Effect of hypoglycemia on baroreflex sensitivity in individuals with type 2 diabetes: implications for autonomic control of cardiovascular function in diabetes.

PURPOSE: Hypoglycemia is associated with increased mortality, though the mechanisms underlying this association are not established. Hypoglycemia impairs the counterregulatory hormonal and autonomic responses to subsequent hypoglycemia. It is unknown whether hypoglycemia elicits a generalized impairment in autonomic control of cardiovascular function in individuals with type 2 diabetes. We tested the hypothesis that in individuals with type 2 diabetes, hypoglycemia impairs a key measure of cardiovascular autonomic homeostasis, baroreflex sensitivity. METHODS: Sixteen individuals with well-controlled type 2 diabetes and without known cardiovascular disease were exposed to two 90-min episodes of experimental hypoglycemia (2.8 mmol/L, 50 mg/dL) on the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). Baroreflex sensitivity was assessed using the modified Oxford method before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 min of hypoglycemia, and the following morning. A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on baroreflex sensitivity. The study is registered at ClinicalTrials.gov (NCT03422471). RESULTS: Baroreflex sensitivity during PM hypoglycemia was reduced compared to baseline, during AM hypoglycemia, and the next day. Insulin levels positively correlated with baroreflex sensitivity at baseline and during AM hypoglycemia. CONCLUSION: Exposure to hypoglycemia impairs a key measure of autonomic control of cardiovascular function and, thus, may increase the risk of cardiac arrhythmias and blood pressure lability in individuals with type 2 diabetes. This effect is attenuated in part by increased insulin levels.

ACTH Infusion Impairs Baroreflex Sensitivity-Implications for Cardiovascular Hypoglycemia-Associated Autonomic Failure.

CONTEXT: Hypoglycemia attenuates cardiovascular homeostatic autonomic control. This attenuation, known as the cardiovascular component of hypoglycemia-associated autonomic failure (HAAF), is characterized most notably by decreased baroreflex sensitivity (BRS) that begins during hypoglycemia and persists until at least the next day, despite return to euglycemia. Understanding the mechanisms underlying this reduction in BRS is important because BRS attenuation is associated with increased morbidity and mortality. OBJECTIVE: The objective of this work is to investigate the role of the adrenocorticotropin (ACTH)-adrenal axis in decreasing BRS. We tested the hypothesis that infusion of ACTH 1-24 (cosyntropin), as compared to placebo, would acutely suppress BRS, and that this decrease in BRS would be present the next day. DESIGN: A double-blind, placebo-controlled, random-order, cross-over study was conducted. SETTING: This study took place in a clinical research center. PARTICIPANTS: Participants included healthy men and women. INTERVENTIONS: Interventions included an intravenous infusion of cosyntropin (70 µg/hour for 2.5 hours in the morning and again in the early afternoon) vs normal saline placebo. MAIN OUTCOME MEASURES: Outcome measures included BRS during and 16 hours after cosyntropin vs placebo infusions. RESULTS: Cosyntropin infusion attenuated BRS (mm Hg/ms) as compared to placebo (baseline 17.8 ±â€…1.38 vs 17.0 ±â€…2.07; during 14.4 ±â€…1.43 vs 17.3 ±â€…1.65; and next day 14.8 ±â€…1.42 vs 18.9 ±â€…2.04; P < .05, time by treatment, analysis of variance). BRS was decreased during the final 30 minutes of the morning cosyntropin infusion as compared to baseline (P < .01) and remained suppressed the next day (16 hours after afternoon infusion) (P < .025). Placebo infusion did not significantly change BRS. Corrected QT interval was not affected. CONCLUSIONS: ACTH attenuates BRS, raising the possibility that hypoglycemia-induced increases in ACTH may contribute to the cardiovascular component of HAAF.

Symptom Recognition Is Impaired in Patients With Orthostatic Hypotension.

Failure to recognize symptoms of orthostatic hypotension (OH) may result in falls, syncope, and injuries. The relationship between orthostatic changes in blood pressure and symptom occurrence and severity is not known. The goal of the present study was to define the relationship between the occurrence and severity of the symptoms of orthostatic hypotension (OH) and (1) the upright systolic blood pressure (SBP) and (2) the fall in SBP after tilting in patients with OH. We prospectively studied 89 patients with OH. Reported BP values include the lowest BP in the first 3 minutes of tilt and the change in blood pressure during tilt. Subjects were queried about symptoms of orthostatic intolerance while supine and during the first 3 minutes of tilt testing using Question 1 of the Orthostatic Hypotension Questionnaire. Mean tilted SBP was 101.6±26.1 mm Hg and mean SBP fall 47.9±18.1 mm Hg. Mean symptom scores when upright were: light-headedness (2.3/10±2.7), dizziness (1.6/10±2.5), and impending blackout (0.8/10±1.9). The majority of patients were asymptomatic or mildly symptomatic and no discrete cutoff for symptoms was observed. The magnitude of the SBP fall (r=-0.07, P=NS) and the lowest upright SBP (r=0.08, P=NS) did not correlate with any reported symptom. These results suggest a poor relationship between the magnitude of the orthostatic BP fall, the upright orthostatic BP, and symptoms. Many patients are asymptomatic despite substantial SBP falls and low orthostatic blood pressures. These findings have implications for clinical care of patients with OH and clinical trials to treat patients with OH.

Baroreflex Sensitivity Impairment During Hypoglycemia: Implications for Cardiovascular Control.

Studies have shown associations between exposure to hypoglycemia and increased mortality, raising the possibility that hypoglycemia has adverse cardiovascular effects. In this study, we determined the acute effects of hypoglycemia on cardiovascular autonomic control. Seventeen healthy volunteers were exposed to experimental hypoglycemia (2.8 mmol/L) for 120 min. Cardiac vagal baroreflex function was assessed using the modified Oxford method before the initiation of the hypoglycemic-hyperinsulinemic clamp protocol and during the last 30 min of hypoglycemia. During hypoglycemia, compared with baseline euglycemic conditions, 1) baroreflex sensitivity decreases significantly (19.2 ± 7.5 vs. 32.9 ± 16.6 ms/mmHg, P < 0.005), 2) the systolic blood pressure threshold for baroreflex activation increases significantly (the baroreflex function shifts to the right; 120 ± 14 vs. 112 ± 12 mmHg, P < 0.005), and 3) the maximum R-R interval response (1,088 ± 132 vs. 1,496 ± 194 ms, P < 0.001) and maximal range of the R-R interval response (414 ± 128 vs. 817 ± 183 ms, P < 0.001) decrease significantly. These findings indicate reduced vagal control and impaired cardiovascular homeostasis during hypoglycemia.

High-pass filter characteristics of the baroreflex--a comparison of frequency domain and pharmacological methods.

Pharmacological methods to assess baroreflex sensitivity evoke supra-physiological blood pressure changes whereas computational methods use spontaneous fluctuations of blood pressure. The relationships among the different baroreflex assessment methods are still not fully understood. Although strong advocates for each technique exist, the differences between these methods need further clarification. Understanding the differences between pharmacological and spontaneous baroreflex methods could provide important insight into the baroreflex physiology. We compared the modified Oxford baroreflex gain and the transfer function modulus between spontaneous RR interval and blood pressure fluctuations in 18 healthy subjects (age: 39±10 yrs., BMI: 26±4.9). The transfer function was calculated over the low-frequency range of the RR interval and systolic blood pressure oscillations during random-frequency paced breathing. The average modified Oxford baroreflex gain was lower than the average transfer function modulus (15.7±9.2 ms/mmHg vs. 19.4±10.5 ms/mmHg, P<0.05). The difference between the two baroreflex measures within the individual subjects comprised a systematic difference (relative mean difference: 20.7%) and a random variance (typical error: 3.9 ms/mmHg). The transfer function modulus gradually increased with the frequency within the low-frequency range (LF), on average from 10.4±7.3 ms/mmHg to 21.2±9.8 ms/mmHg across subjects. Narrowing the zone of interest within the LF band produced a decrease in both the systematic difference (relative mean difference: 0.5%) and the random variance (typical error: 2.1 ms/mmHg) between the modified Oxford gain and the transfer function modulus. Our data suggest that the frequency dependent increase in low-frequency transfer function modulus between RR interval and blood pressure fluctuations contributes to both the systematic difference (bias) and the random variance (error) between the pharmacological and transfer function baroreflex measures. This finding suggests that both methodological and physiological factors underlie the observed disagreement between the pharmacological and the transfer function method. Thus both baroreflex measures contribute complementary information and can be considered valid methods for baroreflex sensitivity assessment.

Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome.

OBJECTIVE: To define the neuropathology, clinical phenotype, autonomic physiology and differentiating features in individuals with neuropathic and non-neuropathic postural tachycardia syndrome (POTS). METHODS: Twenty-four subjects with POTS and 10 healthy control subjects had skin biopsy analysis of intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and autonomic testing. Subjects completed quality of life, fatigue and disability questionnaires. Subjects were divided into neuropathic and non-neuropathic POTS, defined by abnormal IENFD and abnormal small fiber and sudomotor function. RESULTS: Nine of 24 subjects had neuropathic POTS and had significantly lower resting and tilted heart rates; reduced parasympathetic function; and lower phase 4 valsalva maneuver overshoot compared with those with non-neuropathic POTS (P<0.05). Neuropathic POTS subjects also had less anxiety and depression and greater overall self-perceived health-related quality of life scores than non-neuropathic POTS subjects. A sub-group of POTS patients (cholinergic POTS) had abnormal proximal sudomotor function and symptoms that suggest gastrointestinal and genitourinary parasympathetic nervous system dysfunction. CONCLUSIONS AND RELEVANCE: POTS subtypes may be distinguished using small fiber and autonomic structural and functional criteria. Patients with non-neuropathic POTS have greater anxiety, greater depression and lower health-related quality of life scores compared to those with neuropathic POTS. These findings suggest different pathophysiological processes underlie the postural tachycardia in neuropathic and non-neuropathic POTS patients. The findings have implications for the therapeutic interventions to treat this disorder.

Experimental hypoglycemia is a human model of stress-induced hyperalgesia.

Hypoglycemia is a physiological stress that leads to the release of stress hormones, such as catecholamines and glucocorticoids, and proinflammatory cytokines. These factors, in euglycemic animal models, are associated with stress-induced hyperalgesia. The primary aim of this study was to determine whether experimental hypoglycemia in humans would lead to a hyperalgesic state. In 2 separate 3-day admissions separated by 1 to 3 months, healthy study participants were exposed to two 2-hour euglycemic hyperinsulinemic clamps or two 2-hour hypoglycemic hyperinsulinemic clamps. Thermal quantitative sensory testing and thermal pain assessments were measured the day before and the day after euglycemia or hypoglycemia. In contrast to prior euglycemia exposure, prior hypoglycemia exposure resulted in enhanced pain sensitivity to hot and cold stimuli as well as enhanced temporal summation to repeated heat-pain stimuli. These findings suggest that prior exposure to hypoglycemia causes a state of enhanced pain sensitivity that is consistent with stress-induced hyperalgesia. This human model may provide a framework for hypothesis testing and targeted, mechanism-based pharmacological interventions to delineate the molecular basis of hyperalgesia and pain susceptibility.

Antecedent hypoglycemia impairs autonomic cardiovascular function: implications for rigorous glycemic control.

OBJECTIVE: Glycemic control decreases the incidence and progression of diabetic complications but increases the incidence of hypoglycemia. Hypoglycemia can impair hormonal and autonomic responses to subsequent hypoglycemia. Intensive glycemic control may increase mortality in individuals with type 2 diabetes at high risk for cardiovascular complications. We tested the hypothesis that prior exposure to hypoglycemia leads to impaired cardiovascular autonomic function. RESEARCH DESIGN AND METHODS: Twenty healthy subjects (age 28 +/- 2 years; 10 men) participated in two 3-day inpatient visits, separated by 1-3 months. Autonomic testing was performed on days 1 and 3 to measure sympathetic, parasympathetic, and baroreflex function. A 2-h hyperinsulinemic [hypoglycemic (2.8 mmol/l) or euglycemic (5.0 mmol/l)] clamp was performed in the morning and in the afternoon of day 2. RESULTS: Comparison of the day 3 autonomic measurements demonstrated that antecedent hypoglycemia leads to 1) reduced baroreflex sensitivity (16.7 +/- 1.8 vs. 13.8 +/- 1.4 ms/mmHg, P = 0.03); 2) decreased muscle sympathetic nerve activity response to transient nitroprusside-induced hypotension (53.3 +/- 3.7 vs. 40.1 +/- 2.7 bursts/min, P < 0.01); and 3) reduced (P < 0.001) plasma norepinephrine response to lower body negative pressure (3.0 +/- 0.3 vs. 2.0 +/- 0.2 nmol/l at -40 mmHg). CONCLUSIONS: Baroreflex sensitivity and the sympathetic response to hypotensive stress are attenuated after antecedent hypoglycemia. Because impaired autonomic function, including decreased cardiac vagal baroreflex sensitivity, may contribute directly to mortality in diabetes and cardiovascular disease, our findings raise new concerns regarding the consequences of hypoglycemia.

Sympathetic neural activity, sex dimorphism, and postural tachycardia syndrome.

OBJECTIVE: To elucidate the mechanisms whereby postural tachycardia syndrome (POTS) patients maintain orthostatic blood pressure and explain the greater prevalence of female cases in POTS cohorts. METHODS: We investigated muscle sympathetic nerve (MSN) discharge characteristics in 12 female POTS patients and in 9 male and 12 female control subjects using the burst amplitude distribution and the relative contribution of burst frequency and burst amplitude. RESULTS: At rest, burst distribution was shifted toward larger amplitudes in POTS patients (p < 0.005), consistent with increased sympathetic activity. During hypotension, the distribution shifted toward larger amplitude bursts in control subjects (p < 0.001), whereas it did not change in POTS patients. Total MSN activity increase to hypotension did not differ between subject groups, but the relative contribution of burst frequency change to the total activity increase was greater in POTS patients than in female (p < 0.05) and male (p < 0.001) control subjects. In contrast, the relative contribution of burst amplitude change to total MSN activity increase was greater in male compared with female control subjects (p < 0.05) and POTS patients (p < 0.001). INTERPRETATION: At rest, the burst amplitude distribution was consistent with increased sympathetic activity in POTS and did not change in response to hypotension. In response to hypotension, burst frequency makes a proportionally greater contribution to the increase in total MSN activity in POTS patients compared with female control subjects, and female compared with male control subjects. These physiological differences in MSN discharge characteristics, in the setting of sympathetic fiber loss associated with POTS, may contribute to the predisposition to and greater prevalence of POTS in female individuals.

Sympathetic nerve activity in response to hypotensive stress in the postural tachycardia syndrome.

BACKGROUND: Increased central sympathetic activity and/or deficient peripheral sympathetic nerve function are among the proposed pathophysiological changes in patients with the postural tachycardia syndrome (POTS). Little is known about sympathetic nerve outflow and its role in hemodynamic control in this disorder. METHODS AND RESULTS: We recorded peroneal muscle sympathetic nerve activity in 9 POTS patients and 9 control subjects at rest and during a nitroprusside-induced hypotensive stimulus. Baseline blood pressure (BP) and heart rate were significantly higher in POTS patients than in controls. At rest, the burst frequency was similar in POTS patients and controls (18.1+/-6.2 and 20.1+/-7.9 bursts/min, respectively; P=NS), whereas the burst incidence was significantly lower (23.1+/-6.8 versus 32.2+/-11.4 bursts/100 heartbeats, P<0.05). Nitroprusside increased sympathetic outflow significantly more in POTS patients than in controls despite a similar BP decrease (burst frequency 20.4+/-7.5 versus 12.1+/-4.1 bursts/min, P=0.008, and burst incidence 21.8+/-8.4 versus 14.4+/-5.2 bursts/100 heartbeats, P=0.03). The change in mean burst area, a measure of the number of actively firing sympathetic neurons, was similar in patients and controls (117+/-15% versus 114+/-21%, P=NS). CONCLUSIONS: At rest, the tachycardia and normal burst frequency result in normal or even elevated BP in POTS patients. During a hypotensive stimulus, cardiovascular homeostasis is maintained by the increased sympathetic outflow and normal heart rate response despite the lack of concomitant increase in mean burst area that is most likely due to sympathetic denervation.