Cardiovascular and metabolic responses to adrenaline infusion in patients with short-term hypothyroidism

OBJECTIVE: The relation between the clinical manifestations of thyroid disease (both hypo and hyper-thyroidism) and tissue sensitivity to catecholamines remains uncertain. It has been suggested that tissue adrenergic responsiveness is decreased in hypothyroidism, but the reports have been conflicting and have invariably focused on a single physiological response. Therefore the aim of the present study was to determine in patients with moderate, short-term, symptomatic hypothyroidism the responses of heart rate, systolic and diastolic blood pressure, forearm blood flow and metabolic rate to adrenaline infused at a rate known to achieve plasma concentrations in the middle of the physiological range. PATIENTS: Ten subjects (5M, age 43 +/- 3 years, mean +/- SEM) were studied. All were on thyroxine replacement for hypothyroidism following either thyroidectomy or radioactive iodine and had been biochemically euthyroid for at least 6 months. DESIGN: Studies were performed in random order. One study was undertaken on full replacement therapy and the other after 50 micrograms thyroxine daily for 2 weeks. After basal, supine measurements adrenaline was infused at 25 ng/kg/min for 30 minutes. MEASUREMENTS: Heart rate, blood pressure, blood glucose, metabolic rate and forearm blood flow were measured at rest and at 10-minute intervals throughout the adrenaline infusion. RESULTS: Free T4 (10.6 +/- 1.3 vs 17.6 +/- 2.0 pmol/l, P < 0.001) and free T3 (3.6 +/- 0.2 vs 4.6 +/- 0.3 pmol/l, P < 0.01) concentrations were significantly lower on 50 micrograms thyroxine than full replacement therapy. Fasting blood glucose concentrations (4.7 +/- 0.2 vs 4.7 +/- 0.1 mmol/l) were similar. The resting adrenaline concentrations were comparable, 0.29 +/- 0.18 and 0.24 +/- 0.14 nmol/l on 50 micrograms thyroxine and full replacement therapy respectively, and increased to a similar level (2.36 +/- 0.39 and 2.36 +/- 0.35 nmol/l) throughout the adrenaline infusion. The resting heart rate and metabolic rate were significantly lower on 50 micrograms thyroxine than full replacement therapy (68 +/- 2 vs 72 +/- 3 beats/min, P < 0.01; and 4.48 +/- 0.35 vs 4.88 +/- 0.39 kJ/min, P < 0.01) respectively, but the increase in heart rate (7 +/- 2 vs 8 +/- 2 beats/min) and metabolic rate (0.43 +/- 0.09 vs 0.43 +/- 0.06 kJ/min) did not differ on the two study days. Resting systolic blood pressure, diastolic blood pressure and forearm blood flow were comparable on 50 micrograms thyroxine and full replacement therapy as were the changes in systolic blood pressure (1 +/- 1 vs 1 +/- 1 mmHg), diastolic blood pressure (-7 +/- 2 vs -7 +/- 1 mmHg), forearm blood flow (1.4 +/- 0.1 vs 1.7 +/- 0.2 ml/min/100ml forearm) and blood glucose concentration (0.7 +/- 0.1 vs 0.7 +/- 0.1 mmol/l). CONCLUSIONS: Patients with short-term hypothyroidism appear to have a normal response to adrenaline infusion despite reduced baseline heart rate and metabolic rate. Thus, under physiological and mild pathophysiological conditions there appears to be no evidence of any synergy between thyroid status and sensitivity to catecholamines.     

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

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.     

Muscle sympathetic nerve activity is reduced in IDDM before overt autonomic neuropathy

Studies of heart-rate variability have demonstrated that abnormal cardiac parasympathetic activity in individuals with IDDM precedes the development of other signs or symptoms of diabetic autonomic neuropathy. To determine whether IDDM patients have impaired sympathetic activity compared with normal control subjects before the onset of overt neuropathy, we directly recorded MSNA. We also examined the effects of changes in plasma glucose and insulin on sympathetic function in each group. MSNA was recorded by using microneurographic techniques in 10 IDDM patients without clinically evident diabetic complications and 10 control subjects. MSNA was compared during a 15-min fasting baseline period and during insulin infusion (120 mU.m-2.min-1) with 30 min of euglycemia. A cold pressor test was performed at the end of euglycemia. Power spectral analysis of 24-h RR variability was used to assess cardiac autonomic function. IDDM patients had lower MSNA than control subjects at baseline (8 +/- 1 vs. 18 +/- 3 burst/min, P < 0.02). MSNA increased in both groups with insulin infusion (P < 0.01) but remained lower in IDDM patients (20 +/- 3 vs. 28 +/- 3 burst/min, P < 0.01). In the IDDM group, we found no relationships between MSNA and plasma glucose, insulin, or HbA1c concentrations. BP levels did not differ at rest or during insulin. Heart-rate variability and the MSNA response to cold pressor testing in IDDM patients did not differ from those in healthy control subjects. IDDM patients had reduced MSNA at rest and in response to insulin. The lower MSNA is not attributable to differences in plasma glucose or insulin, but, rather, is most likely an early manifestation of diabetic autonomic neuropathy that precedes impaired cardiac parasympathetic control.     

Role of autonomic reflexes in syncope associated with paroxysmal atrial fibrillation

OBJECTIVES: The purpose of this study was to evaluate the role of autonomic reflexes in the genesis of syncope associated with the onset of paroxysmal atrial fibrillation. BACKGROUND: Syncope associated with paroxysmal atrial fibrillation has been interpreted as an ominous finding predictive of rapid ventricular rates. However, various mechanisms may be involved when heart rate is not particularly high. METHODS: Forty patients (age 60 +/- 14 years, 20 men, 20 women) with syncope and atrial fibrillation were compared with atrial fibrillation without syncope. Carotid sinus massage and head-up tilt testing (at 60 degrees for 60 min at baseline and during isoproterenol infusion) were performed during sinus rhythm. A positive response was defined as the induction of syncope. Atrial fibrillation was also induced on a tilt table at 60 degrees by means of short bursts of atrial pacing. RESULTS: Results of carotid sinus massage were positive in 15 (37%) of 40 patients but in no control subjects (p = 0.002). Head-up tilt test findings were positive in 25 (66%) of 38 patients and in 2 (12%) of 16 control subjects (p = 0.0004). The induction of atrial fibrillation in the upright position elicited syncope in 16 (42%) of 38 patients but in none of 16 control subjects (p = 0.001). At the beginning of atrial fibrillation, systolic blood pressure was lower in patients than in control subjects (88 +/- 32 vs. 127 +/- 32 mm Hg), whereas mean heart rate was similar (142 +/- 35 vs. 134 +/- 25 beats/min). The correlation between heart rate and systolic blood pressure was weak (r = 0.35), and in five patients syncope occurred at a heart rate < or = 130 beats/min. At the time of syncope, heart rate decreased (-12 +/- 21 beats/min) in patients with induced syncope, whereas it remained unchanged in patients without induced syncope (+1 +/- 17 beats/min, p = 0.04) or slightly increased in control subjects (+9 +/- 21 beats/min, p = 0.009). CONCLUSIONS: Patients with syncope associated with paroxysmal atrial fibrillation are predisposed to an abnormal neural response during both sinus rhythm and arrhythmia. In some patients the onset of atrial fibrillation triggers vasovagal syncope.     

Is autonomic neuropathy a risk factor for severe hypoglycaemia? The EURODIAB IDDM Complications Study

The hypothesis that diabetic patients with autonomic neuropathy are at increased risk of severe hypoglycaemia was examined in an epidemiological study of over 3000 IDDM patients in Europe (EURODIAB IDDM Complications Study). Autonomic function was assessed by two standard cardiovascular tests: change in heart rate and systolic blood pressure on standing. Severe hypoglycaemia was defined as an attack serious enough to require the help of another person. Compared to patients (68%) reporting no attacks in the last year, those reporting one or more attacks were older (34.0 +/- 10.7 vs 32.1 +/- 9.9 years, mean +/- SD, p < 0.0001), had had diabetes for a longer period (16.6 +/- 9.5 vs 13.8 +/- 9.1 years, p < 0.0001), had better glycaemic control (HbA1c 6.4 +/- 1.8 vs 6.9 +/- 1.9%, p < 0.0001) and were more likely (p = 0.002) to have abnormal responses to both autonomic tests (13.0 vs 7.7%). A single abnormal autonomic response was not associated with an increased risk of severe hypoglycaemia. The odds ratio for severe hypoglycaemia in people with abnormal responses to both autonomic tests, compared to those with normal responses, was 1.7 (95% confidence interval 1.3, 2.2) after controlling for age, duration of diabetes, glycaemic control and study centre. In conclusion, a combined autonomic deficit in heart rate and blood pressure responses to standing is associated with only a modest increase in the risk of severe spontaneous hypoglycaemia. Although the increase in risk is not large, severe hypoglycaemia was a frequently reported event in this study. IDDM patients with deficient autonomic responses who strive for tight glycaemic control may therefore be at particular risk of severe hypoglycaemia.     

Diastolic function parameters and atrial arrhythmias in patients with arterial hypertension

OBJECTIVE: To investigate in patients with arterial hypertension (HT) the extent of left ventricular (LV) hypertrophy and diastolic function in relation to atrial arrhythmias. PATIENTS AND METHODS: In 112 hypertensive patients (40 women, 72 men; mean age 50 +/- 6.6 years) with a mean systolic blood pressure for the cohort of 170 +/- 5 mmHg, their first invasive coronary angiography was performed between July 1995 and October 1997 because of angina pectoris and/or an abnormal stress electrocardiogram. After excluding coronary heart disease LV dimensions and diastolic function were measured by echocardiography; in 59 of the 112 patients LV hypertrophy was demonstrated. In addition, long-term blood pressure monitoring, exercise and long-term electrocardiography, late-potential analysis and measurement of heart rate variability were undertaken. The control group consisted of 51 patients without arterial hypertension after exclusion of coronary heart disease. RESULTS: Even in the hypertensive patients without LV hypertrophy diastolic LV function and ergometric exercise capacity were reduced. The risk of LV arrhythmias was significantly higher in patients with LV hypertrophy than those without and in the control group, as measured by the complexity of atrial arrhythmias (P < 0.001), the incidence of abnormal late potentials (P < 0.001) and reduction in heart rate variability (29.3 +/- 5.3 ms vs 47.8 +/- 12.1 ms vs 60.7 +/- 6.6 ms; P < 0.001). There were similar results regarding severe complex atrial arrhythmias (38.5 vs 15.0 vs 0%; P < 0.001). The incidence of atrial arrhythmias correlated with the LV diameter (r = 0.68, P < 0.001), LV morphological dimensions and diastolic function (isovolumetric relaxation time r = 0.44, P < 0.001) and the ratio of early to late diastolic inflow (r = 0.46; P < 0.001). CONCLUSIONS: Hypertensive patients have a higher risk of atrial and ventricular arrhythmias, depending on the degree of LV hypertrophy. But atrial arrhythmias, in contrary to ventricular arrhythmias, are also closely related to abnormalities in LV diastolic function.     

Increased heart rate in depressed subjects in spite of unchanged autonomic balance?

A clinical study was conducted to examine the effects of depression on cardiac autonomic control. Cardiac autonomic control was measured in 26 nonmedicated patients (19 females) suffering from Major Depression, melancholic type, and in 26 age- and sex-matched normal controls. We measured heart rate and high frequency heart rate variability (respiratory sinus arrhythmia), pulsewave velocity and blood pressure, during 10 min of supine rest under controlled conditions. Using a log transformed time domain measure of respiratory sinus arrhythmia (logRSA), we found an inverse linear dependence between cardiac vagal tone and age in the healthy subjects as well as the depressed patients. logRSA was 0.22+/-0.25 in the patients and 0.25+/-0.16 in the control group. While this difference was not significant (P > 0.1), the deviations from the regression line were significantly (P < 0.0005) greater in the patients (0.21+/-0.12) than in the control group (0.09+/-0.07), indicating a more heterogeneous vagal tone in the depressed patients. Heart rate was also significantly (P < 0.03) greater in the depressed patients (76.6+/-12.4) than in the control group (69.5+/-6.9). No between-group differences were found in pulsewave velocity or systolic blood pressure, but diastolic blood pressure was lower in depressed patients (73.5+/-8.7 vs. 80.8+/-9.1). We discuss the possibility that the increased heart rate seen in the absence of vagal tone changes may not be due to altered vagal or sympathetic tone, as measured in this study. Other factors, including altered autonomous heart rate, may be responsible for the higher heart rate in the depressed group.     

Role of nitric oxide in the vasodilator response to mental stress in normal subjects

Vascular production of nitric oxide (NO) plays an important role in a variety of physiologic processes. This study examines the contribution of NO to the vasodilator response to mental stress. The effects of mental arithmetic testing on forearm vascular dynamics were analyzed in 15 normal subjects (9 men; age 45 +/- 12 years) during intraarterial infusion of either saline or N(G)-monomethyl-L-arginine (L-NMMA; 4 micromol/min for 15 minutes), an inhibitor of NO synthesis. The effect of L-NMMA on endothelium-independent vasodilation induced by intraarterial infusion of sodium nitroprusside was also studied in 11 of the 15 subjects. Forearm blood flow was measured by plethysmography. Mental stress increased forearm blood flow from 2.35 +/- 0.84 to 5.06 +/- 2.66 ml/min/dl (115%) during saline and from 1.72 +/- 0.59 to 2.81 +/- 0.99 ml/min/dl (63%) during L-NMMA infusion. The vasodilator effect of mental stress was significantly lower during L-NMMA infusion than during saline (1.1 +/- 0.65 vs 2.71 +/- 2.15 ml/min/dl; p = 0.01). L-NMMA administration did not significantly change mean arterial pressure and heart rate responses to mental stress. In contrast, the vasodilator effect of sodium nitroprusside (1.6 microg/min) was similar during infusion of L-NMMA and during saline (3.75 +/- 1.55 vs 2.85 +/- 1.38 ml/min/dl; p = 0.16). These findings indicate that local release of NO is involved in the forearm vasodilator response to mental stress.     

Forearm nitric oxide balance, vascular relaxation, and glucose metabolism in NIDDM patients

Endothelium-dependent and -independent vascular responses were assessed in 10 NIDDM patients and 6 normal subjects with no evidence of atherosclerotic disease. Changes in forearm blood flow and arteriovenous (AV) serum nitrite/nitrate (NO2-/NO3-) concentrations were measured in response to intra-arterial infusion of acetylcholine (ACh) (7.5, 15, 30 microg/min, endothelium-dependent response) and sodium nitroprusside (SNP) (0.3, 3, 10 microg/min, endothelium-independent response). Insulin sensitivity (determined by minimal model intravenous glucose tolerance test) was lower in NIDDM patients (0.82 +/- 0.20 vs. 2.97 +/- 0.29 10(4) min x microU(-1) x ml(-1); P < 0.01). Baseline forearm blood flow (4.8 +/- 0.3 vs. 4.4 +/- 0.3 ml x 100 ml(-1) tissue x min(-1); NS), mean blood pressure (100 +/- 4 vs. 92 +/- 4 mmHg; NS), and vascular resistance (21 +/- 1 vs. 21 +/- 1 units; NS), as well as their increments during ACh and SNP, infusion were similar in both groups. No difference existed in baseline NO2-/NO3- concentrations (4.09 +/- 0.33 [NIDDM patients] vs. 5.00 +/- 0.48 micromol/l [control subjects]; NS), their forearm net balance (0.31 +/- 0.08 [NIDDM patients] vs. 0.26 +/- 0.08 micromol/l x 100 ml(-1) tissue x min(-1); NS), and baseline forearm glucose uptake. During ACh infusion, both NO2- and NO3- concentrations and net balance significantly increased in both groups, whereas glucose uptake increased only in control subjects. When data from NIDDM and control groups were pooled together, a correlation was found between the forearm AV NO2- and NO3- differences and blood flow (r = 0.494, P = 0.024). On the contrary, no correlation was evident between NO2- and NO3- concentrations or net balance and insulin sensitivity. In summary, 1) no difference existed in basal and ACh-stimulated NO generation and endothelium-dependent relaxation between uncomplicated NIDDM patients and control subjects; 2) in both NIDDM and control groups, forearm NO2- and NO3- net balance following ACh stimulation was related to changes in the forearm blood flow; and 3) ACh-induced increase in forearm blood flow was associated with an increase in glucose uptake only in control subjects but not in NIDDM patients. In conclusion, our results argue against a role of impaired NO generation and blood flow regulation in determining the insulin resistance of uncomplicated NIDDM patients; rather, it supports an independent insulin regulation of hemodynamic and metabolic effects.     

Preservation of the pattern of tyrosine phosphorylation in human neutrophil lysates

Diabetic cardiovascular autonomic neuropathy increases the risk of deterioration in renal function and is associated with increased mortality in patients with renal failure. Type 1 diabetic patients with long diabetes duration, matched for age (38 +/- 9 years) and diabetes duration (28 +/- 8 years) were studied regarding the association between cardiovascular autonomic nerve function and different degrees of diabetic nephropathy. Eighteen patients were normo- (< 30 mg/l), six micro- (30-300 mg/l), and 13 macroalbuminuric (> 300 mg/l) based on urinary albumin concentrations in three separate morning samples. They were compared with 33 control subjects with similar age. Autonomic nerve function was evaluated by measuring the response of heart rate to deep breathing and active standing. Beat-to-beat finger artery blood pressure (Finapres) was tested during active standing. During deep breathing both change in heart rate (17 +/- 11, 9 +/- 7 and 4 +/- 3 beats/min) and ratio between expiratory and inspiratory R-R intervals (1.32 +/- 0.24, 1.14 +/- 0.15 and 1.05 +/- 0.04) decreased from normo- over micro- to macroalbuminuria (p < 0.05 vs normoalbuminuric and control subjects [17 +/- 5 beats/min and 1.28 +/- 0.10, respectively]). Similar results were obtained during active standing with respect to change in systolic arterial blood pressure (3 +/- 8, 2 +/- 13 and -6 +/- 11 mmHg; p < 0.05 vs control subjects [8 +/- 11 mmHg]). However, the response of diastolic arterial blood pressure or mean heart rate to standing up did not differ between any of the groups. The ratio of maximum to minimum R-R interval during the dynamic response of heart rate to active standing decreased with the degree of nephropathy (1.27 +/- 0.17, 1.11 +/- 0.11 and 1.05 +/- 0.06) with significantly higher values in patients with normo- compared with patients with macroalbuminuria (p < 0.05). All patients groups had significantly lower values than control subjects (1.46 +/- 0.22, p < 0.05). The overshoot of the blood pressure after an initial fall during active standing decreased with the degree of diabetic nephropathy. In conclusion, type 1 diabetic patients with long duration of diabetes have signs of cardiovascular autonomic neuropathy, the severity of which is related to the degree of nephropathy.     

Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus

19 insulin-dependent diabetes mellitus (IDDM) patients participated in a randomized double-blind crossover investigation to investigate the impact of human C-peptide on skin microvascular blood flow. The investigation was also carried out with 10 healthy volunteers. Blood pressure, heart rate, blood sugar, and C-peptide levels were monitored during a 60-min intravenous infusion period of C-peptide (8 pmol kg-1 min-1) or saline solution (154 mmol liter-1 NaCl), and 30 min after stopping the infusion. During the same time period, capillary blood cell velocity (CBV), laser Doppler flux (LDF), and skin temperature were assessed in the feet. In the verum arm, C-peptide levels increased after starting infusion to reach a maximum of 2.3+/-0.2 nmol liter-1 after 45 min, but remained below 0. 15 nmol liter-1 during the saline treatment. Baseline CBV was lower in diabetic patients compared with healthy subjects (147+/-3.6 vs. 162+/-4.2 micron s-1; P < 0.01). During C-peptide administration, CBV in IDDM patients increased progressively from 147+/-3.6 to 167+/-3.7 micron s-1; P < 0.001), whereas no significant change occurred during saline infusion or in healthy subjects. In contrast to the CBV measurements, the investigation of LDF, skin temperature, blood pressure, heart rate, or blood sugar did not demonstrate any significant change during the study. Replacement of human C-peptide in IDDM patients leads to a redistribution in skin microvascular blood flow levels comparable to levels in healthy subjects by increasing the nutritive CBV relative to subpapillary arteriovenous shunt flow.     

Oral glucose ingestion increases endurance capacity in normal and diabetic (type I) humans

The effects of an oral glucose administration (1 g/kg) 30 min before exercise on endurance capacity and metabolic responses were studied in 21 type I diabetic patients [insulin-dependent diabetes mellitus (IDDM)] and 23 normal controls (Con). Cycle ergometer exercise (55-60% of maximal O2 uptake) was performed until exhaustion. Glucose administration significantly increased endurance capacity in Con (112 +/- 7 vs. 125 +/- 6 min, P < 0.05) but only in IDDM patients whose blood glucose decreased during exercise (70.8 +/- 8.2 vs. 82.8 +/- 9.4 min, P < 0.05). Hyperglycemia was normalized at 15 min of exercise in Con (7.4 +/- 0.2 vs. 4.8 +/- 0.2 mM) but not in IDDM patients (12.4 +/- 0.7 vs. 15.6 +/- 0.9 mM). In Con, insulin and C-peptide levels were normalized during exercise. Glucose administration decreased growth hormone levels in both groups. In conclusion, oral glucose ingestion 30 min before exercise increases endurance capacity in Con and in some IDDM patients. In IDDM patients, in contrast with Con, exercise to exhaustion attenuates hyperglycemia but does not bring blood glucose levels to preglucose levels.     

Preservation of physiological responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM

OBJECTIVE: To assess the effects of short-term antecedent hypoglycemia on responses to further hypoglycemia 2 days later in patients with IDDM. RESEARCH DESIGN AND METHODS: We studied eight type I diabetic patients without hypoglycemia unawareness or autonomic neuropathy during two periods at least 4 weeks apart. On day 1, 2 h of either clamped hyperinsulinemic (60 mU.m-2.min-1) hypoglycemia at 2.8 mmol/l or euglycemia at 5.0 mmol/l were induced. Hyperinsulinemic hypoglycemia was induced 2 days later with 40 min glucose steps of 5.0, 4.0, 3.5, 3.0, and 2.5 mmol/l. Catecholamine levels and symptomatic and physiological responses were measured every 10-20 min. RESULTS: When compared with the responses measured following euglycemia, the responses of norepinephrine 2 days after hypoglycemia were reduced (peak, 1.4 +/- 0.4 [mean +/- SE] vs.1.0 +/- 0.3 nmol/l [P < 0.05]; threshold, 3.4 +/- 0.1 vs. 2.9 +/- 0.1 mmol/l glucose [P < 0.01]). The responses of epinephrine (peak, 4.0 +/- 1.4 vs. 3.5 +/- 0.8 nmol/l [P = 0.84]; threshold, 3.8 +/- 0.1 vs. 3.6 +/- 0.1 mmol/l glucose [P = 0.38]), water loss (peak, 194 +/- 34 vs. 179 +/- 47 g-1.m-2.h-1 [P = 0.73]; threshold, 2.9 +/- 0.2 vs. 2.9 +/- 0.2 mmol/l glucose [P = 0.90]), tremor (peak, 0.28 +/- 0.05 vs. 0.37 +/- 0.06 root mean square volts (RMS V) [P = 0.19]; threshold, 3.2 +/- 0.2 vs. 3.1 +/- 0.2 mmol/l glucose [P = 0.70]), total symptom scores (peak, 10.6 +/- 2.1 vs. 10.8 +/- 1.9 [P = 0.95]; threshold, 3.3 +/- 0.2 vs. 3.6 +/0 0.1 mmol/l glucose [P = 0.15]), and cognitive function (four-choice reaction time: threshold, 2.9 +/- 0.2 vs. 3.0 +/- 0.2 mmol/l glucose [P = 0.69]) were unaffected. CONCLUSIONS: The effect on hypoglycemic physiological responses of 2 h of experimental hypoglycemia lasts for 1-2 days in these patients with IDDM . The pathophysiological effect of antecedent hypoglycemia may be of shorter duration in IDDM patients, compared with nondiabetic subjects.     

Autonomic and hemodynamic responses to insulin in lean and obese humans

To study the acute effects of insulin on autonomic control of cardiac function, we performed spectral analysis of heart rate variability and measured cardiac dynamics (by two-dimensional echocardiography) in 18 obese (BMI = 35 +/- 1 kg.m-2) and 14 lean (BMI = 24 +/- 1 kg.m-2) subjects in the basal state and in response to physiological hyperinsulinemia (1 mU.min-1.kg-1 insulin clamp). In the lean group, insulin promptly (within 20 min) and consistently depressed spectral powers, both in the low-frequency and high-frequency range. These changes were twice as large as accounted for by the concomitant changes in heart rate (68 +/- 2 to 70 +/- 2 beats/min). At the end of the 2-h clamp, stroke volume (67 +/- 4 to 76 +/- 9 ml.min-1) and cardiac output (4.45 +/- 0.21 to 5.06 +/- 0.55 l.min-1) rose, whereas peripheral vascular resistance fell. The low-to-high frequency ratio increased from 1.7 +/- 0.2 to 2.3 +/- 0.3 (P < 0.01), indicating sympathetic shift of autonomic balance. In the obese group, all basal spectral powers were significantly lower (by 40% on average) than in the lean group, and were further reduced by insulin administration. The low-to-high frequency ratio was higher than in controls at baseline (2.4 +/- 0.4, P < 0.03), and failed to increase after insulin (2.2 +/- 0.3, P = ns). Furthermore, obesity was associated with higher resting stroke volume (89 +/- 5 vs. 67 +/- 4 ml.min-1, P < 0.01) and cardiac output (6.01 +/- 0.31 vs. 4.45 +/- 0.21 l.min-1, P = 0.001) but lower peripheral vascular resistance (15.1 +/- 0.8 vs. 19.2 +/- 1.1 mmHg.min.L-1, P = 0.002), whereas mean arterial blood pressure was similar to control (90 +/- 2 vs. 86 +/- 2 mmHg, P = not significant). We conclude that physiological hyperinsulinemia causes acute desensitization of sinus node activity to both sympathetic and para-sympathetic stimuli, sympathetic shift of autonomic balance, and a high-output, low-resistance hemodynamic state. In the obese, these changes are already present in the basal state, and may therefore be linked with chronic hyperinsulinemia.     

Enhanced brain natriuretic peptide response to peak exercise in heart transplant recipients

We investigated the atrial (ANP) and brain natriuretic peptides (BNP), catecholamines, heart rate, and blood pressure responses to graded upright maximal cycling exercise of eight matched healthy subjects and cardiac-denervated heart transplant recipients (HTR). Baseline heart rate and diastolic blood pressure, together with ANP (15.2 +/- 3.7 vs. 4.4 +/- 0.8 pmol/l; P < 0.01) and BNP (14.3 +/- 2. 6 vs. 7.4 +/- 0.6 pmol/l; P < 0.01), were elevated in HTR, but catecholamine levels were similar in both groups. Peak exercise O2 uptake and heart rate were lower in HTR. Exercise-induced maximal ANP increase was similar in both groups (167 +/- 34 vs. 216 +/- 47%). Enhanced BNP increase was significant only in HTR (37 +/- 8 vs. 16 +/- 8%; P < 0.05). Similar norepinephrine but lower peak epinephrine levels were observed in HTR. ANP and heart rate changes from rest to 75% peak exercise were negatively correlated (r = -0.76, P < 0.05), and BNP increase was correlated with left ventricular mass index (r = 0.83, P < 0.01) after heart transplantation. Although ANP increase was not exaggerated, these data support the idea that the chronotropic limitation secondary to sinus node denervation might stimulate ANP release during early exercise in HTR. Furthermore, the BNP response to maximal exercise, which is related to the left ventricular mass index of HTR, is enhanced after heart transplantation.     

Ambulatory 24-h blood pressure monitoring in healthy, middle-aged smokeless tobacco users, smokers, and nontobacco users

Ambulatory 24-h blood pressure monitoring was conducted in 135 healthy, normotensive, middle-aged (35 to 60 years) men, with no antihypertensive medication, to study the influence of habitual smokeless tobacco use (n = 47) and smoking (n = 29) on diurnal blood pressure and heart rate. Comparisons were made with nonusers of tobacco (n = 59). Adjustments were made for differences in age, body mass index, waist-hip ratio, physical fitness, and alcohol intake. Daytime ambulatory heart rates were significantly (P < .05) elevated in both smokeless tobacco users and smokers compared with nonusers (69 +/- 14 and 74 +/- 13 beats/min, respectively, versus 63 +/- 12 beats/min). In subjects > or = 45 years old, ambulatory daytime diastolic blood pressures were significantly elevated, on average by 5 mm Hg, in both smokeless tobacco users and smokers (P < .001) compared with nonusers. Clinical measurements of heart rate and systolic blood pressure in smokers were significantly lower compared with the ambulatory mean values. Nighttime measurements showed only minor differences between the tobacco habit groups. The higher heart rates and blood pressures noted during the daytime in smokers and smokeless tobacco users were most likely due to the effects of nicotine. A strong positive relationship was found between cotinine (major nicotine metabolite) and blood pressure in smokeless tobacco users (systolic blood pressure, r = 0.48, P < .001; diastolic blood pressure, r = 0.41, P = .005), whereas an inverse relationship was found in smokers (systolic blood pressure, r = -0.12, P = .47; diastolic blood pressure, r = -0.03, P = .84), indicating additional and more complex influences on vascular tone in smokers than the influence of nicotine in smokeless tobacco users.     

Low prevalence of microalbuminuria in young Italian insulin-dependent diabetic patients with short duration of disease: a population-based study. Piedmont Study Group for Diabetes Epidemiology

Objectives of this study were to determine the prevalence of microalbuminuria and the level of glycaemic control obtained in a young Italian population-based cohort of subjects with short duration of insulin-dependent diabetes mellitus (IDDM). Out of 298 subjects with onset of IDDM in the period 1984-88, 211 were examined (71%) in 1991-92 (duration of disease 3-9 years). Microalbuminuria was defined as albumin excretion rate (AER) 20-200 micrograms min-1 in an overnight urine collection or alb/creat > 2.5 mg mmol-1 in men and > 4.5 mg mmol-1 in women in one first morning urine sample. Twelve subjects had AER 20-200 micrograms min-1 and 4 had elevated alb/creat ratio. Prevalence of microalbuminuria was 7% (95% Cl 4.0-11.1) in subjects with duration of IDDM 3-9 years and 4% (0.3-7.7) in subjects with duration 3-5 years. Only 1 microalbuminuric subject was found out of 52 aged < or = 14 years. Duration of IDDM was significantly higher (6.9 +/- 1.9 years vs 5.7 +/- 1.6, p = 0.007) and HDL-cholesterol lower (1.22 +/- 0.21 mM vs 1.42 +/- 0.34, p = 0.025) in micro- than in normoalbuminuric subjects, even after adjustment for age, systolic and diastolic blood pressure, BMI, and HbA1c. In almost 50% of the cohort, HbA1c levels were over 9%, whereas only in 10.9% HbA1c levels were lower than 6.6% (mean +3 SD). In conclusion, this Italian population-based study showed low prevalence of microalbuminuria in young subjects with short duration of IDDM, even if the glycaemic control obtained was far from ideal.     

Intensive training and cardiac autonomic control in high level athletes

The bioavailability of propranolol depends on the degree of liver metabolism. Orally but not intravenously administered propranolol is heavily metabolized. In the present study we assessed the pharmacokinetics and pharmacodynamics of sublingual propranolol. Fourteen severely hypertensive patients (diastolic blood pressure (DBP) > or = 115 mmHg), aged 40 to 66 years, were randomly chosen to receive a single dose of 40 mg propranolol hydrochloride by sublingual or peroral administration. Systolic (SBP) and diastolic (DBP) blood pressures, heart rate (HR) for pharmacodynamics and blood samples for noncompartmental pharmacokinetics were obtained at baseline and at 10, 20, 30, 60 and 120 min after the single dose. Significant reductions in BP and HR were obtained, but differences in these parameters were not observed when sublingual and peroral administrations were compared as follows: SBP (17 vs 18%, P = NS), DBP (14 vs 8%, P = NS) and HR (22 vs 28%, P = NS), respectively. The pharmacokinetic parameters obtained after sublingual or peroral drug administration were: peak plasma concentration (CMAX): 147 +/- 72 vs 41 +/- 12 ng/ml, P < 0.05; time to reach CMAX (TMAX): 34 +/- 18 vs 52 +/- 11 min, P < 0.05; biological half-life (t1/2b): 0.91 +/- 0.54 vs 2.41 +/- 1.16 h, P < 0.05; area under the curve (AUCT): 245 +/- 134 vs 79 +/- 54 ng h-1 ml-1, P < 0.05; total body clearance (CLT/F): 44 +/- 23 vs 26 +/- 12 ml min-1 kg-1, P = NS. Systemic availability measured by the AUCT ratio indicates that extension of bioavailability was increased 3 times by the sublingual route. Mouth paresthesia was the main adverse effect observed after sublingual administration. Sublingual propranolol administration showed a better pharmacokinetic profile and this route of administration may be an alternative for intravenous or oral administration.     

Power spectral analysis of heart period variability of preceding sinus rhythm before initiation of paroxysmal atrial fibrillation

Time domain analysis of heart period variability in patients without structural heart disease demonstrated increased parasympathetic modulation before paroxysmal atrial fibrillation (AF) occurring predominantly at night. However, diurnal differences in autonomic activity preceding AF episodes in a diverse patient population have not been assessed. Accordingly, we performed spectral analysis of heart period variability on Holter recordings during sinus rhythm preceding AF in 29 patients, 17 with night and 12 with day episodes. Samples taken 5, 10, and 20 minutes before AF onset were compared. Normalized high-frequency (HF) spectral power change was greater when comparing the interval 10 to 5 minutes with 20 to 10 minutes preceding AF in 26 of 29 patients (0.09 +/- 0.07 vs 0.03 +/- 0.02; p < 0.0001). HF spectral power increased before 3 of 12 AF episodes during the day compared with 15 of 17 AF episodes during the night (p = 0.001). Nocturnal AF episodes were preceded by increased HF spectral power in the 5- versus the 20-minute sample expressed as natural logarithm-transformed values (5.6 +/- 4.8 vs 4.2 +/- 4.0; p < 0.005) and normalized values (0.19 +/- 0.09 vs 0.10 +/- 0.07; p < 0.02), a decrease in low-frequency/HF ratio (1.05 +/- 0.61 vs 2.21 +/- 1.75; p < 0.05) and heart rate (60 +/- 13 vs 71 +/- 13 beats/min; p = 0.06). Structural heart disease was more common with daytime than nocturnal AF episodes (58% vs 18%, p < 0.05). In conclusion, HF spectral power change was increased preceding most AF episodes. However, diurnal differences were demonstrated. Contrary to daytime AF, increased parasympathetic activity preceded predominantly nocturnal AF, mostly in younger patients with structurally normal hearts.     

Stress-induced left ventricular outflow tract obstruction: a potential cause of dyspnea in the elderly

OBJECTIVES: We sought to identify the pattern of disturbed left ventricular physiology associated with symptom development in elderly patients with effort-induced breathlessness. BACKGROUND: Limitation of exercise tolerance by dyspnea is common in the elderly and has been ascribed to diastolic dysfunction when left ventricular cavity size and systolic function appear normal. METHODS: Dobutamine stress echocardiography was used in 30 patients (mean [+/-SD] age 70 +/- 12 years; 21 women, 9 men) with exertional dyspnea and negative exercise test results, and the values were compared with those in 15 control subjects. RESULTS: Before stress, left ventricular end-diastolic and end-systolic dimensions were reduced, fractional shortening was increased, and the basal septum was thickened (2.3 +/- 0.5 vs. 1.4 +/- 0.2 cm, p < 0.001, vs. control subjects) in the patients, but posterior wall thickness did not differ from that in control subjects. Left ventricular outflow tract diameter, measured as systolic mitral leaflet septal distance, was significantly reduced (13 +/- 4.5 vs. 18 +/- 2 mm, p < 0.001). Isovolumetric relaxation time was prolonged, and peak left ventricular minor axis lengthening rate was reduced (8.1 +/- 3.5 vs. 10.4 +/- 2.6 cm/s, p < 0.05), suggesting diastolic dysfunction. Transmitral velocities and the E/A ratio did not differ significantly. At peak stress, heart rate increased from 66 +/- 8 to 115 +/- 20 beats/min in the control subjects, but blood pressure did not change. Transmitral A wave velocity increased, but the E/A ratio did not change. Left ventricular outflow tract velocity increased from 0.8 +/- 0.1 to 2.0 +/- 0.2 m/s, and mitral leaflet septal distance decreased from 18 +/- 2 to 14 +/- 3 mm, p < 0.001. In the patients, heart rate rose from 80 +/- 12 to 132 +/- 26 beats/min and systolic blood pressure from 143 +/- 22 to 170 +/- 14 mm Hg (p < 0.001 for each), but left ventricular dimensions did not change. Peak left ventricular outflow tract velocity increased from 1.5 +/- 0.5 m/s (at rest) to 4.2 +/- 1.2 m/s; mitral leaflet septal distance fell from 13 +/- 4.5 to 2.2 +/- 1.9 mm (p < 0.001); and systolic anterior motion of mitral valve appeared in 24 patients (80%) but in none of the control subjects (p < 0.001). Measurements of diastolic function did not change. All patients developed dyspnea at peak stress, but none developed a new wall motion abnormality or mitral regurgitation. CONCLUSIONS: Although our patients fulfilled the criteria for "diastolic heart failure," diastolic dysfunction was not aggravated by pharmacologic stress. Instead, high velocities appeared in the left ventricular outflow tract and were associated with basal septal hypertrophy and systolic anterior motion of the mitral valve. Their appearance correlated closely with the development of symptoms, suggesting a potential causative link.