Assessment of baroreceptor-cardiac reflex sensitivity using time domain analysis in patients with IDDM and the relation to left ventricular mass index

Summary Autonomic dysfunction in insulin-dependent diabetic (IDDM) patients has been associated with abnormalities of left ventricular function and an increased risk of sudden death. A group of 30 patients with IDDM and 30 age, sex and blood pressure matched control subjects underwent traditional tests of autonomic function. In addition, baroreceptor-cardiac reflex sensitivity (BRS) was assessed using time domain (sequence) analysis of systolic blood pressure and pulse interval data recorded non-invasively using the Finapres beat-to-beat blood pressure recording system. ’Up BRS' sequences–increases in systolic blood pressure associated with lengthening of R-R interval, and ’down BRS' sequences–decreases in systolic blood pressure associated with shortening of R-R interval were identified and BRS calculated from the regression of systolic blood pressure on R-R interval for all sequences. We also assessed heart rate variability using power spectral analysis and, after expressing components of the spectrum in normalised units, assessed sympathovagal balance from the ratio of low to high frequency powers. IDDM subjects underwent 2-D echocardiography to assess left ventricular mass index. Standard tests of autonomic function revealed no differences between IDDM patients and control subjects, but dramatic reductions in baroreceptor-cardiac reflex sensitivity were detected in IDDM patients. ’Up BRS' when supine was 11.2 ± 1.5 ms/mmHg (mean ± SEM) compared with 20.4 ± 1.95 in control subjects (p < 0.003) and when standing was 4.1 ± 1.9 vs 7.6 ± 2.7 ms/mmHg (p < 0.001). Down BRS when supine was 11.5 ± 1.2 vs 22 ± 2.6 (p < 0.001) and standing was 4.4 ± 1.9 vs 7.3 ± 2.5 ms/mmHg (p < 0.003). There were significant relations between impairment of the baroreflex and duration of diabetes (p < 0.001) and poor glycaemic control (p < 0.001). From a fast Fourier transformation of supine heart rate data and using a band width of 0.05–0.15 Hz as low-frequency and 0.2–0.35 Hz as high frequency total spectral power of R-R interval variability was significantly reduced in the IDDM group for both low-frequency (473 ± 62.8 vs 746.6 ± 77.6 ms² p = 0.002) and high frequency bands 125.2 ± 12.9 vs 459.3 ± 89.8 ms² p < 0.0001. When the absolute powers were expressed in normalised units the ratio of low frequency to high frequency power (a measure of sympathovagal balance) was significantly increased in the IDDM group (2.9 ± 0.53 vs 4.6 ± 0.55, p < 0.002 supine: 3.8 ± 0.49 vs 6.6 ± 0.55, p < 0.001 standing). Thus, time domain analysis of baroreceptor-cardiac reflex sensitivity detects autonomic dysfunction more frequently in IDDM patients than conventional tests. Impaired BRS is associated with an increased left ventricular mass index and this abnormality may have a role in the increased incidence of sudden death seen in young IDDM patients. [Diabetologia (1996) 39: 1385–1391] Received: 9 April 1996 and in revised form: 19 July 1996     

Baroreflex sensitivity is depressed in microalbuminuric Type I diabetic patients at rest and during sympathetic manoeuvres

Abstract Aims/hypothesis. To evaluate baroreflex sensitivity (BRS) in microalbuminuric and normoalbuminuric Type I (insulin-dependent) diabetic patients without autonomic neuropathy and in healthy control subjects. Methods. Microalbuminuric Type I diabetic patients (n = 15) were matched for age, sex, body mass index (BMI) and smoking habits with 15 normoalbuminuric patients and with 15 healthy control subjects. All subjects had a blood pressure less than 160/95 mmHg, a BMI less than 30 kg/m² and normal autonomic function on standard tests. Blood pressure and heart rate were measured non-invasively (Finapres) at rest and during sympathetic activation (handgrip, mental stress, standing). The baroreflex sensitivity was defined as the mean gain between blood pressure variability and heart rate variability in the 0.07–0.15 Hz frequency band. Results. Resting baroreflex sensitivity was decreased in the microalbuminuric patients (3.5 ± 0.4 ms/mmHg) compared with the normoalbuminuric patients and the healthy subjects (7.6 ± 1.6 and 9.5 ± 1.1 ms/mmHg, respectively, p < 0.001). The sympathetic tests reduced baroreflex sensitivity similarly in the groups without changing the between group differences. Conclusion/interpretation. Baroreflex sensitivity is reduced in Type I diabetic patients with microalbuminuria but without autonomic neuropathy. A prospective study should indicate whether this early abnormality in cardiovascular reflex function is a risk factor of cardiovascular mortality in these patients. [Diabetologia (1999) 42: 1345–1349] Received: 20 May 1999 and in revised form: 8 July 1999     

Early autonomic dysfunction in type 1 diabetes: a reversible disorder?

Aims/hypothesis  Cardiac autonomic neuropathy is associated with increased morbidity and mortality rates in patients with type 1 diabetes. The prevalence of early autonomic abnormalities is relatively high compared with the frequency of manifest clinical abnormalities. Thus, early autonomic dysfunction could to some extent be functional and might lead to an organic disease in a subgroup of patients only. If this is true, manoeuvres such as slow deep-breathing, which can improve baroreflex sensitivity (BRS) in normal but not in denervated hearts, could also modify autonomic modulation in patients with type 1 diabetes, despite autonomic dysfunction. Methods  We compared 116 type 1 diabetic patients with 36 matched healthy control participants and 12 heart-transplanted participants with surgically denervated hearts. Autonomic function tests and spectral analysis of heart rate and blood pressure variability were performed. BRS was estimated by four methods during controlled (15 breaths per minute) and slow deep-breathing (six breaths per minute), and in supine and standing positions. Results  Conventional autonomic function tests were normal, but resting spectral variables and BRS were reduced during normal controlled breathing in patients with type 1 diabetes. However, slow deep-breathing improved BRS in patients with type 1 diabetes, but not in patients with surgically denervated hearts. Standing induced similar reductions in BRS in diabetic and control participants. Conclusions/interpretation  Although we found signs of increased sympathetic activity in patients with type 1 diabetes, we also observed a near normalisation of BRS with a simple functional test, indicating that early autonomic derangements are to a large extent functional and potentially correctable by appropriate interventions.     

24-h blood pressure and autonomic function is related to albumin excretion within the normoalbuminuric range in IDDM patients

Summary Significant changes in both blood pressure, autonomic function and kidney ultrastructure are observed in insulin-dependent diabetic (IDDM) patients with microalbuminuria. Intervention strategies are evaluated at even earlier stages of disease. Identification of patients at risk of developing microalbuminuria must be based on a thorough knowledge of the relations between key pathophysiological parameters in patients with normoalbuminuria. The aim of the present study was to characterize the interactions of urinary albumin excretion (UAE), 24-h ambulatory blood pressure (AMBP), and sympathovagal balance in a large group of normoalbuminuric IDDM patients. In 117 normoalbuminuric (UAE < 20 μg/min) patients we performed 24-h AMBP (Spacelabs 90 207), with assessment of diurnal blood pressure and heart rate (HR) variation, and short-term (three times 5 min) power spectral analysis of RR interval oscillations, as well as cardiovascular reflex tests (HR variation to deep breathing, postural HR and blood pressure response). Patients with UAE above the median (4.2 μg/min) had significantly higher 24-h systolic and diastolic AMBP (125 ± 10.1/76 ± 7.2 mmHg) compared to the low normoalbuminuric group (120 ± 8.4/74 ± 5.1 mmHg), p < 0.01 and 0.02, respectively. Patients with UAE above the median had significantly reduced short-term RR interval variability including both the high frequency component (5.47 ± 1.36 vs 6.10 ± 1.43 ln ms²), and low frequency component (5.48 ± 1.18 ln ms² compared to 5.80 ± 1.41 ln ms²), p < 0.02 and p = 0.04 (ANOVA). In addition, patients with high-normal UAE had reduced mean RR level (faster heart rates) 916 ± 108 compared to 963 ± 140 ms, p < 0.04. These differences were not explained by age, duration of diabetes, gender, level of physical activity, or cigarette smoking. HbA_{1 c} was significantly higher (8.6 ± 1.2 vs 8.2 ± 1.0 %, p = 0.03) in the group with high normal UAE. Comparing normoalbuminuric IDDM patients with UAE above and below the median value, we found significantly higher AMBP in combination with significant differences in sympathovagal balance and significantly poorer glycaemic control in the group with high-normal albumin excretion. Our data demonstrate interactions between albumin excretion, blood pressure, autonomic function, and glycaemic status, already present in the normoalbuminuric range and may describe a syndrome indicative of later complications. [Diabetologia (1997) 40: 718–725] Received: 9 January 1997 and in revised form: 12 March 1997     

Impaired short-term blood pressure regulation and autonomic dysbalance in children with type 1 diabetes mellitus

Aims Because reduction in baroreceptor sensitivity (BRS) has been associated with hypertension in the normal population and with increased cardiovascular morbidity and mortality in patients with diabetes mellitus, we measured BRS in a patient cohort of children with type 1 diabetes mellitus. Methods Two hundred and eight children (150 patients with type 1 diabetes mellitus, mean age 13.9 ± 2.8 years, 70 boys, mean HbA_1c 7.8 ± 1.4%; and 58 healthy controls, mean age 14.1 ± 3.1 years, 32 boys) were studied. BRS and heart rate variability (HRV) were analysed from a short-time ECG and BP recording using the sequence method (BRS) and the frequency domain method (HRV). Results There were 111 of 150 patients (74%) and 5 of 58 controls (8.6%) that showed impaired BRS. Mean BRS differed significantly between patients and controls (18.4 ± 7.2 vs 25.8 ± 8.2 ms/mm, p < 0.001). BRS correlated inversely with systolic BP (r = −0.23, p = 0.009) and was related to diabetes duration (r = −0.194, p = 0.027). Analysis of HRV showed greater sympathetic and less parasympathetic influence in patients than in controls (low frequency/high frequency ratio 1.3 ± 0.8 vs 0.9 ± 0.6, p < 0.05); the low frequency/high frequency ratio was inversely correlated with BRS (r = −0.28, p = 0.001). Conclusions/interpretation Diabetic children show reduced BRS. In our patient group, the single risk factor for this finding was found to be the disease duration. The degree of BRS impairment was related to the degree of autonomic dysbalance. R. Dalla Pozza and S. Bechtold contributed equally to this study.     

Effects of gender and aging on differential autonomic responses to orthostatic maneuvers

Background: There are gender differences in heart rate and blood pressure response to postural change. Also, normal aging is often associated with diminished cardiac autonomic modulation during postural change from supine to upright position. Nevertheless, the exact mechanisms of these physiological alterations are not entirely understood. Methods: A total of 362 volunteers (206 females, age range: 10–88 years) underwent continuous, noninvasive, beat‐to‐beat blood pressure and ECG recordings in supine and upright position. To calculate spontaneous baroreflex sensitivity (BRS), blood pressure and RR interval fluctuations were reconstructed using the time‐domain sequential technique. Furthermore, mean systolic and diastolic blood pressure, mean heart rate, and frequency‐domain parameters of heart rate variability (low‐frequency power [LF], low‐frequency power in normalized units [LFn] high‐frequency power [HF], high‐frequency power in normalized units [HFn], low‐/high‐frequency ratio [LF/HF], and total power [TP]) were analyzed in both supine and standing positions. To investigate age‐related differences, subjects were divided into four equally sized groups (quartile l: 10–33 years; ll: 34–42 years; III: 43–57 years; and lV: 58–88 years), as well as decades (l: 10–19 years; ll: 20–29 years; lll: 30–39 years; lV: 40–49 years; V: 50–59 years; Vl: 60–69 years; Vll: ≥ 70 years). Results: A continuous decline in BRS, LF, HF, and TP was observed with increasing age in both male and female subjects, regardless of posture. Gender comparison showed significantly higher values of LF (supine P < 0.001; upright P < 0.05), LFn (supine P < 0.001; upright P < 0.01), and TP (supine P < 0.05; upright P < 0.05) in men than women in supine and standing positions. HF revealed no gender difference and HFn (supine P < 0.001; upright P < 0.05) was larger in women. Log BRS correlated well with log LF and log HF in both supine and standing positions. Conclusions: There are significant differences in postural cardiac autonomic modulation between men and women, and the degree of autonomic response to orthostatic maneuvers varies with normal aging. These results may explain gender‐ and age‐related differences in orthostatic tolerance.     

Ambulatory pulse pressure, decreased nocturnal blood pressure reduction and progression of nephropathy in type 2 diabetic patients

Aims/hypothesis  We followed type 2 diabetic patients over a long period to evaluate the predictive value of ambulatory pulse pressure (PP) and decreased nocturnal BP reduction (non-dipping) for nephropathy progression. Methods  Type 2 diabetic patients (n = 112) were followed for an average of 9.5 (range 0.5–14.5) years. At baseline, all patients underwent 24 h ambulatory BP measurement. Urinary albumin excretion rate was evaluated by three urinary albumin:creatinine ratio measurements at baseline and follow-up. Results  At baseline, patients who subsequently progressed to a more advanced nephropathy stage (n = 35) had reduced diastolic night/day BP variation and higher 24 h systolic BP and PP values; they also had more advanced nephropathy and were more likely to smoke than those with no progression of nephropathy (n = 77). In a Cox regression analysis, independent predictors of nephropathy progression were 24 h PP (p < 0.01), diastolic night:day BP ratio (p = 0.02) and smoking (p = 0.02). The adjusted hazards ratio (95% CI) for each mmHg increment in 24 h PP was 1.04 (1.01–1.07), whereas the adjusted hazards ratio (95% CI) for each 1% increase in diastolic night:day BP ratio was 1.06 (1.01–1.11). Only one of 33 patients (3.0%) with both a diastolic night:day BP ratio and a 24 h PP below the median progressed, whereas 17 of 32 patients (53.1%) with both a diastolic night:day BP ratio and a 24 h PP equal to or above the median progressed to a more advanced nephropathy stage (p < 0.001). Conclusions/interpretation  Ambulatory PP, impaired nocturnal BP decline and smoking are strong, independent predictors of nephropathy progression in type 2 diabetic patients.     

Ambulatory Blood Pressure Variability Is Increased in Diabetic Hypertensives

The purpose of this study was to examine the possible difference in the 24-hr BP profile—including short-term BP variability, assessed as the standard deviation—between diabetic and non-diabetic hypertensives. We measured 24-hr ambulatory BP in 11 diabetic hypertensives (diabetic HT) and 10 non-diabetic hypertensives (non-diabetic HT) who were hospitalized for the educational program in our hospital and were under stable salt intake. Renal function and sleep apnea were also estimated. There were no significant differences in 24-hr systolic BP (141 mmHg vs. 135 mmHg, ns), daytime systolic BP (143 mmHg vs. 138 mmHg, ns), and nighttime systolic BP (135 mmHg vs. 130 mmHg, ns) between diabetic HT and non-diabetic HT. The values of 24‐hr HR (69.7 beats/min vs. 65.2 beats/min, ns) and 24-hr HR variability (9.9 beats/min vs. 10.1 beats/min, ns) were also similar between the groups. Interestingly, diabetic HT had a significantly greater 24-hr systolic and diastolic BP variability than non-diabetic HT (18.2 mmHg vs. 14.5 mmHg, p < 0.05; 11.5 mmHg vs. 9.6 mmHg, p < 0.05, respectively). The values for creatinine clearance, urinary protein excretion, and apnea-hypopnea index were similar between the groups. Bivariate linear regression analysis demonstrated that fasting blood glucose was the primary determinant of 24-hr diastolic BP variability (r = 0.661, p < 0.01). Multiple stepwise regression analysis revealed that fasting blood glucose was a significant and independent contributor to 24-hr systolic BP variability (r = 0.501, p < 0.05). Taken together, these results demonstrate that BP variability is increased in diabetic hypertensives. Furthermore, it is possible that an elevation of fasting blood glucose may contribute to the enhanced BP variability in hypertensives.     

Acute effects of sildenafil on flow mediated dilatation and cardiovascular autonomic nerve function in type 2 diabetic patients

Background Sildenafil, frequently used as on demand medication for the treatment of erectile dysfunction (ED), has been suggested to improve endothelial function but also to alter blood pressure (BP) and induce sympathetic activation. In people with type 2 diabetes mellitus (T2DM), a high‐risk population, the safety profile and the effects on endothelial function of a maximal sildenafil dose (100 mg) have not been investigated and therefore constituted the aim of our study. Methods A double‐blind, placebo‐controlled, cross‐over trial using a single dose of 100 mg sildenafil or placebo has been conducted in 40 subjects with T2DM without known CVD. Haemodynamic parameters, flow mediated dilatation (FMD) in brachial artery, cardiovascular autonomic function tests and spontaneous baroreflex sensitivity (BRS) were measured. Results Sixty minutes after administration of sildenafil but not placebo, a fall of supine systolic blood pressure (SBP) (?5.41 ± 1.87 vs. + 0.54 ± 1.71 mmHg) and diastolic blood pressure (DBP) (?4.46 ± 1.13 vs. + 0.89 ± 0.94 mmHg), as well as orthostatic SBP (?7.41 ± 2.35 vs. + 0.94 ± 2.06 mmHg) and DBP (?5.65 ± 1.45 vs. + 1.76 ± 1.00 mmHg) during standing occurred, accompanied by an increase in heart rate (+1.98 ± 0.69 vs. ? 2.42 ± 0.59 beats/min) (all p < 0.01 vs. placebo). Changes in BP to standing up, FMD, time domain and frequency domain indices of heart rate variability (HRV) and BRS were comparable between sildenafil and placebo. Conclusions Sildenafil administered at a maximum single dose to T2DM men results in a mild increase in heart rate and decrease in BP, but it induces neither an acute improvement of FMD nor any adverse effects on orthostatic BP regulation, HRV and BRS. Copyright © 2008 John Wiley & Sons, Ltd.     

Abnormal temporal dynamics of blood pressure and RR interval regulation in patients with chronic heart failure: relationship to baroreflex sensitivity

It is not known whether the temporal relationship between blood pressure (BP) and RR interval is modulated by the same mechanisms in normal controls and patients with chronic heart failure (CHF). We investigated this under conditions of controlled slow breathing. Fifty patients with CHF and 17 age-matched normals underwent recordings of BP and RR interval during 0.1 Hz controlled breathing. Fourier analysis was used to determine the phase relationships between the oscillations in respiration, BP and RR interval. There was no significant difference between patients and normals in the distribution of phase angle between respiration and BP (P=0.06) or between respiration and RR interval (P=0.21). There was, however, a significant difference in the phase relationship between BP and RR interval (P=0.03): in normals, BP led RR interval by a mean phase angle of 48.4 degrees (S.D. 16.8 degrees ). In patients with CHF, the distribution of phase difference was much wider [34.4 degrees (S.D. 62.8 degrees )]. The source of this wide distribution was patients with attenuated baroreflex sensitivity (BRS), with those with preserved BRS showing a relationship between BP and RR interval similar to the normal group. During controlled respiration, normal subjects exhibit a stereotyped relationship between oscillations in BP and RR interval, which is mediated by the baroreflex. This relationship is maintained in those patients with CHF who have a preserved BRS. In contrast, patients with an attenuated BRS show a wide distribution in the relationship between BP and RR interval ranging from completely in phase, to anti-phase. This may have important implications for the measurement and interpretation of BRS in patient groups where BRS is weak.     

Utility and limitations of ambulatory blood pressure monitoring and tilting test: evaluation of baroreceptor reflex sensitivity

Ambulatory blood pressure monitoring(ABPM) permits 24-hour measurement of blood pressure(BP) without restricting the subject's activities. The tilting test is used to evaluate BP variability and autonomic nervous responses, especially baroreceptor reflex sensitivity(BRS) during changes of body position. The change of BP and BRS are common to both ABPM and the tilting test. In this instance, BRS is expressed as the ratio between heart rate(HR) variation and systolic BP variation(delta RR/delta SBP). The results were the same as those produced by all other tests including sequential method, squatting test, the neck chamber method, and tilting test. Therefore, we investigated the correlation between BRS and BP changes monitored mainly by means of ABPM. Twenty-four-hour BP variation(SD) manifest both short-term variability(SDh), and long-term variability extending over 24 hours(SD24) (SD2 = SDh2 + SD24(2). In the former case(SDh), atherosclerosis and lowered BRS participate, and in the latter case(SD24), activation of the sympathetic nervous system(SNA) participates strongly. Each BP value during 24 hours(Pi: i = 1, 2, ... 10(5)) is expressed by the product(Pi = phi i x P0) of the ratio of variability(phi i) and sleep-time base BP(P0) values. The phi i is expressed by HR variation and two elements: the cardiovascular response element and the BRS element. In mild cases of essential hypertension, the correlation between Pi and HR variation is high. In severe cases of essential hypertension and in cases of Shy-Drager syndrome, short-term phi i caused by BRS decrease is large, and the correlation between phi i and HR variation during 24 hours drops. Although measuring short-time variability indirectly with ABPM is impossible, BRS can be evaluated on the basis of the product(BI) of diastolic BP(Pd) and pulse interval(RR). The multi-biomedical recorder(TM2425, A&D, Co.) permits 24-hour monitoring of body position and daily activities(acceleration), simultaneous with evaluation of BI, which is related to autonomic nervous activity and BRS. Its employment is, therefore, considered clinically useful.     

Renin--angiotensin--aldosterone system, RR-interval and blood pressure variability during postural changes after myocardial infarction

Low frequency (LF, 0•04–0•15 Hz) and high frequency(HF, 0•15–0•40 Hz) components of heart ratevariability hate been used to evaluate the autonomic nervoussystem. The sympathico-vagal balance as well as the renin-angiotensin-aldosterone(RAA) axis are disturbed in the post-acute phase of acute myocardialinfarction (AMI). This study examined the relationship betweenthe RAA-axis and spectral indices of the RR-interval and bloodpressure (BP) variabilities during postural manoeuvres in thepost-AMI period. Power spectral analysis of the RR-intervaland BP variability was computed from non-invasive beat-to-beatBP measurements 10–12 days post-AMI, using Fast-Fouriertransforms. Concomitantly, hormonal changes of the RAA-axiswere determined and data were further correlated with the leftventricular ejection fraction. When the patient moved from the lying to the supine positionall RAA-axis parameters significantly increased. Both LF andHF components of total RR-interval variability decreased uponstanding, while the LF component of systolic and diastolic BPvariability increased and HF components remained constant Inthe upright position, plasma renin activity (P<0•01)and angiotensin II (borderline) were inversely related withthe LF component of systolic BP. The aldosterone level was dissociatedfrom plasma renin activity and angiotensin II. The left ventricularejection fraction was inversely correlated (P<0•05)with systolic and diastolic BP variabilities and their LF andHF powers. These results suggest that the renin-angiotensinII system in the post-acute phase of AMI patients treated withaspirin and ß-blocking agents is correlated with cardiovascularautoregulation during postural manoeuvres.     

Relationship of QT interval variability to heart rate and RR interval variability

The study investigated whether the beat-to-beat QT interval variability relationship to the mean heart rate and the RR interval variability depended on the cardiovascular autonomic status changed by postural positioning. Repeated long-term 12-lead Holter recordings were obtained from 352 healthy subjects (mean age 32.7 ± 9.1 years, 176 females) while they underwent postural provocative tests involving supine, unsupported sitting and unsupported standing positions. Each recording was processed as a sequence of overlapping 10-second segments. In each segment, the mean RR interval, the coefficients of variance of the RR intervals (RRCV) and the QT intervals (QTCV) were obtained. In each subject, these characteristics, corresponding to different postural positions, were firstly averaged and secondly used to obtain within-subject correlation coefficients between the different characteristics at different postural positions. While the within-subject means of RRCV generally decreased when changing the position from supine to sitting and to standing (4.53 ± 1.95%, 4.12 ± 1.51% and 3.26 ± 1.56% in females and 3.99 ± 1.44%, 4.00 ± 1.24% and 3.53 ± 1.32% in males respectively), the means of QTCV systematically increased during these position changes (0.96 ± 0.40%, 1.30 ± 0.56% and 1.88 ± 1.46% in females and 0.85 ± 0.30%, 1.13 ± 0.41% and 1.41 ± 0.59% in males, respectively). The intra-subject relationship between QTCV, RRCV and mean RR intervals was highly dependent on postural positions. The study concludes that no universally applicable normalization of the QT interval variability for the heart rate and/or the RR interval variability should be assumed. In future studies of the QT variability, it seems preferable to report on the absolute values of QT variability, RR variability and mean heart rate separately.     

Blood pressure variability,impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade

Objective

Elderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR).

Methods

We surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00 h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence.

Results

Aging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan.

Conclusion

ARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs.     

Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study

Aims/hypothesis. Currently, three categories of measures are used to assess cardiovascular autonomic dysfunction: measures of the Ewing-test, measures of heart-rate variability, and measures of baroreflex sensitivity. We studied the determinants of these measures obtained from cardiovascular autonomic function tests in the Hoorn Study. Methods. The study group (n = 631) consisted of a glucose-tolerance-stratified sample from a 50- to 75-year-old group of people. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during (a) spontaneous breathing, (b) six deep breaths over one minute, and (c) an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (three Ewing, six heart-rate variability and one baroreflex sensitivity). As possible determinants we considered age, sex, glucose tolerance, cardiovascular disease, use of anti-hypertensive drugs, anthropometric factors, metabolic factors and lifestyle factors. Results. Multivariate analysis showed that eight of ten cardiovascular autonomic function measures were most strongly associated with glucose tolerance. Furthermore, measures were moderately associated with age, sex, waist-to-hip ratio, use of anti-hypertensive drugs, and insulin. The measures were weakly associated with coronary artery disease but not with lipids. The strongest determinants seemed to differ between subjects with and without diabetes: in the non-diabetic subjects the most strongly associated were age and use of anti-hypertensive drugs and in subjects with diabetes, insulin. No consistent differences in association between the three categories of measures were observed. Conclusion/interpretation. The strongest determinants of autonomic function were age, presence of diabetes and use of anti-hypertensive drugs. [Diabetologia (2000) 43: 561–570] Received: 25 October 1999 and in revised form: 3 January 2000     

Effects of pentoxifylline and pentosan polysulphate combination therapy on diabetic neuropathy in type 2 diabetes mellitus

Vascular dysfunction, including impaired perfusion has a pivotal role in the pathogenesis of microvascular complications in diabetes mellitus. Both pentoxifylline (PF) and pentosan polysulphate (PPS) are known to improve microcirculation. Antioxidant and antiproteinuric effects of PF are also known. In a placebo-controlled study, we determined the possible efficacy of PF-PPS combination therapy on diabetic neuropathy and nephropathy in type 2 diabetic patients. Patients in Verum group (n = 77) received PF-PPS infusions (100–100 mg/day) for 5 days. Control diabetics (Placebo group; n = 12) were given only saline infusions. Specialized cardiovascular autonomic reflex tests, vibration threshold values and urinary albumin excretion were assessed before and after therapy. In Verum group, autonomic score, indicating the severity of cardiac autonomic dysfunction, decreased after therapy (p ≤ 0.001). Of the reflexes, deep breath and handgrip tests also improved after therapy (p ≤ 0.001). Vibration threshold values, an indicator of the loss of sensory nerve function, were increased after therapy (p ≤ 0.001). Results of cardiac autonomic tests and vibration threshold values remained unaltered in Placebo group. Majority of patients had normalbuminuria, which was not affected by PF-PPS. In conclusion, short-term PF-PPS therapy was effective on cardiovascular autonomic function and vibration perception, whereas it failed to reduce albuminuria within normal range in type 2 diabetic patients.     

Cardiac and autonomic nerve function after reduced-intensity stem cell transplantation for hematologic malignancy in patients with pre-transplant cardiac dysfunction

Recent reports have shown that cardiomyopathy caused by hemochromatosis in severe aplastic anemia is reversible after reduced-intensity allogeneic stem-cell transplantation (RIST). We comprehensively evaluated cardiac and autonomic nerve function to determine whether cardiac dysfunction due to causes other than hemochromatosis is attenuated after RIST. In five patients with cardiac dysfunction before transplant, we analyzed the changes in cardiac and autonomic nerve function after transplant, using electrocardiography (ECG), echocardiography, radionuclide angiography (RNA), serum markers, and heart rate variability (HRV), before and up to 100 days after transplant. There was no significant improvement in cardiac function in any patient and no significant alteration in ECG, echocardiogram, RNA, or serum markers. However, on time-domain analysis of HRV, the SD of normal-to-normal RR intervals (SDNN) and the coefficient of variation of the RR interval (CVRR) decreased significantly 30 and 60 days after transplant (P = 0.04 and 0.01, respectively). Similarly, on frequency-domain analysis of HRV, low and high frequency power (LF and HF) significantly and temporarily decreased (P = 0.003 and 0.03, respectively). Notably, in one patient who had acute heart failure after transplantation, the values of SDNN, CVRR, r-MSSD, LF, and HF at 30 and 60 days after transplantation were the lowest of all the patients. In conclusion, this study suggests that (a) RIST is well-tolerated in patients with cardiac dysfunction, but we cannot expect improvement in cardiac dysfunction due to causes other than hemochromatosis; and (b) monitoring HRV may be useful in predicting cardiac events after RIST.     

QT interval prolongation in association with impaired circadian variation of blood pressure and heart rate in adolescents with Type 1 diabetes.

AIMS: The aim of our study was to assess diurnal blood pressure (BP) and heart rate variability and their possible relationship to the duration of the QT interval in adolescents with Type 1 diabetes. METHODS: In 48 normotensive, normoalbuminuric diabetic adolescents, with a mean (+/- sd) age of 17.3 (+/- 4.1) years and a mean (+/- sd) diabetes duration of 8.5 (+/- 3.3) years, 24-h ambulatory BP was recorded. In addition, 24-h heart rate (HR) monitoring was performed and QT and corrected QT (QTc) intervals were estimated as indices of autonomic function. The patients were divided into two groups according to the absence of a decrease (non-dippers) or the presence of a decrease (dippers) in nocturnal diastolic BP (DBP). RESULTS: In comparison with the dippers, the non-dippers showed reduced mean 24-h HR (79.6 vs. 84.0 beats/min, P = 0.05) and reduced mean daytime HR (81.3 vs. 86.0 beats/min, P = 0.05). The QT interval was prolonged in the non-dippers (366.3 vs. 347.5 ms, P = 0.015), and end systolic (28.7 vs. 25.9 mm, P = 0.004) and end diastolic left ventricular diameters (47.8 vs. 45.5 mm, P = 0.037) were greater. In stepwise multiple regression, HR variables were the most important factors affecting DBP ratio or the duration of the QT interval. CONCLUSIONS: In conclusion, normotensive diabetic adolescents with impaired nocturnal BP reduction also have impaired autonomic function tests, in association with prolonged QT interval and increased left ventricular diameters. These findings suggest that diabetic adolescents who have the 'non-dipper' phenomenon may need close follow-up for the possible development of vascular complications, such as cardiac arrhythmias and left-ventricular hypertrophy.     

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

Summary 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. HbA_1c 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 HbA_1c < 7.6 %; Group 1), whereas 6 patients were poorly controlled (mean HbA_1c L 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. [Diabetologia (1998) 41: 443–451] Received: 15 July 1997 and in revised form: 25 November 1997     

Impaired baroreflex sensitivity and cardiac autonomic functions are associated with cardiovascular disease risk factors among patients with metabolic syndrome in a tertiary care teaching hospital of South-India

Background & aimBaroreflex sensitivity (BRS) and heart rate variability (HRV) have been proposed to assess early autonomic dysfunction in metabolic syndrome (MetS) patients. Autonomic dysfunction in MetS patients may increase the risk of developing cardiovascular disease (CVD). However, the association of BRS and HRV with CVD risk factors remains elusive in MetS. The primary aim of this study was to assess the BRS and HRV in MetS patients among South-Indian adults and check whether BRS and HRV are associated with CVD risk factors.MethodsWe performed anthropometric indices, body composition, physiological parameters such as BRS, HRV, and other autonomic function tests in 176 subjects divided into MetS patients (n = 88) and healthy controls (n = 88). Fasting blood samples were collected for biochemical profiles and calculated insulin resistance indices, atherogenic index (AI), and rate pressure product (RPP).ResultsWhen compared to controls, we found significantly reduced BRS and an increased ratio of low-frequency (LF) to high-frequency (HF) power of HRV (LF/HF) in the MetS group. We observed significant differences in body composition and biochemical profiles among the MetS group. BRS and LF/HF ratio of HRV have shown a significant association with CVD risk factors in the MetS group.ConclusionsWe observed autonomic dysfunction as low BRS and high LF/HF ratio of HRV in MetS patients. Additionally, the present results emphasize that the association of BRS and LF/HF ratio with anthropometric, glucose, lipid parameters, and other CVD risk factors may increase the susceptibility of MetS patients to higher CVD risk.