Antonio Cevese

Baroreflex and oscillation of heart period at 0.1 Hz studied by α‐blockade and cross‐spectral analysis in healthy humans

1 Parameters derived from frequency‐domain analysis of heart period and blood pressure variability are gaining increasing importance in clinical practice. However, the underlying physiological mechanisms in human subjects are not fully understood. Here we address the question as to whether the low frequency variability (∼0.1 Hz) of the heart period may depend on a baroreflex‐mediated response to blood pressure oscillations, induced by the α‐sympathetic drive on the peripheral resistance. 2 Heart period (ECG), finger arterial pressure (Finapres) and respiratory airflow were recorded in eight healthy volunteers in the supine position with metronome respiration at 0.25 Hz. We inhibited the vascular response to the sympathetic vasomotor activity with a peripheral α‐blocker (urapidil) and maintained mean blood pressure at control levels with angiotensin II. 3 We performed spectral and cross‐spectral analysis of heart period (RR) and systolic pressure to quantify the power of low‐ and high‐frequency oscillations, phase shift, coherence and transfer function gain. 4 In control conditions, spectral analysis yielded typical results. In the low‐frequency range, cross‐spectral analysis showed high coherence (> 0.5) and a negative phase shift (‐65.1 ± 18 deg) between RR and systolic pressure, which indicates a 1‐2 s lag in heart period changes in relation to pressure. In the high‐frequency region, the phase shift was close to zero, indicating simultaneous fluctuations of RR and systolic pressure. During urapidil + angiotensin II infusion the low‐frequency oscillations of both blood pressure and heart period were abolished in five cases. In the remaining three cases they were substantially reduced and lost their typical cross‐spectral characteristics. 5 We conclude that in supine rest conditions, the oscillation of RR at low frequency is almost entirely accounted for by a baroreflex mechanism, since it is not produced in the absence of a 0.1 Hz pressure oscillation. 6 The results provide physiological support for the use of non‐invasive estimates of the closed‐loop baroreflex gain from cross‐spectral analysis of blood pressure and heart period variability in the 0.1 Hz range.

Post-exercise recovery of autonomic cardiovascular control: A study by spectrum and cross-spectrum analysis in humans

Abstract The recovery of the baseline autonomic control of cardiovascular activity after exercise has not been extensively studied. In 12 healthy subjects, we assessed the time-course of recovery by autoregressive spectrum and cross-spectrum analysis of heart period and systolic blood pressure during the 3 h after the end of 20 min of steady-state exercise at 50% (light workload, LW) and 80% (moderate workload, MW) of the individuals anaerobic threshold. The electrocardiogram and non-invasive blood pressure were simultaneously recorded during 10 min periods in the sitting position, at rest before exercise, and at 15, 60 and 180 min of recovery after exercise. At 15 min we observed a persistent tachycardia and relative hypotension; after MW, at 60 min heart rate was still slightly higher. Spectrum and cross-spectrum analysis showed, at 15 min, an increase in the low frequency component of systolic blood pressure, a reduction in the high frequency component of heart rate (larger in MW), and a decrease in baroreceptor sensitivity. After 60 and 180 min none of these parameters was significantly different from those at rest, although, in MW, some subjects still displayed signs of sympathetic activation after 1 h. We concluded that, after 15 min of recovery, the cardiovascular reflexes were blunted, that sympathetic nerve activity was still enhanced, and that the tone in the vagus had not fully recovered. Only the persistent vagal restraint seemed to be exercise intensity-dependent. For complete restoration of autonomic control after LW 1 h of rest was sufficient, and just enough after MW.

Metabolic Effects of Aerobic Training and Resistance Training in Type 2 Diabetic Subjects A randomized controlled trial (the RAED2 study)

OBJECTIVE To assess differences between the effects of aerobic and resistance training on HbA1c (primary outcome) and several metabolic risk factors in subjects with type 2 diabetes, and to identify predictors of exercise-induced metabolic improvement. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (n = 40) were randomly assigned to aerobic training or resistance training. Before and after 4 months of intervention, metabolic phenotypes (including HbA1c, glucose clamp–measured insulin sensitivity, and oral glucose tolerance test–assessed β-cell function), body composition by dual-energy X-ray absorptiometry, visceral (VAT) and subcutaneous (SAT) adipose tissue by magnetic resonance imaging, cardiorespiratory fitness, and muscular strength were measured. RESULTS After training, increase in peak oxygen consumption (VO2peak) was greater in the aerobic group (time-by-group interaction P = 0.045), whereas increase in strength was greater in the resistance group (time-by-group interaction P < 0.0001). HbA1c was similarly reduced in both groups (−0.40% [95% CI −0.61 to −0.18] vs. −0.35% [−0.59 to −0.10], respectively). Total and truncal fat, VAT, and SAT were also similarly reduced in both groups, whereas insulin sensitivity and lean limb mass were similarly increased. β-Cell function showed no significant changes. In multivariate analyses, improvement in HbA1c after training was independently predicted by baseline HbA1c and by changes in VO2peak and truncal fat. CONCLUSIONS Resistance training, similarly to aerobic training, improves metabolic features and insulin sensitivity and reduces abdominal fat in type 2 diabetic patients. Changes after training in VO2peak and truncal fat may be primary determinants of exercise-induced metabolic improvement.

Does low-frequency variability of heart period reflect a specific parasympathetic mechanism?

Low frequency (LF, approximately 0.1 Hz) spontaneous oscillations of heart period in humans have been attributed to and correlated with the sympathetic efferent control of the heart. However, this interpretation is controversial, because sympathetic blockade does not suppress these oscillations, while parasympathetic blockade strongly affects them. The sympathetic origin of LF of arterial pressure, on the contrary, has been convincingly demonstrated. Four 10 min cycle-by-cycle time series of R-R interval (RR), and systolic (SAP) and diastolic (DAP) arterial pressure were produced by automatic analysis of data obtained with non-invasive methods in 10 healthy humans during supine rest and while standing, both before and after beta 1-selective blockade (atenolol). Time series were analysed by autoregressive transfer function analysis. beta-blockade failed to induce systematic changes on the power of the LF peak of RR, in any condition. The coherence between RR and SAP in the same region remained high (0.77 +/- 0.03) and a constantly negative phase (approximately 50-60 degrees, corresponding to a delay of 1-2 heart beats of RR on SAP) was always seen. beta-blockade decreased the power of the LF peak of SAP, increased the transfer function gain between SAP and RR at LF, and the HF power of RR. We conclude that LF oscillations of RR are not directly generated by the sympathetic drive to the heart but reflect mainly the parasympathetic activity. The results suggest that the LF oscillations of the vagal outflow, and of RR, are generated by the baroreceptor reflex, driven by sympathetically-induced blood pressure LF waves.

Evidence of parasympathetic impairment in some patients with cardiac syndrome X.

OBJECTIVES Cardiac syndrome X (SX) is a clinical condition characterised by angina, positive exercise stress test and negative coronary angiography; it has often been attributed to sympathetic hyperactivity. Here we tested the hypothesis that a parasympathetic, rather than a sympathetic, dysfunction could be the cause of the autonomic imbalance observed in SX. METHODS In 20 subjects with diagnosed SX and in 12 age-matched controls, we studied autonomic function by performing spectral analysis of RR interval and finger arterial pressure (SAP), in supine position and during head-up tilting. We also carried out a set of tests of parasympathetic function. RESULTS The group of SX patients did not differ significantly from control subjects in any of the variables tested. In a subgroup of 13 SX, however, tilting increased the low-frequency power of SAP, but did not induce the expected increase in low-frequency and decrease in high-frequency power of RR. These patients, in supine position, had significantly lower sinus arrhythmia and a higher ratio of low to high frequency of RR, in comparison with control subjects. We interpreted these differences as signs of reduced parasympathetic, but essentially normal sympathetic, activity. The parasympathetic tests confirmed vagal impairment in the same SX subjects. On the other hand, all the tests indicated normal parasympathetic functions in the control subjects and in those SX patients who displayed the expected spectral changes in tilting. CONCLUSIONS In about two thirds of the patients with SX, the pathophysiological mechanism causing the symptoms could be related to the reduced parasympathetic tone, rather than to an augmented sympathetic activity.

Moderate aerobic training improves autonomic cardiovascular control in older women.

Abstract. The decline in the cardiovascular autonomic regulation in advanced age is considered a risk factor for several cardiovascular diseases. We tested, on eleven healthy untreated women aged 60–70 years, whether a six-month period of group-based training exerts positive effects on this age-associated decline.Before and after training, ECG and arterial pressure (Finapres) were recorded in supine position. We calculated mean values ± SEM of R-R period (RR), systolic (SAP) and diastolic (DAP) arterial pressure, as well as, by autoregressive spectral analysis methods, low (∼0.1 Hz) and high (respiratory) frequency oscillations of RR (LFRR, HFRR) and SAP (LFSAP, HFSAP), and the baroreflex sensitivity (BRS). Training induced statistically significant changes (p < 0.05 by paired t-test): increase in RR (mean ± SEM) from 894 ± 41 to 947 ± 31 ms and in heart rate variability (HRV) by 25 %, decrease in DAP from 75.8 ± 3.0 to 70.8 ± 2.2 mmHg, no change in SAP. LFRR and LFSAP increased by more than 100 %, while BRS by 32 %. We suggest that the increase in BRS might be responsible for the observed bradycardia and higher LFRR. An improved modulation, rather than an increase, in tonic sympathetic activity, is also suggested. A specific program of moderate aerobic training is adequate to increase the BRS and the HRV in older women.

Arterial baroreceptors are not essential for low frequency oscillation of arterial pressure

Cardiovascular parameters exhibit spontaneous oscillations at the respiratory frequency, and in the low frequency range (LF < 0.20 Hz). Although LF is attributed to the sympathetic control, the mechanism responsible for the oscillation, whether instability of the baroreflex loop, or activity of a central nervous system pattern generator, is controversial. To answer this question, time series of arterial blood pressure, heart period and left external iliac blood flow from chloralose-anaesthetised dogs were examined by standard statistics as well as by autoregressive spectral and cross-spectral analysis. The circulation to the left hind-limb was isolated and connected to a constant-pressure perfusing system, to obtain mechanical uncoupling from the central circulation. Three steady-state conditions were studied. A device inserted into the common carotid arteries allowed the carotid sinus region to be in continuity with the animals arterial system (CONTROL) or perfused at constant pressure by an external source (CAROTID BUFFER); bilateral cervical vagotomy was also performed (VAGI CUT). Intra-individual (beat-to-beat) variability of each parameter was evaluated by standard deviation (SD) of time series in the three conditions. The average SD of heart period was reduced in CAROTID BUFFER and in VAGI CUT; the SDs of arterial pressure and iliac flow were not changed by these interventions. Autospectra of iliac flow time series in CONTROL showed a prominent peak at 0.05 +/- 0.04 Hz (mean +/- SD of all experiments), accounting for 90 +/- 11% of the total variance.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term hemodynamic effects of intravenous propionyl-L-carnitine in anesthetized dogs

SummaryThe effects of intravenous administration of propionyl-L-carnitine (PLC) were investigated in anesthetized dogs instrumented for the analysis of general hemodynamic and electrocardiographic data, peripheral blood flows, coronary blood flow and oxygen consumption, urine flow, and renal function. PLC was administered in bolus (20, 60, and 200 mg/kg) or by infusion (20 mg/kg/min * 15 min or 30 mg/kg/min * 10 min). In some cases also L-carnitine (LC) and L-carnitine + propionate (LC + P) were administered in doses equimolar to those of PLC. PLC elicited dose-dependent, short-lasting enhancements of cardiac output, both in open-and close-chest conditions. Arterial blood pressure, heart rate, and contractility varied slightly and unpredictably; the substance did not elicit electrocardiographic effects. These responses were not changed by alpha- or beta-adrenergic blockade, nor by the administration of a calcium antagonist, but they were abolished or reversed by the combination of such blocking interventions. Mesenteric and iliac blood flows were increased by both PLC and LC; LC + P increased these, and in addition increased renal blood flow. A strong diuresis obtained with PLC, LC, and LC + P was due to osmotic clearance following the administration of hyperosmotic solutions. PLC elicited coronary vasodilation with reduced oxygen extraction; this effect lasted longer than the general hemodynamic effects and was not seen with LC. All the cardiovascular actions of PLC can be attributed to its pharmacologic properties, rather than to its role as a metabolic intermediate.

Haemodynamic effects of distension of the descending colon in anaesthetized dogs.

1. This study was undertaken to determine whether distension of the descending colon in anaesthetized dogs reflexly affects the heart rate, arterial blood pressure or the left ventricular inotropic state. 2. Experiments were performed on twenty‐six dogs, which were anaesthetized with sodium pentobarbitone and artificially ventilated. A segment of the distal descending colon was isolated and was distended with warm Ringer solution at a steady intraluminal pressure. 3. In each animal, distension of the colon caused an increase in heart rate and aortic blood pressure. The response of an increase in heart rate was augmented by preventing changes in aortic blood pressure, and was graded in seven dogs by step increments in the distending pressure. In the same animals, distension of the colon always caused a small increase in left ventricular (dP/dt)max at constant heart rate and aortic blood pressure. 4. In four of the twenty‐six dogs, cutting the pelvic nerves did not abolish the observed responses to the distension. In seven of the twenty‐six dogs, which included the four animals with sectioned pelvic nerves, cutting the hypogastric nerves completely abolished all the observed responses. 5. In thirteen of the twenty‐six dogs, propranolol or bretylium tosylate completely abolished the reflex increases in heart rate and left ventricular (dP/dt)max, and phentolamine or bretylium tosylate abolished the reflex increase in aortic blood pressure. 6. These results showed that distension of the colon reflexly increased the heart rate, arterial blood pressure and left ventricular inotropic state. These reflex responses were mediated by sympathetic effects and their afferent limb involved the hypogastric nerves.

The effect of distension of the urinary bladder on coronary blood flow in anesthetized dogs

To determine whether distension of the urinary bladder reflexly affects coronary blood flow, experiments were performed in eleven dogs anaesthetized with sodium pentobarbitone. Both ureters were cannulated and the urinary bladder was distended with warm Ringer solution at a steady intravesical pressure. Arterial blood pressure was prevented from changing by a pressurized reservoir of warm Ringer solution connected to the femoral arteries. Coronary blood flow was measured with an electromagnetic flowmeter positioned around the origin of the left circumflex coronary artery. When the reflex increase in heart rate was prevented by atrial pacing in seven dogs, distension of the urinary bladder always caused a decrease in mean coronary blood flow. Similar results were obtained in all eleven dogs after administration of propranolol. The decrease in mean coronary blood flow was significantly reduced by atropine or bilateral cervical vagotomy, and was abolished by bretylium tosylate. The results showed that distension of the urinary bladder reflexly decreased mean coronary blood flow, a response involving efferent cardiac vagal and sympathetic pathways.