Index Of Cardiac Sympathovagal Balance Research Articles

Gestationally administered RAS modulators reprogram endotoxic cardiovascular and inflammatory profiles in adult male offspring of preeclamptic rats.

Previous studies showed that preeclampsia (PE) amplifies cardiovascular dysfunction induced by endotoxemia in adult male, but not female, offspring. Here, we asked if such aggravated endotoxic insult could be nullified by modulators of the renin-angiotensin system (RAS). PE was induced by gestational administration of Nω-nitro-L-arginine methyl ester(L-NAME, a nitric oxide synthase inhibitor). Adult male offspring of PE mothers treated gestationally with angiotensin 1-7 (Ang1-7, angiotensin II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (peroxisome proliferator-activated receptor gamma, PPARγ, agonist), or combined losartan/pioglitazone were instrumented with femoral indwelling catheters and challenged intravenously with a 5-mg/kg dose of lipopolysaccharides (LPS, 5mg/kg). LPS caused significant decreases in blood pressure (BP) and spectral index of overall heart rate variability and increases in heart rate and left ventricular contractility (dP/dtmax). These effects were mostly reduced to similar magnitudes by individual drug therapies. In offspring born to Ang1-7-treated dams, the spectral index of cardiac sympathovagal balance showed elevated sympathetic dominance in response to LPS. Immunohistochemistry revealed that Ang1-7, but not losartan/pioglitazone, abolished the exaggerated increases in toll-like receptor 4 (TLR-4) expression caused by PE/LPS in heart tissues and neuronal circuits of brainstem rostral ventrolateral medulla (RVLM). By contrast, the losartan/pioglitazone regimen, but not Ang1-7, decreased and increased angiotensin converting enzyme (ACE) and ACE2 expression, respectively. Together, gestational fetal reprogramming of Ang II (depression) and Ang1-7 (activation) arms of RAS effectively counterbalance worsened endotoxic cardiovascular and inflammatory profiles in adult male offspring of PE rats.

Dysregulated ACE/Ang II/Ang1-7 signaling provokes cardiovascular and inflammatory sequelae of endotoxemia in weaning preeclamptic rats

Weaning preeclamptic (PE) rats exhibit exaggerated endotoxic signs of hypotension and cardiac autonomic neuropathy. Considering the role of renin-angiotensin system (RAS) in maternal programming during PE, we investigated the hypothesis that gestational modulation of offensive (Angiotensin II, Ang II) and defensive (Ang 1–7) components of RAS alleviates cardiovascular hyperresponsiveness of weaning PE mothers to postpartum endotoxemia. PE was induced by treating pregnant rats with the nitric oxide synthase inhibitor L-NAME (50 mg/kg/day) for 7 consecutive days starting from gestational day 14. The PE-associated elevations in gestational systolic blood pressure and proteinuria were reduced after gestational treatment with Ang 1–7 (Ang II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, with the latter therapy being the most effective. In weaning PE rats, the potentiated falls in mean arterial pressure and spectral index of cardiac sympathovagal balance (low frequency/high frequency ratio) caused by i.v. Lipopolysaccharides (LPS, 5 mg/kg) were attenuated by all therapies. Pioglitazone and Ang 1–7 were more effective in reversing increases and decreases in left ventricular contractility and isovolumic relaxation time constant, respectively, seen in endotoxic PE mothers. Immunohistochemically, cardiac Toll-like receptor 4 (TLR-4) expression was increased in endotoxic PE rats, and this effect was abrogated by Ang 1–7 or losartan/pioglitazone. The same treatments blunted the increased cardiac angiotensin converting enzyme (ACE) expression whereas ACE2 expression was altered by none of the intervening therapies. Overall, the mitigation of Ang II/ACE imbalances alleviates the sensitized cardiovascular and inflammatory actions of endotoxemia in weaning PE mothers.

Gestationally Administered RAS Modulators Reprogram Endotoxic Cardiovascular and Inflammatory Profiles in Adult Offspring of Preeclamptic Rats

Preeclampsia (PE) adversely programs fetal cardiovascular integrity and amplifies cardiovascular dysfunction induced by endotoxemia in adult offspring of preeclamptic mothers. Here, we asked if such aggravated endotoxic insult could be nullified by modulators of the renin-angiotensin system (RAS). PE was induced by gestational administration of L-NAME, a nitric oxide synthase inhibitor. Adult male offspring of PE mothers treated gestationally with Ang 1-7 (Ang II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, were instrumented with femoral indwelling catheters and challenged intravenously with a 5 mg/kg dose of lipopolysaccharides (LPS, 5 mg/kg). LPS caused significant increases in heart rate and decreases in blood pressure and spectral index of overall heart rate variability. These effects were similarly reduced by all drug therapies. In offspring born to Ang 1-7-treated dams, the spectral index of cardiac sympathovagal balance showed elevated sympathetic dominance in response to LPS. Further, pioglitazone and its combination with losartan were more effective than Ang 1-7 or losartan in depressing the LPS-evoked increases in left ventricular contractility (dP/dtmax). Immunohistochemical studies revealed that Ang1-7, but not losartan/pioglitazone, regimen abolished the exaggerated increases in TLR-4 expression caused by PE/LPS in heart tissues and neuronal circuits of brainstem rostral ventrolateral medulla. By contrast, ACE expression in the same two areas was reduced by losartan/pioglitazone but not Ang 1-7. Together, gestational fetal reprogramming of Ang II (depression) and Ang 1-7 (activation) arms of RAS effectively counterbalance worsened endotoxic cardiovascular and inflammatory profiles in adult offspring of PE rats.

Work Ability Assessment and Its Relationship with Cardiovascular Autonomic Profile in Postural Orthostatic Tachycardia Syndrome.

Postural orthostatic tachycardia syndrome (POTS) negatively impacts quality of life. The excessive increase in cardiac sympathetic modulation during standing, which characterizes POTS patients, leads to many symptoms and signs of orthostatic intolerance. Little is known about the consequences of the disease on work performance and its relationship with individual autonomic profiles. Twenty-two POTS patients regularly engaged in working activity (20 females, age 36 ± 12 years) and 18 gender- and age-matched controls underwent a clinical evaluation and filled out the Work Ability Index (WAI) questionnaire. POTS patients completed the Composite Autonomic Symptom Score (COMPASS31) questionnaire, underwent continuous electrocardiogram, blood pressure and respiratory activity recordings while supine and during a 75° head-up tilt (HUT). A power spectrum analysis provided the index of cardiac sympatho-vagal balance (LF/HF). WAI scores were significantly reduced in POTS patients (29.84 ± 1.40) compared to controls (45.63 ± 0.53, p < 0.01). A significant inverse correlation was found between individual WAI and COMPASS31 scores (r = −0.46; p = 0.03), HUT increase in heart rate (r = −0.57; p = 0.01) and LF/HF (r = −0.55; p = 0.01). In POTS patients, the WAI scores were inversely correlated to the intensity of autonomic symptoms and to the excessive cardiac sympathetic activation induced by the gravitational stimulus.

Gonadal hormone receptors underlie the resistance of female rats to inflammatory and cardiovascular complications of endotoxemia

The male gender is more vulnerable to immunological complications of sepsis. Here, we tested the hypotheses that female rats are protected against endotoxemia-evoked hypotension and cardiac autonomic dysfunction, and that gonadal hormone receptors account for such protection. Changes in blood pressure, heart rate, and cardiac sympathovagal balance caused by i.v. lipopolysaccharide (LPS) were determined. In male rats, LPS elevated serum TNFα together with falls in blood pressure and rises in heart rate. The spectral index of cardiac sympathovagal balance (low-frequency/high-frequency ratio, LF/HF) was reduced by LPS, suggesting an enhanced parasympathetic dominance. Remarkably, none of these LPS effects was evident in female rats. We also report that pretreatment of female rats with fulvestrant (nonselective estrogen receptor blocker), PHTPP (estrogen receptor β blocker), or mifepristone (progesterone receptor blocker) uncovered clear inflammatory (increased serum TNFα), hypotensive and tachycardic responses to LPS. However, these female rats, contrary to their male counterparts, exhibited increases in LF/HF ratio. On the other hand, LPS failed to modify inflammatory or cardiovascular states in rats pretreated with MPP (estrogen receptor α blocker). In females treated with formestane (aromatase inhibitor), LPS increased LF/HF ratio but had no effect on blood pressure. In male rats, the hypotensive and cardiac autonomic effects of LPS were (i) eliminated after treatment with estrogen, and (ii) intensified and inhibited, respectively, in flutamide (androgen receptor blocker)-pretreated rats. These findings highlight important roles for female gonadal hormones and functional estrogen receptor β and progesterone receptors in offsetting inflammatory and cardiovascular derangements caused by endotoxemia in female rats.

L/T-type and L/N-type calcium-channel blockers attenuate cardiac sympathetic nerve activity in patients with hypertension

Sympathetic nerve activity is augmented by calcium-channel blocker treatment as a result of decreased blood pressure. Dihydropyridine calcium-channel blockers are divided into three different types. The purpose of the present study was to investigate whether treatment effects on hemodynamics, cardiac autonomic nerve activity and plasma norepinephrine levels differ among amlodipine (L type), efonidipine (L + T type) and cilnidipine (L + N type). We enrolled 14 hypertensive patients (seven males, seven females, 70 ± 6 years old) undergoing a monotherapy of amlodipine, efonidipine or cilnidipine into this prospective, open-labeled, randomized, crossover study. At baseline and every 6 months of the treatment period, we repeated the evaluation of hemodynamics, spectral analysis of heart rate variability and plasma norepinephrine levels. Blood pressure and pulse rate were comparable among the three treatments. The low-frequency (LF)/high-frequency (HF) power ratio, an index of cardiac sympathovagal balance, was significantly lower with efonidipine and cilnidipine than with amlodipine, while the HF/total power ratio, an index of cardiac vagal activity, revealed the opposite results. There was no significant correlation between the LF/HF ratio and plasma norepinephrine levels. Antihypertensive monotherapy with efonidipine or cilnidipine attenuates cardiac sympathetic nerve activity more effectively than amlodipine monotherapy.

Nitric oxide modulates cardiovascular function in the rat by activating adenosine A2A receptors and inhibiting acetylcholine release in the rostral ventrolateral medulla

1. Nitric oxide (NO), a gas transmitter, modulates many physiological processes, including the central regulation of cardiovascular activity. However, the mechanisms underlying the regulation of cardiovascular activity remain relatively unexplored. In the present study, we hypothesized that central NO-dependent sympathetic inhibition is mediated by activation of adenosine A(2A) receptors (A(2A)R) and inhibition of acetylcholine (ACh) release in the rostral ventrolateral medulla (RVLM). 2. L-Arginine (L-Arg; an NO donor; 100 nmol/100 nL) was microinjected into the RVLM of male Sprague-Dawley rats and heart rate variability (HRV) was assessed as an index of cardiac sympathovagal balance. Following microinjection of L-Arg, decreases were seen in mean arterial pressure (MAP), heart rate (HR) and the ratio of the low- to high-frequency components (LF/HF) of HRV. Pretreatment of rats with SCH58261 (40 pmol/60 nL into the RVLM), a competitive antagonist of the A(2A) R, attenuated these effects. 3. Western blot analysis and ELISA revealed that adenosine and A(2A)R levels increased in the RVLM following L-Arg microinjection, whereas ACh and muscarinic M(1) receptor levels decreased significantly, in parallel with the cardiovascular responses to L-Arg microinjection. The decrease in ACh levels was abolished by SCH58261 pretreatment. 4. Microinjection of N(G)-nitro-L-arginine methyl ester (a non-selective inhibitor of NO synthase; 15 nmol/100 nL) into the RVLM significantly increased MAP, HR and sympathetic activity, as evidenced by HRV (LF, HF and the LF/HF ratio were all increased). 5. The results indicate that the central NO/NO synthase system in the RVLM may modulate cardiovascular activity by activating the A(2A)R, which subsequently inhibits activation of the muscarinic M(1) receptor.

Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome

To explore the frequency of polymorphisms in adrenergic cardiovascular control genes in adolescent with chronic fatigue syndrome (CFS) and the relation of such polymorphisms to cardiovascular variables. DNA from 53 patients with CFS, 12-18 years old, was analysed for five single nucleotide polymorphisms (SNPs) in the genes catechol-O-methyltransferase (COMT), the β₂ -adrenergic receptor (two SNPs), the β₁ -adrenergic receptor and the α₂(a) -adrenergic receptor. Frequencies were compared to a reference population constructed from the National Center for Biotechnology Information (NCBI) database, and associations between frequencies and autonomic cardiovascular responses during a 20° head-up tilt-test were explored. For the COMT SNP Rs4680, patients with CFS had a higher frequency of the AA genotype and a lower frequency of the G containing genotypes (AG and GG), when compared to the reference sample (p = 0.046). Also, the AA genotype was associated with a smaller increase in LF/HF ratio (low-frequency:high-frequency heart rate variability ratio, an index of cardiac sympathovagal balance) during head-up tilt when compared to the AG/GG genotypes. For the β₂ -adrenergic receptor SNP Rs1042714, patients with CFS had a lower frequency of the GG genotype and a higher frequency of the genotypes containing C (CG and CC) (p = 0.044). CFS might be related to polymorphisms of COMT and the β₂ -adrenergic receptor. More details of the molecular mechanisms remain to be investigated.

Determination of Baroreceptor‐Stroke Volume Reflex Sensitivity by Power Spectral Analysis: A Quantitative Probe of Baroreceptor‐Cardiac Reflex

Baroreceptor‐cardiac reflex, which consists of baroreceptor‐induced chronotropic and inotropic actions, is a very useful index of cardiac sympathovagal balance. Baroreceptor‐heart rate reflex sensitivity, which reflects baroreceptor‐induced chronotropic action, has been used as a marker of baroreceptor‐cardiac reflex. However, it cannot be used in patients with chronotropic incompetence and/or implanted cardiac pacemaker. We hypothesized that baroreceptor‐stroke volume (SV) reflex sensitivity, which reflects baroreceptor‐induced inotropic action, may also be a useful method for measurement of baroreceptor‐cardiac reflex, similar to the baroreceptor‐heart rate reflex sensitivity. To test this hypothesis, we measured baroreceptor‐SV reflex sensitivity expressed as ratio of low frequency (LF) power to total power of SV fluctuation (LF/TPsv: %/mmHg) by spectral analysis of mean blood pressure and SV fluctuations, the gain in low‐frequency band between two signals in supine and 60° upright positions, and compared these values to baroreceptor‐heart rate reflex sensitivity in 14 healthy subjects. Baroreceptor‐SV reflex sensitivity correlated significantly with baroreceptor‐heart rate reflex sensitivity (r = 0.73, p < 0.0001). In addition, baroreceptor‐SV reflex sensitivity correlated significantly and positively with high frequency (HF) power (r = 0.57, p < 0.005) and negatively with LF/HF ratio (r = − 0.57, p < 0.005) in power spectral analysis of R‐R interval variability. Moreover, baroreceptor‐SV reflex sensitivity in LF/TPSV correlated positively with the R‐R interval (r = 0.70, p < 0.0001) and negatively with diastolic blood pressure (r = − 0.50, p < 0.01). We conclude that baroreceptor‐SV reflex sensitivity in LF/TPSV can be used as a quantitative probe of baroreceptor‐cardiac reflex, similar to the baroreceptor‐heart rate reflex sensitivity in healthy subjects, and it may enable us to estimate inotropic aspect in baroreceptor‐cardiac reflex in patients with chronotropic incompetence and/or implanted pacemaker.

Effects of glucose ingestion on cardiac autonomic nervous system in healthy centenarians: differences with aged subjects.

Spectral analysis of heart rate variability (HRV) investigates the cardiac autonomic nervous system (ANS) activity. In particular, low frequency/high frequency (LF/HF) is considered an index of cardiac sympatho-vagal balance and is stimulated by glucose ingestion in healthy subjects. No studies have evaluated the effect of glucose ingestion on cardiac ANS in centenarians. In 30 healthy centenarians (HC) and 25 aged subjects (AS) power spectral analysis of HRV was investigated during an oral glucose ingestion. Glucose ingestion rose LF/HF ratio in both groups studied. Such stimulatory effects were restrained to the first 60 min of the study. Independent of age, gender, body mass index (BMI) and fasting plasma norepinephrine and FT3 concentrations, HC had basal total power (1318 +/- 546 vs. 1918 +/- 818 msec2, P < 0.01), lower low frequency (LF) (33 +/- 21 vs. 50 +/- 11 n.u., P < 0. 03), and higher high frequency (HF) (74 +/- 18 vs. 43 +/- 15 n.u., P < 0.05) than AS. Consequently, LF/HF ratio (0.43 +/- 0.07 vs. 0.91 +/- 0.05, P < 0.02) was also lower in HC than in AS. In AS, but not in HC, the baseline LF/HF ratio correlated significantly with BMI (r = 0.48, P < 0.01), waist-hip-ratio (WHR) (r = 0.45, P < 0.02), fasting plasma insulin (r = 0.49, P < 0.01) and norepinephrine (r = 0.57, P < 0.02) concentration. Glucose ingestion was associated with a significant rise in LF/HF ratio in both groups studied but per cent changes in glucose mediated stimulation of LF/HF was lower in HC than in AS. In a control study, water administration did not affect power spectral parameters of HRV. Our study demonstrates that basal- and glucose-stimulated LF/HF, an indirect index of cardiac sympatho-vagal balance, are lower in HC than in AS.

Baseline heart rate variability in healthy centenarians: differences compared with aged subjects (&gt;75 years old)

Healthy centenarians have better anthropometric, endocrine, metabolic and immunological parameters than aged subjects (>75 years old). Heart rate variability (HRV) has been demonstrated to be a good index of the cardiac autonomic nervous system. It is not known whether there are any differences in cardiac autonomic nervous system activity between aged subjects and healthy centenarians. It is possible that differences in cardiac autonomic nervous system activity could represent one of a cluster of factors explaining the extreme survival of centenarians. Thus we aimed to answer the following question: is there any difference in baseline HRV parameters between aged subjects and healthy centenarians? Therefore power spectral analysis of HRV at baseline was investigated in 25 aged subjects (age > or = 75 years) and 30 healthy centenarians (age > or = 0 years). Anthropometric measurements were made in all subjects, fasting blood samples were drawn for metabolite determinations, and HRV was determined. Independent of age, gender, body mass index and fasting plasma noradrenaline and free 3,3',5-tri-iodothyronine concentrations, healthy centenarians had lower basal values for total power (1318+/-546 compared with 1918+/-818 ms(2); P<0.01) and the low-frequency component (33+/-21 compared with 50+/-11 normalized units; P<0.03) and a higher value for the high-frequency component (77+/-15 compared with 61+/-18 normalized units; P<0.05) than aged subjects. Consequently, the low-frequency/high-frequency ratio (0.43+/-0.07 compared with 0.91+/-0.05; P<0.02) was also lower in the healthy centenarians than in the aged subjects. Our study demonstrates that the basal low-frequency/high-frequency ratio, an indirect index of cardiac sympathovagal balance, is lower in healthy centenarians than in aged subjects.

Effects of different insulin infusion rates on heart rate variability in lean and obese subjects

The low-frequency to high-frequency ratio ( LF HF ratio) is an index of cardiac sympathovagal balance. We hypothesized that insulin might also stimulate the LF HF ratio. Thus, 15 lean and 15 obese subjects were studied. Each subject underwent sequential hyperinsulinemic clamps (insulin infusion rate 0.50, 1, and 2 mU/kg · min) while the heart rate was recorded by the Holter technique continuously. Indirect calorimetry allowed determination of the respiratory quotient (Rq) and substrate oxidation. The leg blood flow (LBF), leg vascular resistance (LVR), and plasma norepinephrine concentration were also measured. In seven lean subjects, hyperinsulinemic clamps were repeated along with propranolol infusion (0.1 mg · kg −1 as an intravenous bolus dose followed by continuous intravenous infusion of 0.5 mg · kg −1 · min −1 throughout the study). Lean subjects had better insulin action than obese subjects. Insulin infusion was associated with an increase of the ΔLF HF ratio in both lean ( P < .001 for time-dependent changes) and obese ( P < .02 for time-dependent changes) subjects; however, the extent of insulin-mediated stimulation of the LF HF ratio was greater in lean versus obese subjects. Insulin infusion did not significantly affect HF values in both groups. Independently of gender, body fat, changes in the plasma norepinephrine concentration, LBF, and LVR, the ΔLF HF ratio at the end of the fastest insulin infusion (0.8 ± 0.2 v 0.3 ± 0.2, P < .04) was still greater in lean versus obese subjects. The ΔLF HF ratio was also more stimulated during insulin versus insulin + propranolol infusion in lean subjects. In conclusion, insulin stimulates the LF HF ratio in both lean and obese subjects and thus produces a shift in the cardiac autonomic nervous system activity toward sympathetic predominance.

Sympathovagal balance is major determinant of short-term blood pressure variability in healthy subjects.

Short-term blood pressure variability (BPV) has been suggested to provide important information about cardiovascular regulation. However, the background of BPV, its determinants, and physiological correlates have remained obscure. The aim of this study was to characterize physiological correlates of BPV and to investigate associations between BPV and neural and hormonal regulatory systems at rest in healthy subjects. We studied 117 healthy, normal-weight, nonsmoking male and female subjects aged 23-77 yr. Spectral analysis of BPV and heart rate variability (HRV) was performed from 5-min blood pressure (Finapres) and electrocardiogram recordings during controlled breathing. Baroreflex sensitivity (BRS) was measured using the phenylephrine method. In addition, plasma concentrations of norepinephrine, epinephrine, and arginine vasopressin and plasma renin activity were measured. We found that the ratio between the low- and high-frequency components of HRV, an index of cardiac sympathovagal balance, correlated positively with total power and very low- and low-frequency components of systolic and diastolic BPV and inversely with high-frequency components of systolic and diastolic BPV. BRS, predominantly a measure of cardiac vagal regulation, correlated inversely with BPV. Furthermore, age, gender, body mass index, and systolic blood pressure contributed to BPV. Vasoactive hormones were not significant correlates of BPV. We conclude that sympathovagal balance of cardiovascular regulation is the major determinant of BPV. Other factors associated with BPV are age, gender, body mass index, blood pressure, and BRS.

Cardiac Sympathovagal Balance and Peripheral Sympathetic Vasoconstriction

Both epidural and general anesthetics alter autonomic balance. However, the relative differences between epidural (EA) and general anesthetics (GA) with regard to cardiac and peripheral sympathovagal balance have not been described. Twenty consecutive patients scheduled for radical retropubic prostatectomy were randomized to receive EA (n = 10) or GA (n = 10). Power spectral analysis was performed on the electrocardiographic recordings, with the ratio of low (0.05-0.125 Hz)/high (0.125-0.5 Hz) frequency power used an index of cardiac sympathovagal balance. The forearm minus fingertip skin-surface temperature gradient (> 4 degrees C) was used as an indicator of sympathetically mediated peripheral vasoconstriction. Patients in the EA group demonstrated a significantly greater low/high frequency power ratio and a more frequent incidence of peripheral vasoconstriction than the GA group during the intraoperative period. During the postoperative period, the GA group demonstrated an increase in the low/high ratio and the incidence of vasoconstriction relative to the intraoperative period. Intraoperatively, upper body vasoconstriction appears to be accompanied by a significant shift in cardiac sympathovagal balance toward sympathetic predominance with EA relative to GA. Postoperatively, GA is associated with a shift in the sympathovagal balance toward sympathetic predominance. Further research is required to determine whether this results in cardiovascular compromise in the high-risk patient.