Montano, Nicola

The results underscore a multifaceted interaction among cardiopulmonary hemodynamics, right heart pressures, ventilatory response, and autonomic regulation. In particular, altered RV-PA coupling correlated with heightened sympathetic drive, indicating that cardiopulmonary efficiency and hemodynamics may influence central autonomic outputs. This suggests that mechanical stress or overload in the right heart could modulate sympathovagal balance, thereby contributing to altered autonomic responses during exercise in patients with cardiopulmonary disorders.

The relative contributions of a central neural oscillator and of the delay in α-adrenergic transmission within the baroreflex loop in the predominance of low-frequency (LF) cardiovascular variability during sympathetic activation in humans are unclear. We measured R-R interval (RR), muscle sympathetic nerve activity (MSNA), blood pressure (BP), and their variability in 10 normal subjects during sympathetic activation achieved by BP lowering with sodium nitroprusside (SNP) and α-adrenergic blockade using phentolamine. SNP and phentolamine induced comparable reductions in BP ( P > 0.25). Despite tachycardia and sympathetic activation with both SNP and phentolamine, LF variability in RR, MSNA, and BP increased during SNP and decreased during phentolamine (SNP: RR +20 ± 6%, MSNA +3 ± 5%, systolic BP +9 ± 6%, diastolic BP +7 ± 5%; phentolamine: RR −2 ± 7%, MSNA −34 ± 6%, systolic BP −16 ± 8%, diastolic BP −13 ± 4%, P< 0.05 except systolic BP, where P = 0.09). Thus LF variability is reduced when sympathetic activation is induced by α-adrenergic blockade. This suggests that α-adrenergic transmission within the baroreflex loop may contribute importantly to the predominance of LF cardiovascular variability associated with sympathetic excitation in humans.

Spectral analysis of skin blood flow has demonstrated low-frequency (LF, 0.03–0.15 Hz) and high-frequency (HF, 0.15–0.40 Hz) oscillations, similar to oscillations in R-R interval, systolic pressure, and muscle sympathetic nerve activity (MSNA). It is not known whether the oscillatory profile of skin blood flow is secondary to oscillations in arterial pressure or to oscillations in skin sympathetic nerve activity (SSNA). MSNA and SSNA differ markedly with regard to control mechanisms and morphology. MSNA contains vasoconstrictor fibers directed to muscle vasculature, closely regulated by baroreceptors. SSNA contains both vasomotor and sudomotor fibers, differentially responding to arousals and thermal stimuli. Nevertheless, MSNA and SSNA share certain common characteristics. We tested the hypothesis that LF and HF oscillatory components are evident in SSNA, similar to the oscillatory components present in MSNA. We studied 18 healthy normal subjects and obtained sequential measurements of MSNA and SSNA from the peroneal nerve during supine rest. Measurements were also obtained of the electrocardiogram, beat-by-beat blood pressure (Finapres), and respiration. Spectral analysis showed LF and HF oscillations in MSNA, coherent with similar oscillations in both R-R interval and systolic pressure. The HF oscillation of MSNA was coherent with respiration. Similarly, LF and HF spectral components were evident in SSNA variability, coherent with corresponding variability components of R-R interval and systolic pressure. HF oscillations of SSNA were coherent with respiration. Thus our data suggest that these oscillations may be fundamental characteristics shared by MSNA and SSNA, possibly reflecting common central mechanisms regulating sympathetic outflows subserving different regions and functions.

Chemoreflex stimulation elicits both hyperventilation and sympathetic activation, each of which may have different influences on oscillatory characteristics of cardiovascular variability. We examined the influence of hyperventilation on the interactions between changes in R-R interval (RR) and muscle sympathetic nerve activity (MSNA) and changes in neurocirculatory variability, in 14 healthy subjects. We performed spectral analysis of RR and MSNA variability during each of the following interventions: 1) controlled breathing, 2) maximal end-expiratory apnea, 3) isocapnic voluntary hyperventilation, and 4) hypercapnia-induced hyperventilation. MSNA increased from 100% during controlled breathing to 170 ± 25% during apnea ( P = 0.02). RR was unchanged, but normalized low-frequency (LF) variability of both RR and MSNA increased markedly ( P < 0.001). During isocapnic hyperventilation, minute ventilation increased to 20.2 ± 1.4 l/min ( P < 0.0001). During hypercapnic hyperventilation, minute ventilation also increased (to 19.7 ± 1.7 l/min) as did end-tidal CO2 (both P < 0.0001). MSNA remained unchanged during isocapnic hyperventilation (104 ± 7%) but increased to 241 ± 49% during hypercapnic hyperventilation ( P < 0.01). RR decreased during both isocapnic and hypercapnic hyperventilation ( P < 0.05). However, normalized LF variability of RR and of MSNA decreased ( P < 0.05) during both isocapnic and hypercapnic hyperventilation, despite the tachycardia and heightened sympathetic nerve traffic. In conclusion, marked respiratory oscillations in autonomic drive induced by hyperventilation may induce dissociation between RR, MSNA, and neurocirculatory variability, perhaps by suppressing central genesis and/or inhibiting transmission of LF cardiovascular rhythms.

Interactions between mechanisms governing ventilation and blood pressure (BP) are not well understood. We studied in 11 resting normal subjects the effects of sustained isocapnic hyperventilation on arterial baroreceptor sensitivity, determined as the α index between oscillations in systolic BP (SBP) generated by respiration and oscillations present in R-R intervals (RR) and in peripheral sympathetic nerve traffic [muscle sympathetic nerve activity (MSNA)]. Tidal volume increased from 478 ± 24 to 1,499 ± 84 ml and raised SBP from 118 ± 2 to 125 ± 3 mmHg, whereas RR decreased from 947 ± 18 to 855 ± 11 ms (all P < 0.0001); MSNA did not change. Hyperventilation reduced arterial baroreflex sensitivity to oscillations in SBP at both cardiac (from 13 ± 1 to 9 ± 1 ms/mmHg, P < 0.001) and MSNA levels (by −37 ± 5%, P < 0.0001). Thus increased BP during hyperventilation does not elicit any reduction in either heart rate or MSNA. Baroreflex modulation of RR and MSNA in response to hyperventilation-induced BP oscillations is attenuated. Blunted baroreflex gain during hyperventilation may be a mechanism that facilitates simultaneous increases in BP, heart rate, and sympathetic activity during dynamic exercise and chemoreceptor activation.

Background Reappearance of low-frequency (LF) (±0.10 Hz) oscillations in RR interval (RR) after cardiac transplantation is indicative of sympathetic efferent reinnervation. We hypothesized that restored LF oscillations in RR in heart transplant recipients (HTRs) are linked to oscillations in muscle sympathetic nerve traffic (MSNA). Methods and Results RR, RR variability, and MSNA were recorded 5±2 months (n=7, short-term HTRs) and 138±8 months (n=7, long-term HTRs) after heart transplantation and compared with matched hypertensive patients (n=7). A coherence function determined the coupling between LF oscillations in MSNA and RR. RR variance did not differ between short-term and long-term HTRs. However, LF variability was only 1±0.5 ms 2 in the short-term HTRs but was 15±8 ms 2 in the long-term HTRs ( P <0.05). Normalized LF variability was also higher in the long-term HTRs (40±14 normalized unites) versus the short-term HTRs (6±3 normalized united, P <0.05) but did not differ from the LF variability of the hypertensive patients. Long-term HTRs were taking less cyclosporine ( P <0.01) but had higher MSNA than the short-term HTRs (62±7 versus 31±7 burst/min, respectively, P <0.05). Coherence between LF oscillations in MSNA and RR was similar in the long-term HTRs (0.59±0.11) and the hypertensive patients (0.60±0.07) and was 3-fold greater than in the short-term HTRs (0.20±0.06, P <0.05). Conclusions Cardiac reinnervation after long-term heart transplantation is characterized by a restoration of the coherence between LF oscillations in RR and MSNA. Higher MSNA in long-term than in short-term HTRs suggests that time elapsed after cardiac transplantation may be a major determinant of sympathetic excitation in heart transplant recipients.

Respiration contributes importantly to short-term modulation of sympathetic nerve activity. However, the relationship between spontaneous breathing rate, chemoreflex function, and direct measures of sympathetic traffic in healthy humans has not been studied previously. We tested the hypothesis that muscle sympathetic nerve activity and chemoreflex sensitivity are linked independently to respiratory rate in normal subjects. We studied 69 normal male subjects aged 29.6±8.1 years. Subjects were subdivided according to the tertiles of respiratory rate distributions. Mean respiration rate was 10.6 breaths/min in the first tertile, 14.8 breaths/min in the second tertile, and 18.0 breaths/min in the third tertile. Subjects from the third tertile (faster respiratory rate) had greater sympathetic activity than subjects from the first tertile (slower respiratory rate; 29±3 versus 17±2 bursts/min; P <0.001). Stepwise multiple linear regression analysis revealed that only respiratory rate was linked independently to sympathetic activity ( r =0.42; P <0.001). In comparison to subjects with slow respiratory rate, subjects with fast respiratory rate had greater increases in minute ventilation during both hypercapnia (7.3±0.8 versus 3.2±1.0 L/min; P =0.005) and hypoxia (5.7±0.8 versus 2.4±0.7 L/min; P =0.007). Muscle sympathetic nerve activity and chemoreflex sensitivity are linked to spontaneous respiratory rate in normal humans. Faster respiratory rate is associated with higher levels of sympathetic traffic and potentiated responses to hypoxia and hypercapnia. Spontaneous breathing frequency, central sympathetic outflow, and chemoreflex sensitivity exhibit significant and hitherto unrecognized interactions in the modulation of neural circulatory control.

Background— Sympathetic and parasympathetic systems are considered the principal rapidly reacting systems that control heart rate. Methods and Results— We propose a symbolic analysis series to quantify the prevalence of sympathetic or parasympathetic cardiac modulation. This analysis decomposes the heart rate variability series in patterns lasting 3 beats and classifies them into 3 categories: nonvariable, variable, and very variable patterns referred to as 0V, 1V, and 2V patterns. First, we applied this method to experimental and pharmacological conditions characterized by sympathetic activation (tilt test, handgrip, nitroprusside, and high-dose atropine administration) or parasympathetic activation (phenylephrine and low-dose atropine administration) in 60 healthy subjects. An increase in sympathetic modulation and a vagal withdrawal elicited a significant increase in 0V patterns and a decrease in 2V patterns, whereas parasympathetic dominance induced the opposite, reflecting a reciprocal sympathovagal balance. The second part of the study considered a series of 300 beats before the onset of major arrhythmic events in patients with an implantable cardioverter-defibrillator. Symbolic analysis detected an increase in the percentage of 0V patterns before the onset of major arrhythmias compared with baseline (41.6±3.9% and 24.4±2.9%, respectively; P <0.01), indicating a sympathetic prevalence. On the other hand, the 2V patterns did not decrease before major arrhythmias, suggesting the presence of nonreciprocal autonomic modulations. Conclusions— Symbolic analysis of 3 beat sequences takes into account the different time course of sympathetic and parasympathetic cardiac modulations and seems appropriate for elucidating the neural pathophysiological mechanisms occurring during the short periods that precede acute cardiac events.