Alberto Radaelli

Cardiovascular autonomic modulation in essential hypertension. Effect of tilting.

To better understand the role played by the autonomic nervous system in essential hypertension, we used autoregressive power spectrum analysis to study the noncasual oscillations in RR interval, blood pressure, and skin blood flow in 40 subjects with mild to moderate hypertension and in 25 age-matched control subjects at low frequency (index of sympathetic activity to the heart and the peripheral circulation) and high frequency, respiratory related (index of vagal tone to the heart). RR interval, respiration, noninvasive systolic blood pressure, and skin arteriolar blood flow were simultaneously and continuously recorded with subjects in the supine position and immediately after tilting. The low-frequency component was not significantly different in the two groups either at the cardiac level (control versus hypertensive subjects: 39.1 +/- 4.3 versus 39.9 +/- 3.7 normalized units [NU]) or at the vascular level (1.52 +/- 0.17 versus 1.69 +/- 0.13 ln mm Hg2). After head-up tilting, the RR interval fluctuations were less in hypertensive subjects (low-frequency components from 39.9 +/- 3.7 to 48.4 +/- 4.1 NU, P < .05; high-frequency components from 53.9 +/- 3.7 to 44 +/- 4 NU, P < .05) than in control subjects (low-frequency components from 39.1 +/- 4.3 to 64.4 +/- 4.9 NU, P < .001; high-frequency components from 56.0 +/- 4.5 to 31.2 +/- 4.6 NU, P < .001); the low-frequency components in systolic blood pressure increased similarly in hypertensive subjects (to 2.43 +/- 0.17 ln mm Hg2, P < .0001) and in control subjects (to 2.44 +/- 0.21 ln mm Hg2, P < .01), but the low-frequency components in skin blood flow increased only in control subjects (from 5.34 +/- 0.45 to 6.55 +/- 0.53 mm Hg2, P < .01), not in hypertensive subjects (from 5.55 +/- 0.34 to 5.60 +/- 0.35 ln mm Hg2). In hypertensive subjects with left ventricular hypertrophy, the low-frequency components in systolic blood pressure did not increase after tilting (from 1.75 +/- 0.33 to 2.05 +/- 0.41 ln mm Hg2). Baroreflex sensitivity, as assessed by spectrum analysis, was significantly lower in hypertensive than in control subjects (5.17 +/- 0.49 versus 13.18 +/- 2.44 ms/mm Hg, P < .001. Power spectrum analysis did not reveal an increased sympathetic activity or reactivity either at the cardiac or at the vascular level. The decreased baroreceptor sensitivity in hypertensive subjects could explain the reduced change in sympathovagal balance in the tilt position at the cardiac level. In hypertensive subjects without left ventricular hypertrophy, cardiopulmonary reflex deactivation induced by tilting and/or amplification of sympathetic nervous tone by arteriolar structural change could have preserved the sympathetic activation at the vascular level.

Inflammatory Activation During Coronary Artery Surgery and Its Dose-Dependent Modulation by Statin/ACE-Inhibitor Combination

Background—On-pump coronary artery bypass graft (CABG) surgery triggers an inflammatory response (IR) which may impair revascularization. The study aimed at (1) characterizing the temporal profile of the IR by assaying appropriate markers in both systemic and coronary blood, and (2) determining whether (and which doses of) cardiovascular drugs known to have antiinflammatory properties, namely statins and ACE-inhibitors (ACEI), inhibit the response. Methods and Results—Patients scheduled for CABG (n=22) were randomized to statin/ACEI combination treatment at standard doses (STD, ramipril 2.5/simvastatin 20 mg, or atorvastatin 10 mg), or at high doses (HiDo, ramipril 10 mg, or enalapril 20 mg/simvastatin 80 mg, or atorvastatin 40 mg). Plasma levels of interleukin 6, tumor necrosis factor alpha, E-selectin, von Willebrand factor (vWF), and sVCAM-1 were serially assayed (ELISA) before, during, and after CABG. Blood was drawn from an artery, a systemic vein, and the coronary sinus. Myocardial perfusion scans were obtained before and 2 months after surgery in 19 out of 22 subjects. In the STD group both IL-6 and TNF displayed striking increases which were similar at all sites and peaked 10 to 60 minutes after aortic declamping. Such increases were drastically attenuated in the HiDo group. Instead, only modest increases in venous E-selectin, vWF, and sVCAM-1 were observed. Scintigraphic ischemia scores were entirely normalized after versus before CABG in the HiDo but not in the STD treatment group. Conclusions—On-pump CABG surgery is associated with an intense systemic inflammatory response, which can be almost completely prevented by early treatment with high (but not standard) doses of ACE-inhibitors and statins.

Nitric Oxide–Dependent Vasodilation in Young Spontaneously Hypertensive Rats

Conflicting evidence exists on the possible impairment of tonic nitric oxide (NO) mediated vasodilation as a causative factor in the genesis of human as well as experimental hypertension. We evaluated the tonic NO-dependent vasodilation from the pressor response to NO synthesis inhibition by NG-monomethyl-L-arginine (L-NMMA) in 9 conscious, chronically instrumented spontaneously hypertensive rats (SHR) at 12 weeks of age, ie, during the early established hypertensive stage. Nine age-matched Wistar-Kyoto rats (WKY) were used as controls. The pressor responses to L-NMMA (100 mg . kg-1 IV bolus plus 1.5 mg . kg-1 . min-1 infusion for 60 minutes) as well as to non NO-dependent pressor stimuli, namely, vasopressin (2, 4, and 8 ng . kg-1) and phenylephrine (0.5, 1, and 2 microg . kg-1) given as IV boluses, were assessed both under control conditions and during suppression of autonomic reflexes by hexamethonium (30 mg . kg-1 IV bolus+1.5 mg . kg-1 . min-1 infusion). Rather than being reduced, the pressor responses to L-NMMA were 39% and 71% larger in the control and areflexic conditions, respectively, than those observed in WKY (both P<0.01). A similar pattern was observed for the pressor responses to vasopressin (+37% and +68% in the control and areflexic conditions, respectively; both P<0.01) and phenylephrine, (+20% and +52%; both P<0.05). Additional groups of 6-week-old prehypertensive SHR (n=11) and age-matched WKY (n=11) were subjected to an identical protocol: in these animals, the pressor responses to L-NMMA were similar in each strain, as were the pressor responses to vasopressin and phenylephrine in both control and areflexic conditions. In conclusion, our observations indicate that during the developmental phase of hypertension in the SHR model, namely, during the prehypertensive as well as the early established hypertensive stage, NO-dependent vasodilation is preserved (if not enhanced) so that a putative impairment of this function provides no significant pathogenic contribution to the onset of hypertension in this experimental model.

Lack of autonomic contributions to tonic nitric oxide-mediated vasodilatation in unanesthetized free-moving rats.

Objective To clarify the controversial issue of whether autonomic influences modulate vascular nitric oxide-mediated vasodilatation or even directly contribute to production of nitric oxide (NO) via nitroxidergic fibers. Methods Chronic venous and arterial catheters were implanted in Wistar-Kyoto rats (n = 65) for continuous blood pressure measurement, drug administration and blood sampling. Tonic NO-dependent vasodilatation in the conscious free-moving animal was evaluated as the pressor response to inhibition of NO synthesis by intravenous L-monomethylarginine (a 100 mg/kg intravenous bolus plus 0.5 mg/kg per min infusion for 30 min). Experiments were performed under control conditions, chemical sympathectomy by 6-hydroxy-dopamine, ganglionic blockade by hexamethonium, and surgical denervation of sino-aortic baroreceptors. Results Baseline mean arterial pressure was 100 ± 4 mmHg (mean ± SEM) in control rats and 73 ± 3, 62 ± 5, and 105 ± 10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. The peak increase in mean arterial pressure after administration of L-monomethylarginine was 38 ± 3 mmHg in control rats and 51 ± 3, 50 ± 6, and 63 ± 10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. Epinephrine and norepinephrine levels in rats of separate groups of unanesthetized control, sympathectomized and ganglion-blocked animals were measured by high-performance liquid chromatography from an arterial blood sample, the results indicating drastic reductions in levels of both catecholamines in the ganglion-blocked (but not in the sympathectomized) rats compared with those in the control rats. Conclusions Tonic NO-dependent vasodilatation can normally be maintained in the unanesthetized unrestrained rat irrespective of autonomic or humoral adrenergic influences.

Preservation of the Baroreceptor Heart Rate Reflex by Chemical Sympathectomy in Experimental Heart Failure

Background—The mechanisms underlying impaired baroreflex sensitivity in congestive heart failure (CHF) are incompletely understood. The purpose of the present study was to test the hypothesis that this alteration depends on the marked degree of sympathetic overactivity known to characterize the CHF syndrome. Methods and Results—Eight-week-old rats were subjected to induction of postmyocardial infarction CHF obtained by coronary ligation (Lig), chronic chemical sympathectomy by 6-hydroxydopamine (Sx), both interventions (Sx-Lig), or neither intervention (Veh-Sham, sham surgery, and vehicle administration). Four weeks after infarction, in conscious state, baroreflex sensitivity was assessed from the bradycardic responses to graded phenylephrine-induced elevations in blood pressure (BP). Left ventricular (LV) diameter was assessed by echocardiography, and plasma catecholamines were assayed to estimate sympathetic activity. Lungs were eventually excised and weighed (LW). CHF was associated with the following: (1) no changes in BP and heart rate; (2) sympathetic overactivity (norepinephrine, 320.2±53.8 pg/mL for Veh-Lig versus 173.4±20.5 pg/mL for Veh-Sham, P <0.01), prevented by Sx (181.2±35.5 pg/mL for Sx-Lig versus 159.8±33.1 pg/mL for Sx-Sham, P =NS); (3) LV enlargement (10.3±0.7 mm for Veh-Lig versus 6.8±0.6 mm for Veh-Sham, P <0.01), irrespective of Sx (9.7±0.7 mm for Sx-Lig versus 6.6±0.5 mm for Sx-Sham, P <0.01); (4) pulmonary congestion (LW, 7.55±0.40 mg per gram of body weight for Veh-Lig versus 5.21±0.44 mg per gram of body weight for Veh-Sham, P <0.01), marginally attenuated by Sx (6.54±0.28 mg per gram of body weight for Sx-Lig versus 4.98±0.22 mg per gram of body weight for Sx-Sham, P <0.05); (5) reduction in baroreflex sensitivity (0.443±0.032 ms/mm Hg for Veh-Lig versus 0.860±0.420 ms/mm Hg for Veh-Sham, P <0.01), entirely prevented by Sx (1.217±0.058 ms/mm Hg for Sx-Lig versus 1.345±0.093 ms/mm Hg for Sx-Sham, P =NS). Conclusions—In early post-MI CHF, sympathectomy only partially attenuated LV dysfunction and entirely prevented baroreflex sensitivity impairment that arises from enhanced sympathetic activity.

Altered blood pressure variability in patients with congestive heart failure

OBJECTIVE Congestive heart failure (CHF) is characterized by sympathetic overactivity but reduced variability of heart interval and sympathetic nerve activity; little information exists, however, about the alterations in blood pressure variability in this syndrome, especially during excitatory manoeuvres such as tilting or exercise. DESIGN AND METHODS Nine patients with CHF (age 62+/-1 years, NYHA class II-III, ejection fraction 33+/-1%, peak VO2 14.1+/-3.2 ml/min per kg body weight [mean +/- SEM]) and eight healthy control subjects (age 58+/-1 years) with normal left ventricular function were studied. Blood pressure (Finapres), R-R interval (ECG) and respiration (nasal thermistor) were recorded during 15-min periods of supine rest, 70 degree head-up tilting, submaximal bicycling exercise and post-exercise recovery. Total variance and the power of the spectral components of blood pressure (HF, respiratory-related; LF, 0.03-0.14 Hz; and VLF, 0.02-0.003 Hz) were measured. RESULTS Compared with control subjects, CHF patients have, first, a normal overall blood pressure variability during supine rest but a failure to increase this variability in response to head-up tilt and exercise; second, a suppressed LF spectral component of blood pressure at rest and in response to head-up tilt and exercise; and third, reappearance of LF blood pressure power during postexercise recovery. CONCLUSIONS In CHF patients, overall blood pressure variability and its LF spectral component are altered at rest and during sympathoexcitatory manoeuvres. Somewhat paradoxically, however, the depressed LF blood pressure power is partially restored during a 15-min recovery period, indicating that at least part of the CHF-related alterations of blood pressure variability have the potential to revert back towards normal under appropriate physiological circumstances.

Effects of mild physical activity, atenolol and the combination on ambulatory blood pressure in hypertensive subjects.

Objective: To evaluate whether (β-blocker treatment could enhance the effect of a mild physical training programme upon blood pressure. Design and methods: In 12 hypertensive subjects (mean age: 40.3 years) a prospective randomized Latin square-design trial was performed with three treatments: physical training and placebo tablets; atenolol 50 mg once a day and inactivity; and physical training and atenolol 50 mg once a day. Results: Training significantly increased maximal ventilatory oxygen consumption (VO2MAX) and there was a decrease in ambulatory diastolic blood pressure (DBP) which did not reach statistical significance. Atenolol alone significantly reduced ambulatory systolic blood pressure (SBP) and DBP. Atenolol alone did not reduce VO2MAX. The combination of training and atenolol resulted in an increase in VO2MAX compared with atenolol alone, but no additional significant fall in blood pressure. Conclusions: Atenolol did not enhance the effect of physical training upon blood pressure and had little if any effect upon the training-induced increase in exercise tolerance.

Increased pulse wave velocity and not reduced ejection fraction is associated with impaired baroreflex control of heart rate in congestive heart failure.

Background It is known that baroreflex sensitivity (BRS) is impaired in cardiac patients with myocardial infarction (MI). Nevertheless, it is unknown whether factors other than a reduced ejection fraction play a role in the baroreflex impairment of these patients. Methods and results Heart failure patients [congestive heart failure (CHF), n = 31, age 63 ± 1.2 years, mean ± SEM)], age-matched controls (n = 29) and coronary artery disease (CAD) patients without MI (n = 29) had RR interval and arterial blood pressure (BP) continuously monitored. Baroreflex function was assessed by the slope of the regression of RR interval, and BP responses to graded (−10, −20 and −40 mmHg) neck suction stimulation, the slope of bradycardic or tachycardic responses to spontaneous increases or reductions of SBP (sequence analysis) and the baroreflex efficiency index. Pulse wave velocity (PWV) was also measured. Compared with controls, CHF patients had RR interval and BP reflex responses to neck suction reduced by −36 and −54%, respectively (P < 0.01). By contrast, no differences were found between CHF and CAD patients. Similar reductions were observed for the sequence analysis (P < 0.01) in both CHF and CAD patients. Multiple regression analysis showed that in CHF and CAD patients, PWV and SBP and not ejection fraction were correlated with BRS. Conclusion The baroreflex function is impaired in CHF patients, the extent and the degree of baroreflex impairment being similar to that of CAD patients without MI. In CHF and CAD patients, the baroreflex impairment correlates significantly with the increased PWV and not with ejection fraction.

Effects of autonomic ganglion blockade on fractal and spectral components of blood pressure and heart rate variability in free-moving rats

Fractal analysis is a promising tool for assessing autonomic influences on heart rate (HR) and blood pressure (BP) variability. The temporal spectrum of scale coefficients, α(t), was recently proposed to describe the cardiovascular fractal dynamics. Aim of our work is to evaluate sympathetic influences on cardiovascular variability analyzing α(t) and spectral powers of HR and BP after ganglionic blockade. BP was recorded in 11 rats before and after autonomic blockade by hexamethonium infusion (HEX). Systolic and diastolic BP, pulse pressure and pulse interval were derived beat-by-beat. Segments longer than 5 min were selected at baseline and HEX to estimate power spectra and α(t). Comparisons were made by paired t-test. HEX reduced all spectral components of systolic and diastolic BP, the reduction being particularly significant around the frequency of Mayer waves; it induced a reduction on α(t) coefficients at t<2s and an increase on coefficients at t>8s. HEX reduced only slower components of pulse interval power spectrum, but decreased significantly faster scale coefficients (t<8s). HEX only marginally affected pulse pressure variability. Results indicate that the sympathetic outflow contributes to BP fractal dynamics with fractional Gaussian noise (α<1) at longer scales and fractional Brownian motion (α>1) at shorter scales. Ganglionic blockade also removes a fractional Brownian motion component at shorter scales from HR dynamics. Results may be explained by the characteristic time constants between sympathetic efferent activity and cardiovascular effectors. Therefore fractal analysis may complete spectral analysis with information on the correlation structure of the data.

Nitric oxide-dependent vasodilation and the regulation of arterial blood pressure.

Summary: Conflicting evidence has been reported on the hypothesis that vascular nitric oxide (NO) release is modulated by autonomic influences. Another controversial question is whether an insufficient degree of NO‐dependent vasodilation may play a contributory role in the genesis of arterial hypertension. To address these questions we evaluated NO‐dependent vasodilation in conscious rats subjected to various experimental manipulations that interfere with autonomic function: chronic chemical sympathectomy (CCSx), acute ganglionic blockade (AGx) and chronic sinoaortic denervation (CSAD). Experiments were also carried out on 6and 12‐week‐old spontaneously hypertensive rats (SHR) (i.e. during the pre‐hypertensive and the early established hypertensive stage) and in age‐matched Wistar‐Kyoto (WKY) rats. Nitric oxidedependent vasodilation was quantified from the extent of blood pressure (BP) elevation in response to acute inhibition of NO synthesis by L‐nitromonomethyl‐L‐arginine (L‐NMMA). Chronic chemical sympathectomy was produced by repeated 6‐hydroxydopamine injections; AGx was induced by hexamethonium infusion; and CSAD was obtained by aortic nerve section and carotid sinus wall stripping. Nitric oxide synthesis inhibition by L‐NMMA was followed by a marked BP elevation in all groups. Rats with CCSx, Agx or CSAD never showed reduced BP responses to L‐NMMA compared to intact, control rats. Neither 6‐ nor 12‐weekold SHR had attenuated pressor responses to L‐NMMA compared to age‐matched WKY rats. In conclusion, the data indicate that (i) in unanaesthetized quietly‐behaving rats there is no significant modulation of NO release by autonomic influences and (ii) young SHR have unimpaired NO‐dependent vasodilation so it is unlikely that a deficit of vascular NO release plays any etiologic role in the BP elevation of this experimental model.