Breathing cardiovascular variability and baroreflex in mechanically ventilated patients

Heart rate and blood pressure variations during spontaneous ventilation are related to the negative airway pressure during inspiration. Inspiratory airway pressure is positive during mechanical ventilation, suggesting that reversal of the normal baroreflex-mediated pattern of variability may occur. We investigated heart rate and blood pressure variability and baroreflex sensitivity in 17 mechanically ventilated patients. ECG (RR intervals), invasive systolic blood pressure (SBP), and respiratory flow signals were recorded. High-frequency (HF) amplitude of RR and SBP time series and HF phase differences between RR, SBP, and ventilatory signals were continuously computed by Complex DeModulation (CDM). Cross-spectral analysis was used to assess the coherence and the gain functions between RR and SBP, yielding baroreflex sensitivity indices. The HF phase difference between SBP and ventilatory signals was nearly constant in all patients with inversion of SBP variability during the ventilator cycle compared with cycling with negative inspiratory pressure to replicate spontaneous breathing. In 12 patients (group 1), the phase difference between RR and ventilatory signals changed over time and the HF-RR amplitude varied. In the remaining five patients (group 2), RR-ventilatory signal phase and HF-RR amplitude showed little change; however, only one of these patients exhibited a RR-ventilatory signal phase difference mimicking the normal pattern of respiratory sinus arrhythmia. Spectral coherence between RR and SBP was lower in the group with phase difference changes. Positive pressure ventilation exerts mainly a mechanical effect on SBP, whereas its influence on HR variability seems more complex, suggesting a role for neural influences.     

Autonomic Predictors of Hospitalization Due to Heart Failure Decompensation in Patients with Left Ventricular Systolic Dysfunction

Introduction

Autonomic nervous system balance can be significantly deteriorated during heart failure exacerbation. However, it is still unknown whether these changes are only the consequence of heart failure decompensation or can also predict development thereof. Objectives were to verify if simple, non-invasive autonomic parameters, such as baroreflex sensitivity and short-term heart rate variability can provide independent of other well-known clinical parameters information on the risk of heart failure decompensation in patients with left ventricular systolic dysfunction.

Methods

In 142 stable patients with left ventricular ejection fraction ≤ 40%, baroreflex sensitivity and short-term heart rate variability, as well as other well-known clinical parameters, were analyzed. During 23 ± 9 months of follow-up 19 patients were hospitalized due to the heart failure decompensation (EVENT).

Results

Pre-specified cut-off values of baroreflex sensitivity (≤2.4 ms/mmHg) and low frequency power index of heart rate variability (≤19 ms²) were significantly associated with the EVENTs (hazard ratio 4.43, 95% confidence interval [CI] 1.35–14.54 and 5.41, 95% CI 1.87–15.65 respectively). EVENTs were also associated with other parameters, such as left ventricular ejection fraction, NYHA class, diuretic use, renal function, brain natriuretic peptide and hemoglobin level, left atrial size, left and right ventricular heart failure signs. After adjusting baroreflex sensitivity and low frequency power index for each of the abovementioned parameters, autonomic parameters were still significant predictors of hospitalization due to the heart failure decompensation.

Conclusion

Simple, noninvasive autonomic indices can be helpful in identifying individuals with increased risk of hospitalization due to the heart failure decompensation among clinically stable patients with left ventricular systolic dysfunction, even when adjusted for other well-known clinical parameters.     

Phase Synchronization of Hemodynamic Variables at Rest and after Deep Breathing Measured during the Course of Pregnancy

Background

The autonomic nervous system plays a central role in the functioning of systems critical for the homeostasis maintenance. However, its role in the cardiovascular adaptation to pregnancy-related demands is poorly understood. We explored the maternal cardiovascular systems throughout pregnancy to quantify pregnancy-related autonomic nervous system adaptations.

Methodology

Continuous monitoring of heart rate (R-R interval; derived from the 3-lead electrocardiography), blood pressure, and thoracic impedance was carried out in thirty-six women at six time-points throughout pregnancy. In order to quantify in addition to the longitudinal effects on baseline levels throughout gestation the immediate adaptive heart rate and blood pressure changes at each time point, a simple reflex test, deep breathing, was applied. Consequently, heart rate variability and blood pressure variability in the low (LF) and high (HF) frequency range, respiration and baroreceptor sensitivity were analyzed in resting conditions and after deep breathing. The adjustment of the rhythms of the R-R interval, blood pressure and respiration partitioned for the sympathetic and the parasympathetic branch of the autonomic nervous system were quantified by the phase synchronization index γ, which has been adopted from the analysis of weakly coupled chaotic oscillators.

Results

Heart rate and LF/HF ratio increased throughout pregnancy and these effects were accompanied by a continuous loss of baroreceptor sensitivity. The increases in heart rate and LF/HF ratio levels were associated with an increasing decline in the ability to flexibly respond to additional demands (i.e., diminished adaptive responses to deep breathing). The phase synchronization index γ showed that the observed effects could be explained by a decreased coupling of respiration and the cardiovascular system (HF components of heart rate and blood pressure).

Conclusions/Significance

The findings suggest that during the course of pregnancy the individual systems become increasingly independent to meet the increasing demands placed on the maternal cardiovascular and respiratory system.     

Cardiac Impairment Evaluated by Transesophageal Echocardiography and Invasive Measurements in Rats Undergoing Sinoaortic Denervation

Background

Sympathetic hyperactivity may be related to left ventricular (LV) dysfunction and baro- and chemoreflex impairment in hypertension. However, cardiac function, regarding the association of hypertension and baroreflex dysfunction, has not been previously evaluated by transesophageal echocardiography (TEE) using intracardiac echocardiographic catheter.

Methods and Results

We evaluated exercise tests, baroreflex sensitivity and cardiovascular autonomic control, cardiac function, and biventricular invasive pressures in rats 10 weeks after sinoaortic denervation (SAD). The rats (n = 32) were divided into 4 groups: 16 Wistar (W) with (n = 8) or without SAD (n = 8) and 16 spontaneously hypertensive rats (SHR) with (n = 8) or without SAD (SHRSAD) (n = 8). Blood pressure (BP) and heart rate (HR) did not change between the groups with or without SAD; however, compared to W, SHR groups had higher BP levels and BP variability was increased. Exercise testing showed that SHR had better functional capacity compared to SAD and SHRSAD. Echocardiography showed left ventricular (LV) concentric hypertrophy; segmental systolic and diastolic biventricular dysfunction; indirect signals of pulmonary arterial hypertension, mostly evident in SHRSAD. The end-diastolic right ventricular (RV) pressure increased in all groups compared to W, and the end-diastolic LV pressure increased in SHR and SHRSAD groups compared to W, and in SHRSAD compared to SAD.

Conclusions

Our results suggest that baroreflex dysfunction impairs cardiac function, and increases pulmonary artery pressure, supporting a role for baroreflex dysfunction in the pathogenesis of hypertensive cardiac disease. Moreover, TEE is a useful and feasible noninvasive technique that allows the assessment of cardiac function, particularly RV indices in this model of cardiac disease.     

Reduced Heart Rate Variability in Social Anxiety Disorder: Associations with Gender and Symptom Severity

Background

Polyvagal theory emphasizes that autonomic nervous system functioning plays a key role in social behavior and emotion. The theory predicts that psychiatric disorders of social dysfunction are associated with reduced heart rate variability, an index of autonomic control, as well as social inhibition and avoidance. The purpose of this study was to examine whether heart rate variability was reduced in treatment-seeking patients diagnosed with social anxiety disorder, a disorder characterized by social fear and avoidance.

Methods

Social anxiety patients (n = 53) were recruited prior to receiving psychological therapy. Healthy volunteers were recruited through the University of Sydney and the general community and were matched by gender and age (n = 53). Heart rate variability was assessed during a five-minute recording at rest, with participants completing a range of self-report clinical symptom measures.

Results

Compared to controls, participants with social anxiety exhibited significant reductions across a number of heart rate variability measures. Reductions in heart rate variability were observed in females with social anxiety, compared to female controls, and in patients taking psychotropic medication compared to non-medicated patients. Finally, within the clinical group, we observed significant associations between reduced heart rate variability and increased social interaction anxiety, psychological distress, and harmful alcohol use.

Conclusions

The results of this study confirm that social anxiety disorder is associated with reduced heart rate variability. Resting state heart rate variability may therefore be considered a marker for social approach-related motivation and capacity for social engagement. Additionally, heart rate variability may provide a useful biomarker to explain underlying difficulties with social approach, impaired stress regulation, and behavioral inhibition, especially in disorders associated with significant impairments in these domains.     

The Influence of Tobacco Smoking on the Relationship between Pressure and Flow in the Middle Cerebral Artery in Humans

Background

Cigarette smoking is associated with an increased risk of stroke but the mechanism is unclear. The study examined whether acute and chronic cigarette smoking alters the dynamic relationship between blood pressure and cerebral blood flow. We hypothesised that acute and chronic smoking would result in a cerebral circulation that was less capable of buffering against dynamic fluctuations in blood pressure. Further, these changes would be accompanied by a reduction in baroreflex sensitivity, which is reduced after smoking (acute smoking).

Methods

We recruited 17 non-smokers and 15 habitual smokers (13 ± 5 pack years). Continuous measurements of mean cerebral blood flow velocity (transcranial Doppler ultrasound), blood pressure (finger photoplethysmography) and heart rate enabled transfer function analysis of the dynamic relationship between pressure and flow (gain, normalised gain, phase and coherence) and baroreflex sensitivity during supine rest before and after smoking a single cigarette (acute smoking).

Results

There were no between-group differences in gain, phase or coherence before acute smoking. However, both groups showed a reduction in gain and coherence, associated with a reduction in baroreflex sensitivity, and increase in phase after acute smoking.

Conclusions

Contrary to our hypothesis, these findings suggest that in the face of a reduction in baroreflex sensitivity acute smoking may potentially improve the ability of the cerebral circulation to buffer against changes in blood pressure. However, chronic smoking did not alter the dynamic relationship between blood pressure and cerebral blood flow velocity. These results have implications on understanding mechanisms for attenuating stroke risk.     

Behavioral and Cardiorespiratory Responses to Bilateral Microinjections of Oxytocin into the Central Nucleus of Amygdala of Wistar Rats,an Experimental Model of Compulsion

Introduction

The central nucleus of amygdala plays an important role mediating fear and anxiety responses. It is known that oxytocin microinjections into the central nucleus of amygdala induce hypergrooming, an experimental model of compulsive behavior. We evaluated the behavioral and cardiorespiratory responses of conscious rats microinjected with oxytocin into the central nucleus of amygdala.

Methods

Male Wistar rats were implanted with guide cannulae into the central nucleus of amygdala and microinjected with oxytocin (0.5 µg, 1 µg) or saline. After 24 h, rats had a catheter implanted into the femoral artery for pulsatile arterial pressure measurement. The pulsatile arterial pressure was recorded at baseline conditions and data used for cardiovascular variability and baroreflex sensitivity analysis. Respiratory and behavioral parameters were assessed during this data collection session.

Results

Microinjections of oxytocin (0.5 µg) into the central nucleus of amygdala produced hypergrooming behavior but did not change cardiorespiratory parameters. However, hypergrooming evoked by microinjections of oxytocin (1 µg) into the central nucleus of amygdala was accompanied by increase in arterial pressure, heart rate and ventilation and augmented the power of low and high (respiratory-related) frequency bands of the systolic arterial pressure spectrum. No changes were observed in power of the low and high frequency bands of the pulse interval spectrum. Baroreflex sensitivity was found lower after oxytocin microinjections, demonstrating that the oxytocin-induced pressor response may involve an inhibition of baroreflex pathways and a consequent facilitation of sympathetic outflow to the cardiovascular system.

Conclusions

The microinjection of oxytocin (1 µg) into the central nucleus of amygdala not only induces hypergrooming but also changes cardiorespiratory parameters. Moreover, specific oxytocin receptor antagonism attenuated hypergrooming but did not affect pressor, tachycardic and ventilatory responses to oxytocin, suggesting the involvement of distinct neural pathways.     

Orthostatic Change in Blood Pressure and Incidence of Atrial Fibrillation: Results from a Bi-Ethnic Population Based Study

Background

Autonomic fluctuations are associated with the initiation and possibly maintenance of atrial fibrillation (AF). However, little is known about the relationship between orthostatic blood pressure change, a common manifestation of autonomic dysfunction, and incident AF.

Methods

We examined whether supine-to-standing changes in systolic blood pressure (SBP) are associated with incident AF in 12,071 African American and white men and women aged 45–64 years, enrolled in the Atherosclerosis Risks in Communities (ARIC) study. Orthostatic hypotension (OH) was defined as a supine-standing drop in SBP by ≥20 mmHg or diastolic blood pressure by ≥10 mmHg. AF cases were identified based on study scheduled 12-lead ECG, hospital discharge ICD codes, and death certificates through 2009.

Results

OH was seen in 603 (5%) at baseline. During an average follow-up of 18.1 years, 1438 (11.9%) study participants developed AF. Incident AF occurred more commonly among those with OH than those without, a rate of 9.3 vs. 6.3 per 1000 person years, (p<0.001). The age, gender, and race adjusted hazard ratio (95%CI) of AF among those with OH compared to those without was 1.62 (1.34, 2.14). This association was attenuated after adjustment for common AF risk factors to HR 1.40 (1.15, 1.71), a strength similar to that of diabetes or hypertension with AF in the same model. A non-linear relationship between orthostatic change in SBP and incident AF was present after multivariable adjustment.

Conclusions

OH is associated with higher AF incidence. Whether interventions that decrease OH can reduce AF risk remains unknown.     

New GOLD classification: longitudinal data on group assignment

Rationale

Little is known about the longitudinal changes associated with using the 2013 update of the multidimensional GOLD strategy for chronic obstructive pulmonary disease (COPD).

Objective

To determine the COPD patient distribution of the new GOLD proposal and evaluate how this classification changes over one year compared with the previous GOLD staging based on spirometry only.

Methods

We analyzed data from the CHAIN study, a multicenter observational Spanish cohort of COPD patients who are monitored annually. Categories were defined according to the proposed GOLD: FEV₁%, mMRC dyspnea, COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ), and exacerbations-hospitalizations. One-year follow-up information was available for all variables except CCQ data.

Results

At baseline, 828 stable COPD patients were evaluated. On the basis of mMRC dyspnea versus CAT, the patients were distributed as follows: 38.2% vs. 27.2% in group A, 17.6% vs. 28.3% in group B, 15.8% vs. 12.9% in group C, and 28.4% vs. 31.6% in group D. Information was available for 526 patients at one year: 64.2% of patients remained in the same group but groups C and D show different degrees of variability. The annual progression by group was mainly associated with one-year changes in CAT scores (RR, 1.138; 95%CI: 1.074-1.206) and BODE index values (RR, 2.012; 95%CI: 1.487-2.722).

Conclusions

In the new GOLD grading classification, the type of tool used to determine the level of symptoms can substantially alter the group assignment. A change in category after one year was associated with longitudinal changes in the CAT and BODE index.     

Plasma Brain-Derived Neurotrophic Factor and Reverse Dipping Pattern of Nocturnal Blood Pressure in Patients with Cardiovascular Risk Factors

Context

Basic studies have shown that brain-derived neurotrophic factor (BDNF) has critical roles in the survival, growth, maintenance, and death of central and peripheral neurons, while it is also involved in regulation of the autonomic nervous system. Furthermore, recent clinical studies have suggested potential role of plasma BDNF in the circulatory system.

Objective

We investigated the mutual relationships among plasma BDNF, patterns of nocturnal blood pressure changes (dippers, non-dippers, extra-dippers, and reverse-dippers), and cardiac autonomic function as determined by heart rate variability (HRV).

Design

This was a cross-sectional study of patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Study from October 2010 to November 2012.

Patients

Two-hundred fifty patients with 1 or more cardiovascular risk factor(s) (obesity, smoking, presence of cardiovascular event history, hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease) were enrolled.

Results

Plasma BDNF levels (natural logarithm transformed) were significantly (p = 0.001) lower in reverse-dipper patients (7.18±0.69 pg/ml, mean ± SD, n = 36) as compared to dippers (7.86±0.86 pg/ml, n = 100). Multiple logistic regression analysis showed that BDNF (odds ratios: 0.417, 95% confidence interval: 0.228–0.762, P = 0.004) was the sole factor significantly and independently associated with the reverse-dippers as compared with dippers. Furthermore, plasma BDNF level was significantly and positively correlated with the time-domain (SDNN, SDANN5, CVRR) and frequency-domain (LF) of HRV parameters. Finally, multiple logistic regression analyses showed that the relationship between plasma BDNF and the reverse-dippers was weakened, yet remained significant or borderline significant even after adjusting for HRV parameters.

Conclusions

Low plasma BDNF was independently associated with patients showing a reverse-dipper pattern of nocturnal blood pressure, in which an imbalance of cardiac autonomic function may be partly involved.     

Impact of Rifaximin on the Frequency and Characteristics of Spontaneous Bacterial Peritonitis in Patients with Liver Cirrhosis and Ascites

Background

Rifaximin is a non-absorbable antibiotic used to prevent relapses of hepatic encephalopathy which may also be a candidate for prophylaxis of spontaneous bacterial peritonitis (SBP).

Aim

To detect the impact of rifaximin on the occurrence and characteristics of SBP.

Methods

We prospectively studied all hospitalized patients that underwent a diagnostic paracentesis in our department from March 2012 to April 2013 for SBP and recorded all clinical data including type of SBP prophylaxis, prior use of rifaximin, concomitant complications of cirrhosis, as well as laboratory results and bacteriological findings. Patients were divided into the following three groups: no antibiotic prophylaxis, prophylaxis with rifaximin or with systemically absorbed antibiotic prophylaxis.

Results

Our study cohort comprised 152 patients with advanced liver cirrhosis, 32 of whom developed SBP during the study period. As expected, our study groups differed regarding a history of hepatic encephalopathy and SBP before inclusion into the study. None of the 17 patients on systemic antibiotic prophylaxis developed SBP while 8/27 patients on rifaximin and 24/108 without prophylaxis had SBP (p = 0.02 and p = 0.04 versus systemic antibiotics, respectively). In general, episodes of SBP were similar for patients treated with rifaximin and those without any prophylaxis. However, Escherichia coli and enterococci were dominant in the ascites of patients without any prophylaxis, while mostly klebsiella species were recovered from the ascites samples in the rifaximin group.

Conclusion

Rifaximin pretreatment did not lead to a reduction of SBP occurrence in hospitalized patients with advanced liver disease. However, the bacterial species causing SBP were changed by rifaximin.     

Discrete and Effortful Imagined Movements Do Not Specifically Activate the Autonomic Nervous System

Background

The autonomic nervous system (ANS) is activated in parallel with the motor system during cyclical and effortful imagined actions. However, it is not clear whether the ANS is activated during motor imagery of discrete movements and whether this activation is specific to the movement being imagined. Here, we explored these topics by studying the baroreflex control of the cardiovascular system.

Methodology/Principal Findings

Arterial pressure and heart rate were recorded in ten subjects who executed or imagined trunk or leg movements against gravity. Trunk and leg movements result in different physiological reactions (orthostatic hypotension phenomenon) when they are executed. Interestingly, ANS activation significantly, but similarly, increased during imagined trunk and leg movements. Furthermore, we did not observe any physiological modulation during a control mental-arithmetic task or during motor imagery of effortless movements (horizontal wrist displacements).

Conclusions/Significance

We concluded that ANS activation during motor imagery is general and not specific and physiologically prepares the organism for the upcoming effortful action.     

Cardiovascular Variability Analysis and Baroreflex Estimation in Patients with Type 2 Diabetes in Absence of Any Manifest Neuropathy

Introduction

Indexes derived from spontaneous heart period (HP) and systolic arterial pressure (SAP) fluctuations can detect autonomic dysfunction in individuals with type 2 diabetes mellitus (DM) associated to cardiovascular autonomic neuropathy (CAN) or other neuropathies. It is unknown whether HP and SAP variability indexes are sensitive enough to detect the autonomic dysfunction in DM patients without CAN and other neuropathies.

Methods

We evaluated 68 males aged between 40 and 65 years. The group was composed by DM type 2 DM with no manifest neuropathy (n = 34) and healthy (H) subjects (n = 34). The protocol consisted of 15 minutes of recording of HP and SAP variabilities at rest in supine position (REST) and after active standing (STAND). The HP power in the high frequency band (HF, from 0.15 to 0.5 Hz), the SAP power in the low frequency band (LF, from 0.04 to 0.15 Hz) and BRS estimated via spectral approach and sequence method were computed.

Results

The HF power of HP was lower in DM patients than in H subjects, while the two groups exhibited comparable HF power of HP during STAND. The LF power of SAP was similar in DM and H groups at REST and increased during STAND in both groups. BRSs estimated in the HF band and via baroreflex sequence method were lower in DM than in H and they decreased further during STAND in both populations.

Conclusion

Results suggest that vagal control of heart rate and cardiac baroreflex control was impaired in type 2 DM, while sympathetic control directed to vessels, sympathetic and baroreflex response to STAND were preserved. Cardiovascular variability indexes are sensitive enough to typify the early, peculiar signs of autonomic dysfunction in type-2 DM patients well before CAN becomes manifest.     

An international randomised placebo-controlled trial of a four-component combination pill ("polypill") in people with raised cardiovascular risk

Background

There has been widespread interest in the potential of combination cardiovascular medications containing aspirin and agents to lower blood pressure and cholesterol (‘polypills’) to reduce cardiovascular disease. However, no reliable placebo-controlled data are available on both efficacy and tolerability.

Methods

We conducted a randomised, double-blind placebo-controlled trial of a polypill (containing aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg and simvastatin 20 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated 5-year cardiovascular disease risk over 7.5%. The primary outcomes were systolic blood pressure (SBP), LDL-cholesterol and tolerability (proportion discontinued randomised therapy) at 12 weeks follow-up.

Findings

At baseline, mean BP was 134/81 mmHg and mean LDL-cholesterol was 3.7 mmol/L. Over 12 weeks, polypill treatment reduced SBP by 9.9 (95% CI: 7.7 to 12.1) mmHg and LDL-cholesterol by 0.8 (95% CI 0.6 to 0.9) mmol/L. The discontinuation rates in the polypill group compared to placebo were 23% vs 18% (RR 1.33, 95% CI 0.89 to 2.00, p = 0.2). There was an excess of side effects known to the component medicines (58% vs 42%, p = 0.001), which was mostly apparent within a few weeks, and usually did not warrant cessation of trial treatment.

Conclusions

This polypill achieved sizeable reductions in SBP and LDL-cholesterol but caused side effects in about 1 in 6 people. The halving in predicted cardiovascular risk is moderately lower than previous estimates and the side effect rate is moderately higher. Nonetheless, substantial net benefits would be expected among patients at high risk.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12607000099426     

Heart Rate Response to Blood Pressure Variations: Sympathetic Activation versus Baroreflex Response in Patients with End-Stage Renal Disease

Background

Continuous systolic blood pressure (SBP) and interbeat intervals (IBI) recordings reveal sequences of consecutive beats in which SBP and heart rate change in opposite direction, representing negative feedback baroreflex mechanisms, as well as sequences in which SBP and heart rate change in the same direction (non-baroreflex), believed to represent feedforward control mechanisms. The present study was undertaken to assess the relationship between baroreflex and non-baroreflex sequences in end stage renal insufficiency.

Methodology/Principal Findings

Continuous beat-to-beat SBP and IBI monitoring was performed in patients on chronic hemodialysis (HD, n=72), in age-matched patients after renal transplantation (TX, n=41) and healthy (control) individuals (C, n=34). The proportion of baroreflex and nonbaroreflex episodes and the b coefficients (the regression line slope of SBP-IBI correlation) were determined using a newly developed 1 minute sliding window method, the classical sequence technique and the "Z" coefficient method. Analysis using the 1 minute sliding window showed an increased proportion of baroreflex episodes in controls and HD, and predominance of nonbaroreflex episodes in TX. An increased proportion of nonbaroreflex episodes in TX patients relative to HD was also revealed by the "Z" method. Baroreflex and nonbaroreflex b coefficients obtained by all methods were markedly decreased in HD. This alteration was reversed at least partly in TX. In HD, both baroreflex and nonbaroreflex b coefficients were inversely correlated to age and CRP levels; in TX, the nonbaroreflex b coefficient was influenced by the type of calcineurin inhibitor.

Conclusion/Significance

Renal status affects the contribution of baroreflex and nonbaroreflex mechanisms and the strength of SBP-IBI relationship. The predominant contribution of nonbaroreflex mechanisms in TX may be suggestive of enhanced central sympathetic control. Our data may be relevant for understanding of the pathogenesis and selection of appropriate treatment of post-transplant hypertension.     

Control of cardiovascular variability during undisturbed wake-sleep behavior in hypocretin-deficient mice

The central neural mechanisms underlying differences in cardiovascular variability between wakefulness, non-rapid-eye-movement sleep (NREMS), and rapid-eye-movement sleep (REMS) remain poorly understood. These mechanisms may involve hypocretin (HCRT)/orexin signaling. HCRT signaling is linked to wake-sleep states, involved in central autonomic control, and impaired in narcoleptic patients. Thus, we investigated whether HCRT signaling plays a role in controlling cardiovascular variability during spontaneous behavior in HCRT-deficient mice. HCRT-ataxin3 transgenic mice lacking HCRT neurons (TG), knockout mice lacking HCRT peptides (KO), and wild-type controls (WT) were instrumented with electrodes for sleep recordings and a telemetric blood pressure transducer. Fluctuations of systolic blood pressure (SBP) and heart period (HP) during undisturbed wake-sleep behavior were analyzed with the sequence technique, cross-correlation functions, and coherent averaging of SBP surges. During NREMS, all mice had lower SBP variability, greater baroreflex contribution to HP control at low frequencies, and greater amplitude of the central autonomic and baroreflex changes in HP associated with SBP surges than during wakefulness. During REMS, all mice had higher SBP variability and depressed central autonomic and baroreflex HP controls relative to NREMS. HP variability during REMS was higher than during NREMS in WT only. TG and KO also had lower amplitude of the cardiac baroreflex response to SBP surges during REMS than WT. These results indicate that chronic lack of HCRT signaling may cause subtle alterations in the control of HP during spontaneous behavior. Conversely, the integrity of HCRT signaling is not necessary for the occurrence of physiological sleep-dependent changes in SBP variability.     

Blood Pressure Control with a Single-Pill Combination of Indapamide Sustained-Release and Amlodipine in Patients with Hypertension: The EFFICIENT Study

Objective

Despite antihypertensive treatment, most hypertensive patients still have high blood pressure (BP), notably high systolic blood pressure (SBP). The EFFICIENT study examines the efficacy and acceptability of a single-pill combination of sustained-release (SR) indapamide, a thiazide-like diuretic, and amlodipine, a calcium channel blocker (CCB), in the management of hypertension.

Methods

Patients who were previously uncontrolled on CCB monotherapy (BP≥140/90 mm Hg) or were previously untreated with grade 2 or 3 essential hypertension (BP≥160/100 mm Hg) received a single-pill combination tablet containing indapamide SR 1.5 mg and amlodipine 5 mg daily for 45 days, in this multicenter prospective phase 4 study. The primary outcome was mean change in BP from baseline; percentage of patients achieving BP control (BP<140/90 mm Hg) was a secondary endpoint. SBP reduction (ΔSBP) versus diastolic BP reduction (ΔDBP) was evaluated (ΔSBP/ΔDBP) from baseline to day 45. Safety and tolerability were also assessed.

Results

Mean baseline BP of 196 patients (mean age 52.3 years) was 160.2/97.9 mm Hg. After 45 days, mean SBP decreased by 28.5 mm Hg (95% CI, 26.4 to 30.6), while diastolic BP decreased by 15.6 mm Hg (95% CI, 14.5 to 16.7). BP control (<140/90 mm Hg) was achieved in 85% patients. ΔSBP/ΔDBP was 1.82 in the overall population. Few patients (n = 3 [2%]) reported side effects, and most (n = 194 [99%]) adhered to treatment.

Conclusion

In patients who were previously uncontrolled on CCB monotherapy or untreated with grade 2 or 3 hypertension, single-pill combination indapamide SR/amlodipine reduced BP effectively—especially SBP— over 45 days, and was safe and well tolerated.

Trial Registration

Clinical Trial Registry – India CTRI/2010/091/000114     

Decreased heart rate variability in HIV positive patients receiving antiretroviral therapy: importance of blood glucose and cholesterol

The presence of autonomic dysfunction in HIV patients is largely unknown. Early studies found autonomic dysfunction in patients with AIDS. Antiretroviral combination therapy (ART) has dramatically changed the course of the disease and improved prognosis and decreased morbidity.

Aim

To evaluate whether autonomic dysfunction is present in an ART treated HIV population and if so to identify factors of importance.

Methods

HIV patients receiving ART for at least 12 months (n = 97) and an age-matched control group of healthy volunteers (n = 52) were included. All were non-diabetic and had never received medication for hypertension. Following a 10 min resting period a 15 min ECG recording was performed. Heart-rate variability (HRV) analysis was performed in accordance with current guidelines and data reported as mean [interquartile range].

Results

Mean normal-to-normal (NN) and total HRV measured as standard deviation of normal-to-normal (SDNN) was lower in HIV patients compared to controls (905 vs. 982 ms; p<0.001 and 48 vs. 54 ms; p = 0.028, respectively). No differences were found between the groups in parasympathetic activity measured as square root of the mean squared difference of successive NN-intervals (RMSSD) or the percent of differences between adjacent NN intervals greater than 50 ms (pNN50). In the HIV positives, haemoglobin A1c correlated inversely with SDNN, RMSSD and pNN50 (p<0.05). Total cholesterol and LDL-C correlated inversely with RMSSD and pNN50 (p<0.05). Neither HIV duration, HIV-RNA, CD4 cell count nor CD4 nadir correlated with time or phase domain HRV variables.

Conclusions

Moderate autonomic dysfunction is present in HIV positives patients even with suppressed viral load due to ART. The dysfunction is correlated with HbA1c and hypercholesterolemia but not to duration of HIV or whether the patients were receiving protease inhibitors as part of the ART regime.     

Brain Areas Controlling Heart Rate Variability in Tinnitus and Tinnitus-Related Distress

Background

Tinnitus is defined as an intrinsic sound perception that cannot be attributed to an external sound source. Distress in tinnitus patients is related to increased beta activity in the dorsal part of the anterior cingulate and the amount of distress correlates with network activity consisting of the amygdala-anterior cingulate cortex-insula-parahippocampus. Previous research also revealed that distress is associated to a higher sympathetic (OS) tone in tinnitus patients and tinnitus suppression to increased parasympathetic (PS) tone.

Methodology

The aim of the present study is to investigate the relationship between tinnitus distress and the autonomic nervous system and find out which cortical areas are involved in the autonomic nervous system influences in tinnitus distress by the use of source localized resting state electroencephalogram (EEG) recordings and electrocardiogram (ECG). Twenty-one tinnitus patients were included in this study.

Conclusions

The results indicate that the dorsal and subgenual anterior cingulate, as well as the left and right insula are important in the central control of heart rate variability in tinnitus patients. Whereas the sympathovagal balance is controlled by the subgenual and pregenual anterior cingulate cortex, the right insula controls sympathetic activity and the left insula the parasympathetic activity. The perceived distress in tinnitus patients seems to be sympathetically mediated.     

Arterial Baroreceptor Reflex Counteracts Long-Term Blood Pressure Increase in the Rat Model of Renovascular Hypertension

Introduction

The present study tested the hypothesis that long-term effects of baroreceptor activation might contribute to the prevention of persistent arterial blood pressure (BP) increase in the rat model of renovascular hypertension (HTN).

Methods

Repetitive arterial baroreflex (BR) testing was performed in normo- and hypertensive rats. The relationship between initial arterial BR sensitivity and severity of subsequently induced two-kidney one-clip (2K1C) renovascular HTN was studied in Wistar rats. Additionally, the time course of changes in systolic BP (SBP) and cardiac beat-to-beat (RR) interval was studied for 8 weeks after the induction of 2K1C renovascular HTN in the rats with and without sinoaortic denervation (SAD). In a separate experimental series, cervical sympathetic nerve activity (cSNA) was assessed in controls, 2K1C rats, WKY rats, and SHR.

Results

The inverse correlation between arterial BR sensitivity and BP was observed in the hypertensive rats during repetitive arterial BR testing. The animals with greater initial arterial BR sensitivity developed lower BP values after renal artery clipping than those with lower initial arterial BR sensitivity. BP elevation during the first 8 weeks of renal artery clipping in 2K1C rats was associated with decreased sensitivity of arterial BR. Although SAD itself resulted only in greater BP variability but not in persistent BP rise, the subsequent renal artery clipping invariably resulted in the development of sustained HTN. The time to onset of HTN was found to be shorter in the rats with SAD than in those with intact baroreceptors. cSNA was significantly greater in the 2K1C rats than in controls.

Conclusions

Arterial BR appears to be an important mechanism of long-term regulation of BP, and is believed to be involved in the prevention of BP rise in the rat model of renovascular HTN.