Autonomic nervous system response to remote ischemic conditioning: heart rate variability assessment.

BACKGROUND: Remote ischemic conditioning (RIC) is a procedure applied in a limb for triggering endogenous protective pathways in distant organs, namely brain or heart. The underlying mechanisms of RIC are still not fully understood, and it is hypothesized they are mediated either by humoral factors, immune cells and/or the autonomic nervous system. Herein, heart rate variability (HRV) was used to evaluate the electrophysiological processes occurring in the heart during RIC and, in turn to assess the role of autonomic nervous system. METHODS: Healthy subjects were submitted to RIC protocol and electrocardiography (ECG) was used to evaluate HRV, by assessing the variability of time intervals between two consecutive heart beats. This is a pilot study based on the analysis of 18 ECG from healthy subjects submitted to RIC. HRV was characterized in three domains (time, frequency and non-linear features) that can be correlated with the autonomic nervous system function. RESULTS: RIC procedure increased significantly the non-linear parameter SD2, which is associated with long term HRV. This effect was observed in all subjects and in the senior (> 60 years-old) subset analysis. SD2 increase suggests an activation of both parasympathetic and sympathetic nervous system, namely via fast vagal response (parasympathetic) and the slow sympathetic response to the baroreceptors stimulation. CONCLUSIONS: RIC procedure modulates both parasympathetic and sympathetic autonomic nervous system. Furthermore, this modulation is more pronounced in the senior subset of subjects. Therefore, the autonomic nervous system regulation could be one of the mechanisms for RIC therapeutic effectiveness.

Pharmacological assessment of the contribution of the arterial baroreflex to sympathetic discharge patterns in healthy humans.

To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5-1.2 µg·kg-1·min-1, n = 13) or PE (0.2-1.0 µg·kg-1·min-1, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP ( P < 0.01). AP incidence (326 ± 66 to 579 ± 129 APs/100 heartbeats) and AP content per integrated burst (8 ± 1 to 11 ± 2 APs/burst) increased with NTP ( P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 ± 3 to 24 ± 3 max cluster number, 9 ± 1 to 11 ± 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE ( P < 0.05). PE decreased AP incidence (406 ± 128 to 166 ± 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 ± 2 to 9 ± 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered ( P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher-threshold units occurring with steady-state hypotensive stress. NEW & NOTEWORTHY To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside and phenylephrine and measured sympathetic outflow with wavelet-based methodology. Baroreflex unloading increased sympathetic activity by increasing firing probability of low-threshold axons (rate coding) and recruiting new populations of high-threshold axons. Baroreflex loading decreased sympathetic activity by decreasing the firing probability of larger axons (derecruitment); however, the components of an integrated burst were unaffected.

[Resistant hypertension and carotid baroreceptors stimulation]. / HTA résistante et barostimulation carotidienne.

Resistant hypertension remains a frequent and difficult situation; its management has been recently clarified by guidelines from the French Society of Hypertension. Baroreceptor stimulation (BAROSTIM) is an emerging technique aimed at decreasing blood pressure in resistant hypertension. BAROSTIM interferes with baroreflex loop by stimulating baroreceptors and afferences of the baroreflex. There is only one randomized control trial with this technique which showed a modest but apparently durable blood pressure reduction. More evidences are required to refine the place of BAROSTIM, particularly with new devices. Together with renal denervation, BAROSTIM belongs to a new family of interventional techniques which should be considered as potential add-on therapies while optimal medical therapy remains the cornerstone of hypertension management.

Similarities and differences between renal sympathetic denervation and carotid baroreceptor stimulation.

The two novel approaches recently introduced for the treatment of resistant hypertension, i.e. carotid baroreceptor stimulation and renal denervation, share a number of similarities but are also characterized by important differences. The similarities include the evidence that both interventions have as common pathophysiological background the state of sympathetic overdrive characterizing essential hypertension. In addition both procedures 1) are invasive, 2) exert in the short-term period clearcut blood pressure lowering effects and 3) still face a number of open questions, particularly related to the long-term blood pressure lowering effects, impact on end-organ damage and on cardiovascular events. The differences include the fact that two procedures act on distinct targets that trigger sympathetic activation and consequently blood pressure increase. In addition, only in the case of carotid baroreceptor stimulation the blood pressure effects can be easily assessed immediately following the implantation. Finally, the economic costs, metabolic effects and impact on vagal modulation of heart rate are different between the two interventions. This paper will provide a comparison of the background, effects and outcome of renal denervation and carotid baroreceptor stimulation, stressing whenever possible the clinical implications of the main features of the two interventions.

Assessment of chemoreflex sensitivity in free breathing young subjects by correction for respiratory influence.

BACKGROUND: The assessment of autonomic function is an important tool for risk stratification in critically ill patients. Peripheral cardiac chemoreflex sensitivity has been considered a marker for increased risk of sudden cardiac death. In normals, the evaluation of peripheral cardiac chemoreflex sensitivity is performed under controlled breathing conditions during inhalation of hypoxic gas. Since this is poorly tolerated by patients, they are commonly studied under hyperoxic conditions, which are not physiological. METHODS: We studied 20 healthy volunteers who underwent free and controlled breathing of a hypoxic gas mixture (10% O2 in N2) over 5 min. Values of peripheral cardiac chemoreflex sensitivity, corrected for respiratory influence, were compared with the results obtained experimentally under controlled breathing conditions in the same subjects. RESULTS: We found a substantial difference between values obtained during free and controlled breathing (3.64 +/- 0.81 vs. 1.53 +/- 0.32 ms/mmHg, respectively; P < 0.05). After application of a respiratory correction, described and validated in this article, no significant difference was seen for these values (0.89 +/-0.91 vs. 1.53 +/- 0.32 ms/mmHg, P = 0.46). CONCLUSIONS: This approach allows the evaluation of peripheral cardiac chemoreflex sensitivity in free breathing subjects. This correction could improve the assessment of cardiac chemoreflex sensitivity in patients with cardiorespiratory disorders, who find it difficult to control their breathing according to an experimental protocol.

Assessment of continuous skeletal muscle blood flow during exercise in humans.

The ability to measure regional blood flow from exercising skeletal muscles is of great interest. However, noninvasive techniques such as venous occlusion plethysmography and pulsed Doppler duplex ultrasonography only allow determination of blood flow at rest. The aim of our study was to investigate the influence of position on continuous measured skeletal muscle blood flow response in the upright and supine positions during graded maximal exercise by means of the local (133)Xenon washout technique with portable CdTe(Cl) detectors. Fifteen healthy subjects (8 women and 7 men, mean age 46 +/- 11 years) performed graded maximal bicycle exercise in both supine and upright positions in random order on 2 subsequent days. Blood flow in the musculus tibialis anterior was measured using the local (133)Xenon washout technique. A total of 55-110 MBq of (133)Xenon dissolved in isotonic saline was injected intramuscularly and the gamma emission was registered by light-weight portable CdTe(Cl) detectors. During supine exercise skeletal muscle blood flow increased continuously with increasing work load. However, during upright exercise blood flow increased only at the initial three work loads, then it decreased gradually. Immediately after exercise blood flow returned to preexercise values for both positions. The skeletal muscle blood flow at maximum work load for each subject was 74% (relative flow values) (P < 0.05) higher in the supine compared with the upright position. There was no significant difference in absolute or relative blood flow values at similar time points. Exercise time was longer in the supine (1345 +/- 548 s) compared with the upright position (1148 +/- 453 s) (P < 0.005). The local (133)Xenon washout technique with portable CdTe(Cl) detectors allows continuous determination of skeletal muscle blood flow during graded bicycle exercise in supine and upright positions. Furthermore, blood flow at maximum work load and exercise time was increased in supine compared with upright exercise.

[Basic concepts on the assessment of arterial baroreceptor sensitivity with non invasive methods. Estimate of the spontaneous gain of the arterial baroreceptor]. / Conceitos básicos da avaliação da sensibilidade dos barorreceptores arteriais por métodos não invasivos. Cálculo do ganho espontâneo do barorreceptor arterial.

Arterial baroreceptors are sensitive to variation in both blood and pulse pressure. When there is an increase in those pressures, the baroreceptors increase the rhythm in which electric impulses are discharged. The impulses are transmitted by the receptors to the nervous centres of the brainstem. Once processed, these signals turn into sympathetic and vagal impulses. The vagal efferents control heart rate and the sympathetic efferents control heart rate, myocardial contractility and peripheral resistance. If there is an increase in blood pressure, then there will be a reflex decrease in the sympathetic activity and an increase in the parasympathetic one. The cardiac cronotropic response to blood pressure variation is very fast-with a delay of one or two beats. The amplitude of the response is a sigmoidal function. The greatest inclination of the response curve, that is to say, the area of greatest variation of the RR interval per unit of pressure, characterises the gain of the baroreceptors. The traditional method for obtaining the gain of the baroreceptor is a pharmacological one. Generally, the patient is given phenilephrine intravenously, in bolus and then the correlation between heart rate and the increase in intra-arterial blood pressure (reflex bradycardia) is calculated. Lately, it has been used the calculation of the spontaneous gain of the baroreceptor starting from a study carried out on the normal fluctuations in blood pressure and in the pulse interval both in time and frequency domain. The first case deals with the calculation of the gain of the function of transfer between the variations both in blood pressure and the RR intervals in the LF and the HF bands. The second case deals with the analysis of the occurrence of sequences of three beats with successive increases or decreases in blood pressure and in the RR interval. The gain is obtained from the linear regression of all the sequences. The application of these techniques to the recordings of blood pressure obtained by non-invasive methods (Finapress) makes possible that this procedure be followed under real conditions since it requires no previous stimulation of the cardiovascular system, which would probably interfere with the mechanisms to be evaluated, and requires no equipment in the condition which is normally required by experimental methodology.

Model for the assessment of heart period and arterial pressure variability interactions and of respiration influences.

A model which assesses the closed-loop interaction between heart period (HP) and arterial pressure (AP) variabilities and the influence of respiration on both is applied to evaluate the sources of low frequency (LF approximately 0.1 Hz) and high frequency (HF, respiratory rate approximately 0.25 Hz) in conscious dogs (n = 18) and humans (n = 5). A resonance of AP closed-loop regulation is found to amplify LF oscillations. In dogs, the resonance gain increases slightly during baroreceptor unloading (mild hypotension obtained with nitroglycerine (NTG) i.v. infusion, n = 8) and coronary artery occlusion ((CAO), n = 6), and it is abolished by ganglionic transmission blockade ((ARF), Arfonad i.v. infusion, n = 3). In humans, this gain is considerably increased by passive tilt. Different, possibly central, sources of LF oscillations are also evaluated, finding a strong rhythmic modulation of HP during CAO. At HF, a direct respiratory arrhythmia is dominant in dogs at control, while it is considerably reduced during CAO. On the contrary, in humans, a strong influence of respiration on AP is shown which induces a reflex respiratory arrhythmia. An index of the gain of baroreceptive response, alpha cl, was decreased by NTG and CAO, and virtually abolished by chronic arterial baroreceptive denervation (TABD, n = 4) and ARF.

[A noninvasive assessment of the gain in baroceptor control of the heart rate in man]. / Valutazione noninvasiva del guadagno del controllo barocettivo della frequenza cardiaca nell'uomo.

In this study we addressed the problem of the noninvasive evaluation of the overall gain of baroreceptor control of heart period. We studied a population of healthy controls (n = 49, age 30 +/- 2 years, systolic arterial pressure [by Finapres] 114 +/- 1 mmHg) and a group of mild hypertensive subjects (n = 14, age 51 +/- 2 years, systolic arterial pressure 151 +/- 5 mmHg). Subjects were studied at rest both in absence and in presence of chronic beta-adrenergic receptor blockade (atenolol: controls 50 mg po oid x 4 days; hypertensives 100 mg po oid x 2 weeks). Spectral analysis of RR interval and of systolic arterial pressure variabilities provided noninvasive markers of autonomic control of the SA node and of the vasculature. The index alpha, obtained from bivariate cross spectral and spectral analysis provided a quantitative assessment of the closed loop gain of baroreceptor control of the heart period. The index alpha resulted more elevated in the normotensive than in the hypertensive group. Additionally it appeared significantly increased at the end of the treatment with the beta-adrenergic blocking drug atenolol. Furthermore, alpha appeared significantly and negatively correlated with age, systolic arterial pressure and, although weakly, with low frequency; it was positively correlated with the average RR interval. In conclusion, this study suggested an important link between the average level of sympathetic activity and baroreceptor control of heart rate in normotensive and mild hypertensive subjects. The clinical importance of this sympathetic modulation of the gain of the heart period/arterial pressure relationship can now be assessed with this noninvasive approach.

Assessment of cardiovascular reflexes is of limited value in predicting maximal +Gz-tolerance.

The importance of +Gz-induced loss of consciousness as a major cause of inflight incapacitation emphasizes the need for predicting +Gz-tolerance and investigating its possible determinants. The cardiovascular changes from +Gz-stress are initially counteracted reflexly by the cardiovascular autonomic system. The integrity of neural cardiovascular reflex control can be assessed by analysing the blood pressure (BP) and heart rate (HR) responses to different maneuvers, such as the Valsalva maneuver, standing and forced respiratory sinus arrhythmia. The aim of the present study was to investigate a possible relation between the cardiovascular responses to these tests and +Gz-tolerance. In 10 healthy subjects continuous Finapres BP and HR responses to the tests have been determined and correlated with their G-levels of peripheral light loss (PLL) during centrifuge-runs (0.1 G/s). Only mean BP recovery during Valsalva maneuver correlated marginally significantly with PLL (r = 0.63, p = 0.049). Cardiovascular findings were within normal range revealing no cardiovascular autonomic dysfunction. These results indicate that intact neural cardiovascular control seems to be a condition for tolerating +Gz-stress without determining maximal +Gz-tolerance. We conclude that assessment of cardiovascular reflexes may only confirm baroreflex integrity. However, they have limited value in predicting +Gz-tolerance.

Assessment of gain of tachycardia and bradycardia responses of cardiac baroreflex.

The cardiac baroreflex was studied in humans by means of vasoactive drugs and in conscious rabbits by the drug and perivascular cuff methods, which provide somewhat different afferent drive. Mean arterial pressure (MAP)-heart rate (HR) curves were derived using 1) a single symmetric logistic function and 2) a compound function, where the two halves of separate logistic functions were centered on the resting value, one for the tachycardia response and the other for the bradycardia response. There were some differences in overall reflex parameters (plateaus, HR range, gain) between the two methods because of minor degrees of asymmetry. But the differences were small, and the single symmetric logistic adequately describes the overall properties. With the compound function, we assessed average gain, Gt and Gb, for the tachycardia and bradycardia responses and the corresponding normalized (range-independent) gains, Ct and Cb. The resting HR has a large effect on Gt/Gb, since it determines the HR range of each logistic. Moreover, Gt/Gb depends on both resting autonomic tone and reflex changes. However, Ct and Cb provide information about "intrinsic" differences in sensitivity; they are independent of resting HR but entirely dependent on reflex autonomic changes. In rabbits Ct and Cb tended to be larger with the cuff than with the drug method; in addition, with the former Ct less than Cb, whereas with the drug method Ct greater than or equal to Cb, which was consistent with differences in afferent drive. There were also differences between humans and rabbits in Ct/Cb of the vagal component of the reflex. The assessment of the normalized gains of the compound logistic function has substantial advantages over previous methods for assessing gain of the tachycardia and bradycardia responses.

Assessment of threshold and saturation pressure in the baroreflex function curve: a new mathematical analysis.

The baroreflex function has been assessed with logistic function analysis, a mathematical model suitable for function curves of sigmoid shape. The nonlinear (sigmoid) relationship between carotid sinus pressure (CSP) and systemic arterial pressure (SAP) reflects threshold and saturation of the SAP responses to CSP changes. The threshold and saturation pressures (TP and SP) are often determined by gross inspection from the experimental recordings. Objective and accurate determination of TP and SP may be achieved by mathematical analysis. Kent et al. (Cardiology, Vol. 57, pp. 295-310, 1972) provided equations that estimated SP and TP to be +/- 1.317/k from the midrange CSP (k, the slope coefficient of a curve). Tan et al. (Circ. Res., Vol. 65, pp. 63-70, 1989) recently used an equation to calculate TP based on the consideration that it is about 95% of the maximal SAP. In this report, we elaborated new equations for the estimation of SP and TP, which approximate midrange pressure +/- 2/k. The accuracy of these new equations compared to other equations was tested using various sets of simulation data. In addition, experiments were conducted in anesthetized dogs with isolated carotid sinus. The open-loop CSP-SAP curves were obtained following various holding pressure (HPs) to demonstrate the phenomenon of baroreflex acute resetting. The effects of using different equations on the values of TP, SP, and delta TP/delta HP (extent of resetting) were analyzed. Both simulation and experimental data revealed that the equations of Kent et al. gave rise to values of TP and SP far different from the realistic values. The values of TP calculated by equation of Tan et al. were dependent on the maximal SAP and the slope of the function curve. The TP and SP (+/- 2/k from the midrange pressure of the sigmoid curve) obtained by our new equations were not significantly affected by the maximal SAP and the curve slope. The mathematical analysis may be particularly useful for comparison among various baroreflex curves with different maximal SAP and/or curve slope.

Assessment of baroreceptor reflex function during mental stress and relaxation.

This paper describes a method of measuring baroreceptor cardiac reflex sensitivity noninvasively from spontaneous patterns of blood pressure and interbeat interval, and the application of this technique in psychophysiology. Baroreflex function was assessed in 24 female volunteers during relaxation and performance of the cold pressor test and a non-verbal mental arithmetic task. Blood pressure and interbeat interval were monitored continuously from the finger using the vascular unloading technique. Sequences of three or more cardiac cycles were identified over which systolic blood pressure increased progressively in conjunction with lengthening interbeat interval, or systolic blood pressure decreased as interbeat interval was reduced. The regression between systolic blood pressure and interbeat interval was computed as an index of baroreflex sensitivity. Relaxation was associated with a small prolongation of interbeat interval, whereas baroreflex sensitivity increased from 17.1 to 19.8 ms/mmHg. Baroreflex sensitivity was reduced significantly during mental arithmetic (mean 14.2 ms/mmHg) but not during the cold pressor test (mean 17.4 ms/mmHg). The difference between mental arithmetic and the cold pressor test may be related to the relative intensity of cardiac and vascular responses in the two situations. The implications of these results for the understanding of behavioural influences on haemodynamic function are discussed and the advantages of noninvasive methods are considered.

Assessment of cardiopulmonary baroreflex function in hypertensive and normotensive subjects with or without hypertensive relatives.

1. To investigate whether cardiopulmonary baroreflex control contributes to the pathogenesis and progression of hypertension, we have evaluated the function of the cardiopulmonary baroreflex in 22 patients with essential hypertension and in 17 volunteers with normotension. The normotensive group consisted of 8 subjects with a family history of hypertension and nine with no family history. 2. Forearm vascular resistance (FVR) and central venous pressure (CVP) were measured under control conditions when -10 mmHg lower body negative pressure was applied; the cardiopulmonary slope (CPS = delta FVR/delta CVP) was calculated as an index of the cardiopulmonary baroreflex function. 3. CPS was significantly higher in hypertensives (6.0 +/- 3.93 [s.d.], P less than 0.01) and also tended to be higher in normotensives with a family history of hypertension (3.9 +/- 3.53, P less than 0.05), compared with normotensives without a family history of hypertension (1.7 +/- 0.88). 4. When the hypertensives were divided into two groups, depending on whether CPS was greater or less than 6.0 units, cardiac wall thickness (20 +/- 1.6 mm vs 23 +/- 3.2 mm, P less than 0.05) and the renal vascular resistance (20.9 +/- 6.52 units vs 28.9 +/- 7.32 units, P less than 0.05) were both significantly higher in the Low CPS group. 5. These findings suggest that cardiopulmonary baroreflex function was augmented even in normotensive subjects with hypertensive relatives, as compared with those without hypertensive subjects. Furthermore, cardiopulmonary baroreflex function was augmented in the early stages of hypertension and diminished further with increasing severity.

Assessment of baroreceptor reflex sensitivity by means of spectral analysis.

A method of determining baroreceptor reflex sensitivity is proposed that is based on spectral analysis of systolic pressure values and RR interval times, namely, the modulus (or gain) in the mid frequency band (0.07-0.14 Hz) between these two signals. Results using this method were highly correlated (0.94; n = 8) with results of the phenylephrine method. In addition, compared with the values for the preceding rest period, the modulus decreased during mental challenge, as might be expected from the literature.