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Obesity is associated with an increased risk of several chronic comorbidities, which may also be determined by dysfunctional autonomic nervous system (ANS). The influence of bariatric surgery (BS) on ANS balance was explored in previous studies, but with high heterogeneity in both the assessment timing and methods employed. In the present observational study, we applied a clinical protocol which considers two subsequent phases. Twenty-nine non-diabetic obese subjects were studied at baseline (T0), after one month of lifestyle modification (prehabilitation) (phase 1-T1), and after eight months following BS (phase 2-T2). ANS regulation was assessed across the three study epochs by means of ANSI, a single composite percent-ranked proxy of autonomic balance, being free of gender and age bias, economical and simple to apply in a clinical setting. The aim of the present study was to investigate the effects of the clinical protocol based on prehabilitation and subsequent BS on the ANS regulation by means of ANSI. Potential intertwined correlations with metabolic parameters were also investigated. Notably, we observed a progressive improvement in ANS control, even by employing ANSI. Moreover, the reduction in the markers of sympathetic overactivity was found to significantly correlate with the amelioration in some metabolic parameters (fasting glucose, insulin levels, and waist circumference), as well as in stress and tiredness perception. In conclusion, this study provides convincing evidence that a unitary proxy of cardiac autonomic regulation (CAR) may reflect the progressive improvement in autonomic regulation following behavioral and surgical interventions in obese patients. Intriguingly, this might contribute to reducing cardiovascular and metabolic risk.

The association between left atrial (LA) impairment and cardiovascular diseases (CVD) and between dyslipidaemia and CVD are well known. The present study aims to investigate the relationships between metabolic factors and LA dimensions and compliance, as well as test the hypothesis that metabolic factors influence LA function independent from hemodynamic mechanisms. Arterial blood pressure (BP), waist and hip circumference, metabolic indices, and a complete echocardiographic assessment were obtained from 148 selected inhabitants (M/F 89/59; age 20–86 years) of Linosa Island, who had no history of CVD. At enrollment, 27.7% of the subjects met the criteria for metabolic syndrome (MetS) and 15.5% for arterial hypertension (HTN). LA compliance was reduced in subjects with MetS compared to those without (53 ± 27% vs. 71 ± 29%, p = 0.04) and was even lower (32 ± 17%, p = 0.01) in those with MetS and HTN. At multiple regression analysis, the presence of MetS independently determined LA maximal area (r = 0.56, p < 0.001), whereas systolic BP and the total cholesterol/HDL cholesterol ratio determined LA compliance (r = 0.41, p < 0.001). In an apparently healthy population with a high prevalence of MetS, dyslipidaemia seems to independently influence LA compliance. At a 5-year follow-up, LA compliance was reduced in both all-cause and CVD mortality groups, and markedly impaired in those who died of CVD. These findings may contribute to understanding the prognostic role of LA function in CVD and strengthen the need for early and accurate lipid control strategies.

Exercise is one of the major determinants of a healthy lifestyle, which is particularly important in childhood and serves as a powerful preventive tool. On the other hand, obesity and arterial hypertension rates are increasing in children, representing a huge risk for developing major cardiovascular and metabolic diseases in adult life. Of fundamental importance is the modality and volume of exercise required to obtain benefits. In this feasibility study, we considered a group of obese children, studied before and after a 12-week online exercise training program, and subdivided the participants into two groups considering the volume of exercise performed (above or below 1200 MET·min/week). This threshold level was applied in two different ways: subdivision A considered the total weekly physical activity volume (considering both time spent walking for at least 10 min consecutively and time spent performing structured exercise) and subdivision B considered only the weekly volume of structured exercise. We assessed autonomic and metabolic control and auxological and lifestyle parameters. We observed that the improved volume of structured exercise was associated with reduced arterial pressure percentile only in subdivision B and an improvement in markers of vagal and metabolic control was evident. Moreover, the 12-week online exercise training program, defined considering individual fitness level and progressively adapted as the goal was reached, proved to be sustainable from an economical and organizational point of view.

Background Spectral analysis of Heart Rate Variability (HRV) is a simple, non-invasive technique that is widely used in sport to assess sympatho-vagal regulation of the heart. Its employment is increasing partly due to the rising usage of wearable devices. However data acquisition using these devices may be suboptimal because they cannot discriminate between sinus and non-sinus beats and do not record any data regarding respiratory frequency. This information is mandatory for a correct clinical interpretation. Methods This study involved 974 elite athletes, all of them underwent a complete autonomic assessment, by way of Autoregressive HRV analysis. Results In 91 subjects (9% of the total population) we observed criticalities of either cardiac rhythm or respiration. Through perusal of one-lead ECG analysis we observed that 77 subjects had atrial or ventricular ectopy, i.e. conditions which impair stationarity and sinus rhythm. Running anyway autonomic nervous system analysis in this population, we observed that RR variance and raw values of LF and HF regions are significantly higher in arrhythmic subjects. In addition 14 subjects had slow (about 6 breath/min, 0.1Hz) respiration. This condition clouds the separation between LF from HF spectral regions of RR interval variability, respectively markers of the prevalent sympathetic and vagal modulation of SA node and of their synergistic interaction. Conclusions Caution must be payed when assessing HRV with non-ECG wearable devices. Recording ECG signal and ensuring that respiratory rate is higher than 10 breath/min are both prerequisites for a more reliable analysis of HRV particularly in athletes.

Lifestyle modification programs (LMP) represent a new approach to cardiometabolic/oncologic risk reduction. Successful LMP in clinical practice must be feasible, cost effective, efficacious and consider home-based exercise. Likewise, multiple mechanisms implied in cardiometabolic risk reduction such as cardiac autonomic regulation (CAR) should be easily evidenced, in spite of the computational complexity involved. This goal could be facilitated by employing novel, friendlier, simpler techniques, such as the Autonomic Nervous System Index (ANSI), which can be treated as a proxy of CAR. In this observational study, we introduce a simple LMP (based on cognitive behavioral strategies and patient-tailored prescription of nutrition and home-based exercise, managed by a single physician) into the currently existing clinical practice of secondary cardiometabolic prevention. In 26 subjects, we assessed CAR (autoregressive spectral analysis of cardiovascular variabilities), body mass composition (bioelectrical impedance analysis) and stress perception (questionnaires). After LMP, ANSI and lipid profile were improved; % of fat mass, waist circumference and stress perception were reduced. We conclude that this preliminary, proof of concept study provides significant evidence in favor of the hypothesis that it is possible to introduce a convenient, cost effective LMP into the currently existing clinical practice of secondary cardiometabolic prevention. Findings suggest a successful comprehensive behavioral change, possibly facilitated by the simplified approach employed in this study, capable of improving cardiac autonomic regulation in addition to body mass composition and stress perception.

The dynamics of vagal withdrawal and reactivation during pulses of exercise are described by indices computed from heart period (RR) variations, which may be sensitive to duration and load. We sought to assess the consistency over time of these indices, which is not well established.We recorded continuous electrocardiogram during series of five successive bouts (2 min) of submaximal exercise (at 40 and 70% of VO(2peak), different days). Autonomic responsiveness was inferred from quantification of onset and offset of RR dynamics of each individual bout. Consistency of results was assessed with intraclass correlation (ICC).During exercise bouts, indices from tachycardic and bradycardic transients reach lower levels in response to higher exercise loads and progression of exercise. There is a significant effect of load and time (i.e., bout repetition) for all examined variables, with a clear interaction. However, no interaction is observed with the 60 s change in heart rate. ICC analysis demonstrates that various indices are characterized by large differences in stability, which is generally greater within the same day (e.g., tachyspeed ICC at 40% = 0.751, at 70% = 0.704, both days = 0.633; bradyspeed, respectively, = 0.545, 0.666, 0.516).Intensity and duration of exercise modulate vagal withdrawal and reactivation. Analysis of RR variations, during successive brief exercise bouts at lower and higher intensity, ensures a consistency similar to that reported for autonomic cardiac regulation at rest and might guide the choice among multiple indices that are obtained from the tachogram.

Sleep disorders are associated to a number of cardiovascular disturbances that might increase cardiovascular risk. Sleep deprivation, in particular, might, by inducing autonomic dysregulation, raise arterial pressure and hypertensive risk. Available evidence however is contradictory.We tested the main hypothesis that one night sleep deprivation in 24 volunteers might alter hemodynamics (heart rate and Arterial Pressure - AP), autonomic regulation (mono and bivariate spectral analysis of RR and non invasive AP variability) and baroreflex control (spectral index alpha and spontaneous baroreflex slope), performance indices (reaction time) and subjective stress (questionnaires and salivary cortisol). Volunteers were studied in normal living conditions and while kept in isolation and confinement, to test the presence of possible bias related to environmental stress.Results indicate that there were no differences between normal living conditions and isolation and confinement (Intraclass Correlation Coefficient0.75 for most variables). Conversely, after one night sleep deprivation subjects felt tired (p0.05), and performance deteriorated (p0.05), while cortisol profile was substantially maintained, hemodynamic parameters did not change and HRV and index alpha increased slightly.Findings support the contention that one night sleep deprivation, in absence of significant additional stress or disturbances, does not lead to increased arterial pressure values or to changes in autonomic or baroreflex profiles that could conceivably favor hypertension development, but induces the expected increase in tiredness and reduction in performance.

Di Rienzo M, Castiglioni P, Iellamo F, Volterrani M, Pagani M, Mancia G, Karemaker JM, Parati G. Dynamic adaptation of cardiac baroreflex sensitivity to prolonged exposure to microgravity: data from a 16-day spaceflight. J Appl Physiol 105: 1569-1575, 2008. First published August 28, 2008; doi:10.1152/japplphysiol.90625.2008.-This study explored the process of arterial baroreflex adaptation to microgravity, starting from the first day of flight, during the 16-day STS-107 Columbia Space Shuttle mission. Continuous blood pressure (BP), ECG, and respiratory frequency were collected in four astronauts on ground (baseline) and during flight at days 0-1, 6-7, and 12-13, both at rest and during moderate exercise (75 W) on a cycle ergometer. Sensitivity of the baroreflex heart rate control (BRS) was assessed by sequence and spectral alpha methods. Baroreflex effectiveness index (BEI); low-frequency (LF) power and high-frequency (HF) power of systolic BP (SBP), diastolic BP (DBP), and R-R interval (RRI); the RRI LF/HF ratio; and the RRI root mean square of successive differences (RMSSD) index were also estimated. We found that, at rest, BRS increased in early flight phase, compared with baseline (means +/- SE: 18.3 +/- 3.4 vs. 10.4 +/- 1.2 ms/mmHg; P

Work stress may increase cardiovascular risk either indirectly, by inducing unhealthy life styles, or directly, by affecting the autonomic nervous system and arterial pressure. We hypothesized that, before any apparent sign of disease, work-related stress is already accompanied by alterations of RR variability profile and that a simple onsite stress management program based on cognitive restructuring and relaxation training could reduce the level of stress symptoms, revert stress-related autonomic nervous system dysregulation, and lower arterial pressure. We compared 91 white-collar workers, enrolled at a time of work downsizing (hence, in a stress condition), with 79 healthy control subjects. Psychological profiles were assessed by questionnaires and autonomic nervous system regulation by spectral analysis of RR variability. We also tested a simple onsite stress management program (cognitive restructuring and relaxation training) in a subgroup of workers compared with a sham subgroup (sham program). Workers presented an elevated level of stress-related symptoms and an altered variability profile as compared with control subjects (low-frequency component of RR variability was, respectively, 65.2±2 versus 55.3±2 normalized units; P P

Chronic non-communicable diseases represent the major drivers of disease burden, being responsible for the majority of health care cost and deaths. Almost half of premature deaths is due to behaviors amenable to change. Accordingly, addressing behavior might represent a strategic change in the health delivery system. Improving lifestyle requires a specific strategy embedding the active collaboration of individuals with a multilevel team-oriented medical practice. With the present study we sought to assess whether the implementation of cognitive-behavioral strategies, following the principles of lifestyle medicine in an outpatient clinic provides better results in weight reduction as compared to simpler strategies as presently executed in General Practitioners' offices.This is an observational study on 173 subjects (age 53.1 ± 11.5), comparing three different groups of preventive practice: a personalized lifestyle medicine, combining cognitive behavioral strategies with patient tailored prescription of exercise and nutrition (Group A); a semi-structured approach with generic counseling (Group B); and an unstructured advice (Group C).At the end of the intervention period (17-20 months), group A showed an average weight loss of 5.4 ± 5.1 kg, which was significantly (p0.001)more than observed in group B (2.8 ± 5.1 kg) and group C (1.2 ± 4.8 kg). Likewise BMI and waist were progressively more reduced from A to C.It is possible to implement preventive cognitive-behavioral lifestyle strategies in outpatient internal medicine clinics. This methodology appears more efficacious in inducing weight reduction after more than a year as compared to usual family medicine approaches.

One of the most important features of prolonged weightlessness is a progressive impairment of muscular function with a consequent decrease in exercise capacity. We tested the hypothesis that the impairment in musculo-skeletal function that occurs in microgravity results in a potentiation of the muscle metaboreflex mechanism and also affects baroreflex modulation of heart rate (HR) during exercise. Four astronauts participating in the 16 day Columbia shuttle mission (STS-107) were studied 72-71 days before launch and on days 12-13 in-flight. The protocol consisted of 6 min bicycle exercise at 50% of individual V(o2,max) followed by 4 min of postexercise leg circulatory occlusion (PECO). At rest, systolic (S) and diastolic (D) blood pressure (BP), R-R interval and baroreflex sensitivity (BRS) did not differ significantly between pre- and in-flight measurements. Both pre- and in-flight, SBP increased and R-R interval and BRS decreased during exercise, whereas DBP did not change. During PECO preflight, SBP and DBP were higher than at rest, whereas R-R interval and BRS recovered to resting levels. During PECO in-flight, SBP and DBP were significantly higher whereas R-R interval and BRS remained significantly lower than at rest. The part of the SBP response (delta) that was maintained by PECO was significantly greater during spaceflight than before (34.5 +/- 8.8 versus 13.8 +/- 11.9 mmHg, P = 0.03). The tachycardic response to PECO was also significantly greater during spaceflight than preflight (-141.5 +/- 25.2 versus - 90.5 +/- 33.3 ms, P = 0.02). This study suggests that the muscle metaboreflex is enhanced during dynamic exercise in space and that the potentiation of the muscle metaboreflex affects the vagally mediated arterial baroreflex contribution to HR control.

Computer analysis of spontaneous cardiovascular beat-by-beat variability has gained wide credibility as a means of inferring disturbances of autonomic cardiovascular regulation in a variety of cardiovascular conditions, including hypertension, myocardial infarction and heart failure. Recent applications of spectral analysis to muscle sympathetic nerve activity (MSNA) offer a new approach to a better understanding of the relationship between cardiovascular oscillations and autonomic regulation. However, areas of uncertainty and unresolved debates remain, mostly concerning different methodologies and interpretative models that we will consider in this article. Perusal of all available literature suggests that average sympathetic nerve activity and its oscillatory components, although correlated to some extent, are likely to provide different types of information. In addition, the specific experimental context is of paramount importance, as the rules that seem to govern the relationship between average and oscillatory properties of MSNA appear to be different in usual conditions and in conditions of extremes of activation or disease. In general, dynamic experiments, such as with graded tilt or with vasoactive drugs, are more suited to investigations of the complexity of autonomic regulation than are static comparisons. In addition, because the information is spread across variables and is affected by a potentially large error, it appears that several different techniques should be perceived as complementary rather than as mutually exclusive. Available evidence suggests that low-frequency and high-frequency oscillations in peripheral signals of variability might have a predominantly central, rather than a peripheral, origin and that this applies in particular to low-frequency oscillations. A crucial point in the assessment of the meaning of spectral components relates to consideration of the varying level of very-low-frequency noise, and the mathematical manipulation of derived indices, particularly using a normalization procedure. This appears easier to obtain with auto-regressive than with fast Fourier techniques. With this approach, discrepant interpretations seem to be resolved, provided adequate care is taken in separating direct physiological data from derived meaning, which relates to hidden information and neural codes; in the case of sympathetic discharge, the latter display greater complexity than simple average spike activity per unit time. Accordingly we believe, in conclusion, that the judicious use of spectral methodology, in addition to other techniques, might provide unprecedented, useful insights into autonomic cardiovascular regulation, in both physiopathological and clinical circumstances.

Nicotine patch administration is often used to sustain tobacco abstinence in smoking-cessation programs. There is some concern regarding safety issues, as a consequence of the sympathomimetic action of nicotine. We used spectral analysis of RR interval and (noninvasive) systolic arterial pressure (SAP) beat-by-beat variabilities in a crossover double-blind design to assess the autonomic effects of cigarette smoking, of transdermal nicotine, and of placebo. The study group consisted of 27 heavy smokers (age 43 +/- 2 years). The RR interval and its variability were significantly reduced in the smoking group, as compared with nicotine or placebo groups. The LF component of RR interval variability (in normalized units, nu), and the LF/HF ratio showed greatest values during smoking, as compared with placebo. Values of LF(RR) and LF/HF during nicotine patch treatment were slightly, but not significantly, greater than observed with placebo. No differences were observed in SAP and its variability components. The index alpha (a frequency domain measure of baroreflex gain) was minimal in the smoking period. Habitual cigarette smoking is associated with signs of sympathetic predominance in the autonomic control of the sinoatrial (SA) node. Nicotine patches produce only minor disturbances of autonomic regulation. This corroborates their safe use in smoking-cessation strategies.

Myocarditis has been described during and after a wide variety of infectious agents: viral, rickettsial, bacterial, protozoal, and metazoal diseases may cause cardiac inflammation. We report a case of toxoplasma myocarditis in a young healthy man.

We studied the effects of common antihypertensive regimens on autonomic cardiovascular control. We considered calcium channel antagonists (nicardipine twice a day and isradipine once a day, respectively) and also examined, as reference treatments, once-a-day atenolol and cilazapril. A noninvasive evaluation of autonomic cardiovascular profile was obtained with spectral analysis of RR interval and systolic arterial pressure variability. We studied moderate essential hypertensives before and after 2 weeks of treatment, both at rest and during active standing and mental arithmetic. All treatments reduced arterial pressure equally well; however, marked differences in spectral profiles were observed. The low-frequency spectral component of RR interval variability [in normalized units, marker of sympathetic modulation of the sinoatrial (SA) node] tended to be greater at rest and during stimuli (p < 0.001) in subjects treated with dihydropyridines. No differences at rest, but striking increases of the low-frequency component of systolic arterial pressure variability were observed in nicardipine-treated patients during both standardized excitatory stimuli, suggesting a marked increase in sympathetic vasomotor drive. As to reference treatments, patients treated with atenolol displayed the lowest values, and patients treated with cilazapril (for 4 weeks) provided intermediate values. In conclusion, shorter acting dihydropyridine calcium channel antagonists may induce an exaggerated increase in sympathetic vasomotor drive during standardized laboratory stressors.

The activity of sinus node pacemaker cells is under continuous regulation mainly effected by neural mechanisms. Hence the study of the variability of heart period, especially when assessed in the frequency domain with spectral analysis, was proposed about 15 years ago [l] as a probe for the evaluation of its autonomic control. Initially three spectral components of heart rate variability (HRV) were defined, while the factors considered as modulating them included sympathetic and parasympathetic activities, humoral factors such as the renin-angiotensin system or complex patterns like thermoregulation. On the basis of (i) an attempt to analyse cardiovascular neural regulation in closed-loop conditions, (ii) a different spectral methodology using autoregressive algorithms [21, (iii> simultaneous spectral analysis of both heart rate and arterial pressure variabilities providing the possibility of calculating crossspectra and their coherence, we reached the conclusion that only two spectral components were soundly analysable in a time span of a few hundred cycles-i.e., the time series usually selected to afford an adequate number of events, adequate stationarity and some appraisal of dynamic changes [3]. Hence, apart from a very low frequency (VLF) component [41, short-term variability appeared to consist mainly of an oscillation at low frequency (LF), usually around 0.1 Hz largely related to vasomotor activity, and of a high frequency (HF) oscillation, related to respiratory activity and under control conditions often around 0.25 Hz. Since our initial studies [2], we observed that the power of the LF component was percentually increased during manoeuvres exciting sympathetic activity while HF was

The time series of successive heart periods present important variations around its mean value, determining the phenomenon of heart rate variability (HRV), assessed with both time and frequency domain approaches. A low standard deviation of the heart period (a time domain index of HRV) is a powerful prognostic indicator of sudden coronary death in patients recovering from acute myocardial infarction. Spectral analysis of HRV usually demonstrates two major components: indicated as LF (low frequency, approximately 0.1 Hz) and HF (high frequency, approximately 0.25 Hz). They are defined by center frequency and associated power, which is expressed in msec2 or normalized units. When assessed in normalized units, LF and HF provide quantitative indicators of neural control of the sinoatrial node. Numerous experimental and clinical studies have consistently indicated that the LF component is a marker of sympathetic modulation and HF a marker of vagal modulation; the LF/HF ratio is a synthetic index of sympathovagal balance. In the analysis of 24-hour Holter recordings of normal subjects, a circadian rhythmicity of spectral markers of sympathetic and vagal modulation is clearly present, with a sympathetic predominance during the day and a vagal predominance during the night. In patients recovering from an acute myocardial infarction, spectral analysis of HRV revealed an increased sympathetic and decreased vagal activity during early convalescence, and a return to their normal balance by 6 to 12 months. A clear increase of LF was also evident in patients studied within a few hours of the onset of symptoms related to an acute myocardial infarction, independent of its location. Similarly, LF increased during transient myocardial ischemia. An increase in markers of sympathetic activity has also been observed prior to episodes of malignant arrhythmias. Spectral analysis of HRV could help in the understanding of the role of abnormal neural mechanisms in sudden coronary death, thus contributing to its prevention.

Study objective — The aim was to determine the effects of the stable prostacyclin analogue iloprost (ZK 36374) on systemic haemodynamics and on cardiovascular neural control. Design — The buffering effect was examined of intravenous and intracoronary iloprost infusion on the excitatory sympathetic reflexes elicited from the heart by (1) intracoronary injections of bradykinin and (2) transient coronary artery occlusion. Subjects — 22 conscious mongrel dogs of either sex, weight 20-25 kg, were used. Measurements and main results — ECG, systemic arterial pressure, left atrial pressure, and left ventricular pressure and contractility (dP/dt) were continuously monitored for the duration of the experiments. Iloprost infusion reduced left ventricular pressure, mean arterial pressure, and dP/dt without causing significant changes in heart rate. Transient non-hypertensive coronary artery occlusion increased heart rate and depressed contractility. During intravenous iloprost infusion, coronary artery occlusion no longer elicited an increase in heart rate, while left ventricular dP/dt was more drastically reduced. This pattern of response was not substantially modified by β adrenergic blockade, whereas the blockade of muscarinic receptors with atropine was accompanied by hypotension and a greater reduction of dP/dt. The observation of a reduced pressor response to the intracoronary injections of bradykinin during iloprost administration further indicated a restraining effect of iloprost on the sympathetic reflexes elicited from the heart. Conclusions — The data suggest the hypothesis that the protective effects on the ischaemic myocardium observed with iloprost infusions may arise not only from its vasodilator and antiplatelet properties, but also from its capacity to blunt excitatory sympathetic reflexes.

Over the last few decades, thanks to the rapid development of computer applications, several laboratories provided evidence suggesting that spectral analysis of time series of RR interval and arterial pressure variabilities could be used as a tool capable of providing information on autonomic dysfunction of clinical and prognostic relevance (Malliani et al. 1991)). Initially, the investigative focus was especially on RR variability, as a means to estimate the sympathovagal balance regulating systolic arterial (SA) node beat-by-beat variability. However, still now there are discrepant positions regarding techniques (fast Fourier transfer (FFT) vs. autoregression (AR)) and mathematical handling of data (e.g. absolute vs. normalized units). Concerning this latter, we reported that focusing on the information provided by normalized units and using non-parametric statistics, it was possible to recognize, individual by individual, well-defined physiological conditions related to the different autonomic profiles associated with posture (Malliani et al. 1997)). We also stated that low-frequency (LF) oscillation evaluated from systolic arterial pressure (SAP) variability in various physiopathological conditions appears to be a convenient marker of the sympathetic modulation of vasomotor activity. This statement was corroborated by studies in which low-frequency (LF) variability of SAP was contrasted with a simultaneous measure of sympathetic efferent activity to muscles (MSNA) (Pagani et al. 1997; Furlan et al. 2000)) showing that, across small perturbations, oscillation characteristics of MSNA (in particular after normalization) were closely mirrored by oscillations of SAP. Overall our results indicate a compelling relationship between changes in autonomic drive and cardiovascular oscillations. Interpretation of MSNA is, however, not immediate. The multiunit signal depends heavily on the specific electrode, the (chance) tip position within the nerve bundle, the destination of (efferent) sympathetic nerve fibres, progressive recruitment of units during activation, possible damage and electronic settings (amplification, filtering and modality of integration). In addition, measurements require standards to be used across different conditions, subjects and laboratories, which are still not available for MSNA. It may thus be surmised that with MSNA analysis the experimental variance is still very high. Single-unit recordings might solve some of these problems, as classically done in animals (Pagani et al. 1974)) and recently tested in humans. Lower experimental error with multiunit recordings might also be obtained using high-frequency acquisition of the raw MSNA signal without filtering. The key issue with MSNA, however, is in regard to the code of interpretation (Pagani & Malliani, 2000)) in order to attach meaning to measures: average sympathetic nerve activity and its oscillatory components, although correlated to some extent, are likely to provide different, yet complementary, types of information, related to different modalities considering not only the simple spike activity per unit time (intensity code), but also more complex codes, based on pattern, correlation, rhythm, oscillation and synchronization, which are rarely considered. What can be taken for certain is the non-linearity of the system, inclusive of the quantal release of synaptic transmitter (a local event) and the influence of the humoral–endothelial milieu in the generation of arterial oscillations (a global phenomenon). Ryan et al. (2011), reporting in a recent issue of The Journal of Physiology, should accordingly be praised for their attempt to specifically map the relationship between MSNA and LF oscillations of arterial pressure, considering data not only as a group but rather individually. These authors provide further evidence that across a wide range of sympathetic drive, as produced by progressively intense lower body negative pressure, there is overall a significant link between average MSNA and LF component of arterial pressure, and a very strong (r2= 0.97) relationship between LF oscillations of blood pressure and similar LF oscillations of MSNA. Regarding individual relationships, using parametric statistics, however, these authors, observe that only in a portion of the population is this relationship highly significant. On this basis, the authors conclude that data do not support the use of low-frequency oscillations in arterial pressure as a non-invasive surrogate of MSNA. We believe that these data are of importance as they confirm the stronger role of oscillatory rather than amplitude code in autonomic nerve activity. We also would like to conceive that the data of Ryan et al., if anything, corroborate the use of low-frequency oscillations of systolic arterial pressure SAPLF in providing information on autonomic vascular oscillatory modulation. We might argue that the suboptimal coherence between LF oscillations of SAP and MSNA in the data of Ryan et al. might depend on different techniques (FFT vs. AR) and on the strong non-linear nature of the MSNA signal, which might not allow a consistent recognition of individual (linear) correlations, although from their Fig. 4C it appears evident that in all subjects, both SAPLF and low-frequency oscillations of muscle sympathetic nerve activity (MSNALF) change in the same direction. Individual non-linearities might not preclude, however, a clear detection of global correlation. Strictly speaking, and considering the above limitations, it may even be difficult to clearly characterize the pathophysiology of autonomic regulation from MSNA (Fatouleh & Macefield, 2011)). We would like to conclude that SAPLF is not a measure of MSNA, but more simply a broad index of the vascular sympathetic modulation. As such it appears as one of the multiple non-invasive, non-intrusive, autonomic indices that might be useful in the clinical management of conditions characterized by a disturbed autonomic regulation, such as hypertension (Lucini et al. 2002)) or diabetes (Lucini et al. 2009)). We hope that in throwing away the water we will avoid throwing away the baby too.

This study was designed to assess, using the echocardiographic acoustic quantification technique, the influence of respiration on left ventricular (LV) function and its modifications connected with the ageing process, quantifying in a non-invasive way the respiratory contribution to the LV volume variability. An automated algorithm is applied to extract the beat-to-beat measurements of LV function parameters from the LV volume signal, obtained from recordings lasting a few minutes. Mean values, amount of variability and spectral content were studied in a population of 17 normal young (mean age 25 +/- 1 years) and 12 normal old (mean age 64 +/- 2 years) subjects. Mean values of the beat-to-beat measurements of LV function parameters were able to point out alterations connected with the ageing process in peak filling rate, peak atrial filling rate and peak ejection rate. Spectral analysis, applied to the extracted variability series, displayed a predominance of the high-frequency (HF) component corresponding to respiration in all LV function parameters; moreover, age related changes of HF variability were observed in peak ejection rate. The HF power spectrum component of beat to beat series extracted from the LV signal can provide a non-invasive assessment of the fluctuations in ventricular parameters associated with respiration.

The changes in left ventricular (LV) dynamics induced by brief periods of ischemia (100 seconds) and subsequent reperfusion were analyzed in conscious dogs. Global LV ischemia, induced by partially occluding the left main coronary artery, reduced LV flow homogeneously and impaired LV function as reflected by decreases in LV stroke "work" (89 +/- 4% M +/- SE), systolic shortening (72 +/- 4%), velocity of shortening (56 +/- 6%), LV systolic pressure (34 +/- 5%), and dP/dt (59 +/- 6%). Regional LV ischemia, induced by occluding either the left circumflex or anterior descending coronary artery completely, reduced flow to the ischemic segment (82 +/- 3%) while decreasing segment work (96 +/- 5%), shortening (82 +/- 3%), and velocity of shortening (70 +/- 5%), with minimal depression of overall LV function. In both groups the extent of shortening was reduced more rapidly and greater (P less than 0.01) than shortening velocity. Moreover, with localized ischemia, segment work was reduced more (P less than 0.01) than shortening. With reperfusion, a transient overshoot in function above preischemic control levels was observed in both groups (global work increased by 60 +/- 12% and regional work by 28 +/- 4% above control). This overshoot was not dependent on adrenergic mechanisms, but was prevented by inhibiting reactive hyperemia. Thus myocardial ischemia induces a dissociation between extent and rate of myocardial shortening. A further dissociation between shortening and work is apparent with regional ischemia. After reperfusion there is a transient overshoot in function which appears to be dependent upon the associated reactive hyperemia.

A system providing high quality direct arterial blood pressure recordings and electrocardiograms in ambulatory patients was devised using a modified commercially available Holter type magnetic tape recorder together with a microminiature Millar (3F) tip transducer. This system did not require a perfusion line and solved the major drawbacks of other available systems. Pressure and electrocardiographic data were fed directly from the playback unit into a minicomputer for automatic beat to beat waveform analysis. Thus the blood pressure and RR interval variability signals could be simultaneously analysed with autoregressive modelling techniques to provide a quantitative estimate of sympathovagal balance in ambulant patients. The system was reliable, simple, and safe to use.

The cardiac systolic and diastolic effects of the two major calcium blockers, verapamil and nifedipine, were studied and compared with those produced by dilazep, a relatively new vasodilator with calcium blocking properties, in conscious instrumented dogs to avoid the complications of anaesthesia and recent surgery. Mean arterial pressure was reduced by nifedipine and dilazep but not by verapamil, whereas peak left ventricular pressure was reduced only by dilazep and verapamil. Consistent tachycardia occurred, the rate being highest with nifedipine and lowest with dilazep. Left ventricular dP/dt was unaffected by dilazep, reduced by verapamil, and increased by nifedipine; this increase was no longer observed after beta adrenergic blockade. Ventricular relaxation was assessed by calculating the time relaxation constant, tau. Verapamil increased tau significantly only after beta adrenergic blockade, whereas nifedipine and dilazep reduced it both before and after beta adrenergic blockade. These data suggest that reflex beta adrenergic mechanisms may modulate the effects of calcium blockade on both systolic and diastolic performance.

This paper describes the development of several important modifications that were incorporated into the ultrasonic, transit-time dimension system in order to obtain multiple simultaneous, instantaneous, and continuous measurements of the external dimensions of the aorta and its major branches in conscious, unrestrained animals. At operation a pair of small piezoelectric crystals was sutured to arterial adventitia, and a miniature pressure gauge was implanted in the vessel at the same cross-sectional plane. After recovery from surgery, wall motion was not altered appreciably and scarring was minimal. This technique allows long-term monitoring of aortic pressure-dimension relations and is applicable for small (fetal and neonatal) as well as large (adult dogs and sheep) animals. When vessel wall thickness is measured, stress-radius analysis can be performed so as to compute vascular elastic stiffness as a function of stress. Moreover, the suitability for radiotelemetry of the pressure and dimension signals measured with this technique enables the study of these parameters in unrestrained animals, e.g., during spontaneous severe exercise.

The role of pressor sympathetic reflexes in circulatory control was investigated in conscious dogs. Animals were previously instrumented with a 6- to 8-cm rigid core cannula covered by an inflatable rubber cylinder in the thoracic aorta, a pressure catheter implanted in the aorta above the cannula, and a second catheter inserted into the aorta below the cannula through a femoral artery. Two piezoelectric crystals were positioned at opposing adventitial sites to measure aortic distension with ultrasound techniques. After recovery from surgery, the diameter of the aortic segment surrounding the cannula was increased by 9.6 +/- 0.4% from 16 +/- 1 mm by inflating the rubber cylinder, without obstructing blood flow. Mean aortic pressure rose 31 +/- 3% from 100 +/- 3 mm Hg and heart rate 20 +/- 3% from 91 +/- 3 beats/min (P less than 0.01). The pressor response was abolished by alpha-adrenergic blockade (phentolamine 1 mg/kg, iv). The heart rate response was reduced either by beta-blockade (propranolol 1 mg/kg, iv) or muscarinic blockade (atropine 0.2 mg/kg, iv) and abolished by their combination. During aortic stretch, the sensitivity of the baroreflex was reduced 57 +/- 7% from 18 +/- 2 msec/mm Hg (P less than 0.01). The pressor response was increased by 49 +/- 8% after bilateral carotid sinus nerve section and vagotomy. These excitatory reflex responses were obtained in absence of any pain reaction. Thus, in the conscious dog, aortic distension within physiological ranges induces a potent pressor sympathetic reflex with positive feedback characteristics. Such a pressor reflex not only occurs in the presence of functioning baroreflexes, but is also capable of reducing their sensitivity.