth loss, and temporomandibular joint dysfunction were examined in 45 patients with long-term type 2 diabetes mellitus and in 77 control subjects. The occurrence of neuropathy was evaluated by neurophysiologic tests. RESULTS: Of patients with diabetes, 56% suffered from dry mouth and 18% from glossodynia; of controls, correspondingly, 36% and 7% (P <.05); 2 or more mucosal lesions were detected in 42% and 20%, respectively (P =. 008). Temporomandibular joint dysfunction was found in 27% of subjects with diabetes and in 16% of control subjects. Peripheral neuropathy was present in 42% of patients with diabetes and in none of the controls (P <.01), and autonomic parasympathetic neuropathy in 54% and 31%, respectively (P =.02). Peripheral and autonomic parasympathetic neuropathies were independent risk factors for tooth loss and temporomandibular dysfunction. CONCLUSIONS: Diabetic neuropathy was found to be associated with tooth loss and temporomandibular joint dysfunction.

Leucine 7 to proline 7 polymorphism in the neuropeptide Y gene is associated with enhanced carotid atherosclerosis in elderly patients with type 2 diabetes and control subjects.

We have recently demonstrated that subjects having Pro7 in the signal peptide ofneuropeptide Y (NPY) have higher serum cholesterol and apolipoprotein B levels than individuals with wild-type (Leu7Leu7) signal peptide sequence. We investigated the association of Leu7Pro polymorphism with common carotid intima media thickness (IMT) assessed by ultrasonograph in patients with type 2 diabetes (n = 81; 41 men and 40 women; mean age, 67.1 yr) and nondiabetic subjects (n = 105; 48 men and 57 women; mean age, 65.5 yr) and genotyped for the Leu7Pro polymorphism in prepro-NPY. The frequency of Pro7 in prepro-NPY was 9.9% (8 of 81) in diabetic patients and 14.3% (15 of 105) in control subjects (P = 0.360). The mean common carotid IMT was 1.04 +/- 0.02 mm in nondiabetic subjects without the Leu7Pro polymorphism and 1.14 +/- 0.04 mm in nondiabetic subjects with in (P = 0.156) and 1:18 +/- 0.03 and 1.58 +/- 0.21mm in diabetic patients without and with the Leu7Pro polymorphism (P = 0.004), respectively. In the analysis of covariance of the entire group, the mean common carotid IMT was independently associated with the Leu7Pro polymorphism (F = 5.165; P = 0.024) after adjustment for known risk factors. Thus, the presence of the Pro7 substitution in the prepro-NPY associates with increased carotid atherosclerosis.

Does plasma L-arginine level play a role in regulation of blood pressure during exercise and autonomic nervous function?

Little is known of L-arginine's role in autonomic nervous regulation and physiological responses to dynamic exercise. We assessed heart rate and blood pressure during a maximal bicycle ergometer test and heart rate variability at rest in 15 healthy male volunteers, age 22-38 years. Venous blood samples for plasma L-arginine measurements were taken when subjects were sitting at rest before and at the end of exercise. The autonomic nervous function was assessed with time and frequency domain analysis of heart rate variability. Plasma L-arginine level decreased during maximal exercise from 71.4 mumol l-1 to 51.0 mumol l-1 (P < 0.0001) for all subjects studied. The systolic blood pressure during the maximal exercise test was inversely correlated with plasma L-arginine level at rest (r = -0.70, P < 0.01). Normalized low frequency band of power spectral analysis of heart rate variability correlated with L-arginine level at rest (r = 0.66, P < 0.01). In conclusion, plasma L-arginine level decreased in physical exercise, and plasma L-arginine level at rest was positively associated with the sympathetic component of power spectral analysis of heart rate variability at rest, and inversely with systolic blood pressure during physical exercise.

Saliva in non-insulin-dependent diabetic patients and control subjects: The role of the autonomic nervous system.

OBJECTIVE: The purpose of this investigation was to study the flow rate and organic constituents of whole saliva in relation to autonomic nervous function in patients with non-insulin-dependent diabetes. STUDY DESIGN: We studied the associations of saliva factors and autonomic nervous function in 45 patients with non-insulin-dependent diabetes (mean age, 68 +/- 6 years) and 77 control subjects (mean age, 67 +/- 5 years). The metabolic evolution was well known over a 10-year period from the time of diagnosis. Resting and paraffin-wax-stimulated whole saliva samples were collected and analyzed. Autonomic nervous function was evaluated by measuring heart rate variation during deep breathing and change in systolic blood pressure during orthostatic testing and by means of power spectral analysis of heart rate variability while standing. The effect of drugs used on saliva was also studied. RESULTS: No difference was seen in flow rate between the patients with diabetes and the control subjects; resting flow rates were 0.3 +/- 0.3 ml/min in the patients with diabetes and 0.3 +/- 0.2 ml/min in the control subjects, and stimulated flow rates were 1.2 +/- 1.4 ml/min in the patients with diabetes and 1.2 +/- 0.8 ml/min in the control subjects. The number of drugs used daily correlated with salivary flow rates of the control subjects (p < 0.001) but not with flow rates of the patients with diabetes. The effect of xerogenic medication on salivary flow rates was stronger in patients with diabetes than in control subjects, however. There were no statistically significant differences between patients with diabetes and control subjects in the organic constituents of saliva. The stimulated saliva secretion was associated with total power (rs = 0.343; p = 0.035), medium-frequency power (rs = 0.375; p = 0.020), and high-frequency power (rs = 0.414; p = 0.010) of heart rate variability in patients with diabetes. CONCLUSION: Saliva secretion might be more affected by xerogenic drugs and autonomic nervous dysfunction in patients with non-insulin-dependent diabetes than in nondiabetic control subjects.

Divergent association of apolipoprotein E polymorphism with vascular disease in patients with NIDDM and control subjects.

We analysed a well-characterized group of 83 patients (43 men, 40 women; mean age +/- SEM: 65.5 +/- 0.6 years at the 10-year examination) with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and in 123 control subjects (56 men, 67 women; mean age +/- 0.9 years) retrospectively for the relationship of apolipoprotein E (apo E) genotypes (E2/3, E3/3 vs E3/4, E4/4) to the incidence of clinical macrovascular disease and its risk factors and the incidence of microvascular complications of diabetes during the first 10 years of NIDDM, as well as carotid intima-media thickness measured by B-mode ultrasound at the 10-year examination. In patients with NIDDM, apo E4 genotype showed no relationship to clinical events or carotid intima-media thickness. However, in the control subjects with apo E4, the incidence of non-fatal myocardial infarction during the follow-up was increased (apo E4 positivity: 17.1%; apo E4 negativity 5.1%; p = 0.035) and they had higher common carotid intima-media thickness than those with apo E2/3 or apo E3/3 (1.15 +/- 0.05 mm vs 1.01 +/- 0.03 mm, p = 0.008). Apo E genotype groups showed no relationship to microvascular complications of diabetes, although control subjects with apo E4 positivity showed a higher frequency of microalbuminuria than those lacking apo E4. We conclude that apo E4 was a marker of vascular disease and increased atherosclerosis in non-diabetic subjects, whereas in the diabetic patients these relationships were absent. It is likely that NIDDM per se influences the vascular risk so overwhelmingly that the effects of other risk factors are obscured.

Do high proinsulin and C-peptide levels play a role in autonomic nervous dysfunction?: Power spectral analysis in patients with non-insulin-dependent diabetes and nondiabetic subjects.

BACKGROUND: Immunoreactive insulin has been shown to predict the development of parasympathetic autonomic neuropathy. It is possible that constituents of immunoreactive insulin could explain this association. In this cross-sectional study, the relationship of specific insulin, C-peptide, and proinsulin with autonomic nervous dysfunction was evaluated in 57 NIDDM patients and 108 control subjects. METHODS AND RESULTS: The frequency-domain analysis of heart rate variability was determined by using spectral analysis from stationary regions of registrations while the subjects breathed spontaneously in a supine position. Total power was divided into three frequency bands: low (0 to 0.07 Hz), medium (MFP, 0.07 to 0.15 Hz), and high (HFP, 0.15 Hz to 0.50 multiplied by the frequency equal to the mean RR interval). In NIDDM patients, total power, the three frequency bands (P<.001 for each), and the MFP/HFP ratio (P=.016), which expresses sympathovagal balance, were reduced compared with control subjects. Fasting proinsulin (r(s)=-.324, P=.014 for diabetics and r(s)=-.286, P=.003 for control subjects), C-peptide (r(s)=-.492, P<.001 for diabetics and r(s)=-.304, P=.001 for control subjects), and total immunoreactive insulin (r(s)=-.291, P=.028 for diabetics and r(s)=-.228, P=.017 for control subjects) were inversely related to MFP/HFP. For proinsulin and C-peptide the results did not change after controlling for the effects of age, body mass index, and fasting glucose. CONCLUSIONS: Both proinsulin and C-peptide levels were significantly associated with the sympathovagal balance of autonomic nervous function in NIDDM patients and control subjects, but this study cannot determine whether these compounds are directly involved in autonomic nervous dysfunction.

Divergent development of autonomic and peripheral somatic neuropathies in NIDDM.

There is no information on the mutual occurrence and the development of autonomic and peripheral somatic neuropathies based on long-term follow-up of patients with non-insulin-dependent diabetes mellitus (NIDDM). We investigated the relation between the changes in autonomic function values and electrodiagnostic values, and the relation between the occurrence of autonomic neuropathy and peripheral somatic polyneuropathy in a group of patients with newly diagnosed NIDDM (n = 133, aged 45-65 years) at baseline and 5 and 10 years later. Parasympathetic autonomic neuropathy was diagnosed on the basis of heart rate variability during deep-breathing and sympathetic autonomic neuropathy on the basis of fall in systolic blood pressure while changing from supine to standing. Polyneuropathy was diagnosed on the basis of both clinical criteria and electrodiagnostic studies (nerve conduction velocity and response-amplitude values). In 10 years 36 patients died, mainly from cardiovascular causes. Altogether 78 patients completed the study. At 10 years, parasympathetic autonomic neuropathy was diagnosed in 61.3% of those with polyneuropathy and 66.7% of those without. Likewise, the frequency of sympathetic autonomic neuropathy was similar in those with polyneuropathy (21.9%) and those without (26.5%). The respective figures for combined (both parasympathetic and sympathetic) autonomic neuropathy were 10.0% and 18.8%. The worsening of parasympathetic and sympathetic autonomic function values was not related to the worsening in electrodiagnostic results with time. In conclusion, the development of autonomic and peripheral somatic neuropathies was divergent in patients with NIDDM suggesting different pathophysiological processes for these neuropathies.

Are three-dimensional surface-shaded SPET images better than planar and coronal SPET images in the assessment of regional pulmonary perfusion?

Although single photon emission tomographic (SPET) imaging has been shown to be more sensitive than planar imaging in the diagnosis of pulmonary embolism, it has yet to be used routinely in clinical practice. The aims of this study were (1) to compare a new three-dimensional surface-shaded version of SPET (3-D SPET) with conventional planar imaging and coronal SPET slices, and (2) to evaluate observer agreement among these three modalities in the assessment of regional pulmonary perfusion. Compared with a consensus score (based on revised PIOPED criteria) of 29 cases, including nine with a clinical diagnosis of pulmonary embolism, 3-D SPET showed the highest number of normal scans, suggesting better specificity than planar or coronal SPET images. Five observers evaluated the three image sets twice within a 3-6 month period. Agreement with the consensus score was slightly better for the second reading and the average perfect agreement was 71-76%. No one image set was superior to any other in this respect. In conclusion, the number of normal scans using 3-D SPET is significantly greater relative to planar and coronal SPET scans as defined by the consensus view. Observer agreement rates are very similar with all three modalities.

Regional cerebral perfusion in cardiovascular reflex syncope.

Little is known about the regional cerebral perfusion in subjects with presyncope or syncope, and the impact that autonomic nervous dysfunction has on it. Seven subjects with cardiovascular vasodepressor reflex syncope were studied. A baseline test was performed with the patients standing in the 70 degrees upright position, while the passive head-up tilt table test with and without isoprenaline infusion was employed for provocation. Regional cerebral perfusion was assessed by means of single-photon emission tomography with technetium-99m labelled V-oxo-1,2-N, N1-ethylenedylbis-l-cysteine diethylester (baseline, and during blood pressure decline in the provocation test) and the autonomic nervous function by means of spectral analysis of heart rate variability (baseline, and before blood pressure decline in the provocation test). Every subject showed an abrupt decline in blood pressure in the provocation test (five with presyncope and two with syncope). The systolic and diastolic blood pressures decreased significantly (P<0.001) between the baseline and the provocation study time points (radiopharmaceutical injection and lowest systolic blood pressure). Mean cerebral perfusion as average count densities decreased upon provocation as compared with baseline (190+/-63 vs 307+/-90 counts/voxel, respectively, P=0.013). Hypoperfusion was most pronounced in the frontal lobe. These results suggest that cerebral perfusion decreases markedly during presyncope or syncope with systemic blood pressure decline in subjects with cardiovascular vasodepressor syncope. Furthermore, the autonomic nervous function remains unchanged before the systemic blood pressure decline.

Autonomic neuropathy predicts the development of stroke in patients with non-insulin-dependent diabetes mellitus.

BACKGROUND AND PURPOSE: Our aim was to determine the predictive factors for stroke in patients with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: We studied 133 patients with NIDDM at the time of diagnosis and 5 and 10 years later. RESULTS: The number of new fatal or nonfatal strokes was 19 (14.7%; 14 after 5-year examination). High initial fasting blood glucose (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.04 to 1.4) and the use of beta-blocking agents (OR, 6.7; 95% CI, 2.1 to 21.5) at baseline and the presence of parasympathetic neuropathy (OR, 6.7; 95% CI, 1.5 to 29.9), or sympathetic autonomic nervous dysfunction (OR, 1.1; 95% CI, 1.01 to 1.2), hypertriglyceridemia (OR, 5.7; 95% CI, 1.1 to 31.0), or use of beta-blocking agents (OR, 6.4; 95% CI, 1.3 to 31.2), and high fasting plasma glucose (OR, 1.2; 95% CI, 1.0 to 1.5) determined at 5-year examination predicted the development of stroke. CONCLUSIONS: Autonomic neuropathy is an independent risk factor for stroke in NIDDM.

Occurrence, predictors, and clinical significance of autonomic neuropathy in NIDDM. Ten-year follow-up from the diagnosis.

Little is known about the occurrence and predictive factors of autonomic neuropathy and its relationship to cardiovascular mortality in NIDDM patients, and no long-term follow-up studies including nondiabetic control subjects are available. A total of 133 patients with newly diagnosed NIDDM (70 men) and 144 control subjects (62 men) were examined at baseline and after 5 and 10 years of follow-up. Deep-breathing tests (baseline, 5-year, and 10-year) and active orthostatic tests (5- and 10-year) were performed. Criteria for autonomic neuropathy were parasympathetic (expiration-to-inspiration ratio /- 30 mmHg in the orthostatic test), and combined autonomic neuropathy (parasympathetic with sympathetic neuropathy). The frequency of parasympathetic neuropathy (NIDDM patients versus control subjects) was 4.9 vs. 2.2% (P = 0.224) at baseline, 19.6 vs. 8.5% (P = 0.017) at 5 years, and 65.0 vs. 28.0% (P < 0.001) at 10 years of follow-up. The frequency of sympathetic neuropathy was 6.8 vs. 5.6% (P = 0.709) at 5 years and 24.4 vs. 9.0% (P = 0.003) at 10 years of follow- up. These figures for combined autonomic neuropathy were 2.1 vs. 1.8% (P = 0.869) at 5 years and 15.2 vs. 4.2% (P = 0.007) at 10 years of follow-up. NIDDM patients with parasympathetic neuropathy at the 10-year examination showed worse glycemic control and higher insulin values than those without parasympathetic neuropathy. Furthermore, in our subjects, women were more prone to have parasympathetic neuropathy than men. Parasympathetic neuropathy at baseline was more frequent in those who died from a cardiovascular cause than those who did not (13 vs. 3%, P = 0.045). Similarly, sympathetic autonomic nervous dysfunction at the 5-year examination predicted the 10-year cardiovascular mortality. In conclusion, the frequency of autonomic neuropathy in NIDDM patients increases sharply with time. The development of autonomic neuropathy is connected with poor glycemic control. Interestingly, a high insulin level seems to have a predictive role in the development of parasympathetic autonomic neuropathy irrespective of obesity and glycemia.

Day-to-day variability of cardiac autonomic regulation parameters in normal subjects.

We examined the reproducibility of day-to-day variability in cardiovascular autonomic nervous function parameters (classical clinical tests and domain analysis of heart rate variability) in four healthy men during a period of 1 working week. The results did not show any significant difference in any of the parameters over the five repeated measurements. The maximum-minimum difference as percentage of the mean was under 15% for expiration to inspiration (E/I) ratio, Valsalva ratio, tachycardia ratio, 30/15 ratio, acceleration index and brake index; about 45% for baroreflex sensitivity for systolic and diastolic blood pressure and for root mean square difference (RMSSD) of successive R-R intervals; about 65-85% for low and high frequency bands, total power and medium to high frequency ratio; and about 125% for medium frequency band. The intraclass correlation coefficient (ICC) values showed that the agreement for classical autonomic parameters (except for brake index) was good. ICC for RMSSD, baroreflex sensitivity for systolic blood pressure and the spectral estimates of heart rate variation were less good. Coefficient of variation (CV) was 4% for E/I ratio, 2% for 30/15 ratio, 6% for Valsalva, 3% for tachycardia ratio, 4% for acceleration index and 5% for brake index. CV for baroreflex sensitivity and for RMSSD was about 20%. It is concluded that the variation in baroreflex sensitivity is clearly larger than in the classical autonomic nervous function parameters. One-minute fixed pace breathing period seems to be too short to allow reproducible measurement of RMSSD and the spectral parameters of heart rate variation. Learning effect could be excluded.