Respiratory patterns and baroreflex function in heart failure.

Little is known on the effects of respiratory patterns on baroreflex function in heart failure (HF). Patients with HF (n = 30, age 61.6 ± 10 years, mean ± SD) and healthy controls (CNT, n = 10, age 58.9 ± 5.6 years) having their R-R interval (RRI, EKG), systolic arterial blood pressure (SBP, Finapres) and respiratory signal (RSP, Respitrace) monitored, were subjected to three recording sessions: free-breathing, fast- (≥ 12 bpm) and slow- (6 bpm) paced breathing. Baroreflex sensitivity (BRS) and power spectra of RRI, SBP, and RSP signals were calculated. During free-breathing, compared to CNT, HF patients showed a significantly greater modulation of respiratory volumes in the very-low-frequency (< 0.04 Hz) range and their BRS was not significantly different from that of CNT. During fast-paced breathing, when very-low-frequency modulations of respiration were reduced, BRS of HF patients was significantly lower than that of CNT and lower than during free breathing. During slow-paced breathing, BRS became again significantly higher than during fast breathing. In conclusion: (1) in free-breathing HF patients is present a greater modulation of respiratory volumes in the very-low-frequency range; (2) in HF patients modulation of respiration in the very-low and low frequency (around 0.1 Hz) ranges contributes to preserve baroreflex-mediated control of heart rate.

Patterns of cardiovascular variability after long-term sino-aortic denervation in unanesthetized adult rats.

Baroreflex dysfunction is a diffuse chronic condition that is expected to be followed by a profound loss of organization of BP and HR variability. Nevertheless, long-term effects of baroreflex withdrawal are still debated. Aim of our work was to study BP and HR changes long term after sino-aortic denervation (SAD). Inter-beat-interval (IBI) and intra-arterial BP were recorded beat-by-beat in 43 Wistar-Kyoto rats (Controls, n = 33; SAD rats, n = 10). Power spectra were calculated in controls and in SAD rats within three days and at seven months from denervation. Compared to controls, chronic SAD rats showed 1) similar mean BP (control vs SAD: 95 ± 16 vs 87 ± 22 mmHg) and IBI (171 ± 22 vs 181 ± 15 ms) values, 2) dramatically higher values of BP variance (12 ± 2 vs 64 ± 2 mmHg2, p < 0.01) and of ultra- (ULF) and very-low-frequency (VLF) BP oscillations, 3) dramatically higher values of IBI variability (24 ± 2 vs 71 ± 4 ms2, p < 0.01) and of ULF-IBI oscillations that were synchronized with BP oscillations. Chronic SAD rats reveal a marked change in the pattern of cardiovascular variability characterized by the appearance of synchronized slower oscillations of BP and HR. The cardiovascular system, therefore, retains a high level of organization despite the absence of a reflex control mechanism.

Cardiovascular variability is similarly altered in coronary patients with normal left ventricular function and in heart failure patients.

OBJECTIVE: After myocardial infarction (MI), baroreflex function is impaired and heart rate (HR) variability is reduced. An impaired baroreflex has been observed also in coronary patients with no previous MI, leading to hypothesize alterations of HR variability also in these patients. The aim of the present work was, therefore, to study whether and to what extent cardiovascular variability is altered in coronary patients with no previous MI. METHODS: Thirty-two individuals were studied: eleven patients with coronary artery disease but no previous MI [coronary artery disease (CAD)], eleven patients with a reduced left ventricular ejection fraction [congestive heart failure (CHF)] and ten age-matched controls (CNT). RESULTS: Overall HR variability was significantly and similarly reduced in CAD (630 ±â€Š272 ms) and CHF patients (594 ±â€Š395 ms) with respect to CNT (1405 ±â€Š837 ms), this being the case also for the low and high frequency spectral components. Low-frequency oscillations of blood pressure (BP) were also significantly and similarly less pronounced in CAD (0.7 ±â€Š0.7 mmHg) and CHF patients (0.7 ±â€Š0.7 mmHg) compared with CNT (1.8 ±â€Š1.4 mmHg). Moreover, both CAD and CHF patients showed a significantly reduced baroreflex function and an increased pulse-wave velocity with respect to CNT. CONCLUSION: Our study shows that in coronary patients with no MI and no left ventricular dysfunction, there is a profound alteration of both HR and BP variability as in CHF patients, presumably because of a marked impairment of the autonomic modulation of the heart and blood vessels.

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.

Infusion of Escherichia coli lipopolysaccharide toxin in rats produces an early and severe impairment of baroreflex function in absence of blood pressure changes.

The assessment of baroreflex function since the first appearance of endotoxemia is important because the arterial baroreflex should exert a protective role during sepsis. Nevertheless, contrasting results were previously reported. This could be due to the hemodynamic instability characterizing this condition that may per se interfere with reflex cardiovascular adjustments. The aim of our study was therefore to study the baroreflex function (a) since the very beginning of infusion of Escherichia coli lipopolysaccharide (LPS) toxin and (b) in absence of the unloading effect produced by a decrease in blood pressure. Lipopolysaccharide was infused in 10 rats for 20 min at the infusion rate of 0.05 mg · kg · min. Blood pressure was continuously measured before, during, and after infusion, and the baroreflex function was evaluated analyzing spontaneous fluctuations of systolic blood pressure and pulse interval by the sequence and transfer-function techniques. Plasma concentrations of inflammatory (interleukin 6, tumor necrosis factor α) and anti-inflammatory (interleukin 10) cytokines were measured in other eight rats, similarly instrumented, four of which receiving the same LPS infusion. We found that blood pressure levels did not change with the infusion of LPS, whereas inflammatory cytokines increased significantly. The baroreflex sensitivity was significantly reduced 10 min after the beginning of LPS infusion, reached values about half those at baseline within 15 min after the start of infusion, and remained significantly low after the end of infusion. In conclusion, we documented that septic shock inducing LPS infusion is responsible for a very rapid impairment of the baroreflex function, independent from the level of blood pressure.

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.

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.

Effects of physical training on cardiovascular control after heart transplantation.

BACKGROUND: Exercise performance in heart-transplanted patients increases with respect to pre-transplantation but remains subnormal, and it does not improve with time after surgery. Possible causes include persisting denervation, and sympathetic vasoconstriction inducing functional vascular abnormalities that prevent adequate increase in blood flow to the exercising limbs. We tested the effects of physical training on baroreceptors-mediated control of heart rate and blood pressure in recently heart-transplanted subjects. METHODS: Patients were randomly allocated to physical training (n=13, 30 min cycling at 60-70% of peak oxygen consumption for 5 days/week for 6 months) or to control (n=11). Upright exercise test to exhaustion was performed at the beginning of the study after 3 and 6 months. Reflex changes in RR interval and blood pressure in response to sinusoidal neck suction (6 and 12 cycles/min 0 to -30 mm Hg swing) were considered as evidence of reinnervation and baroreflex control of blood pressure, respectively. RESULTS: After 6 months peak oxygen consumption (p<0.001), exercise time (p<0.01) and workload (p<0.01) increased in trained patients. Before training RR interval and blood pressure were not modified by neck suction. After physical training systolic (p<0.01) and diastolic blood pressure decreased, RR interval and blood pressure could be modulated (p<0.05) by slow (6 cycles/min) neck suction, indicating initial cardiac sympathetic reinnervation and restored sensitivity to autonomic modulation on the arteries. No changes were observed in controls. CONCLUSIONS: Physical training improved exercise performance and the control exerted by the autonomic nervous system through the sympathetic nerves at both cardiac and vascular level.

Enhanced baroreceptor control of the cardiovascular system by polyunsaturated Fatty acids in heart failure patients.

OBJECTIVES: The intention of this study was to test the hypothesis that, in heart failure patients, dietary supplementation of polyunsaturated fatty acids (PUFA) enhances arterial baroreceptor control of the cardiovascular system. BACKGROUND: Administration of PUFA reduces the risk of life-threatening arrhythmias in patients surviving myocardial infarction. This might result from potentiation of arterial baroreflexes, but whether or not PUFA enhance baroreflex function has never been studied in humans. METHODS: Patients with post-myocardial infarction left ventricular dysfunction underwent beat-to-beat blood pressure (BP) (Finapres, Ohmeda Inc., Englewood, Colorado) and R-R interval (electrocardiogram) recording; baroreceptor reflexes were assessed from the bradycardic and depressor responses to graded neck suction (NS) as well as by computation of the alpha "spontaneous" baroreflex sensitivity index. Assessments were repeated after prolonged treatment with PUFA (2 g/die, n = 15) or placebo (n = 10). RESULTS: Baseline BP and R-R interval were unaffected by PUFA. Both reflex depressor and bradycardic responses to NS increased after PUFA (respectively from -0.09 +/- 0.01 to -0.16 +/- 0.01 mm Hg x mm Hg(-1), p < 0.01, and from 1.25 +/- 0.9 to 1.76 +/- 1.1 ms x mm Hg(-1), p < 0.04) but not after placebo. The spontaneous baroreflex sensitivity increased in the PUFA (from 8.99 +/- 1.4 to 12.2 +/- 1.2 ms x mm Hg(-1), p < 0.02) but not in the placebo group. Polyunsaturated fatty acids (but not placebo) treatment also significantly increased R-R interval total variance and low-frequency and high-frequency spectral powers. CONCLUSIONS: Dietary PUFA supplementation markedly potentiates baroreflex function and enhances heart rate variability in patients with stable congestive heart failure.

Adrenergic origin of very low-frequency blood pressure oscillations in the unanesthetized rat.

Spectral analysis of cardiovascular signals has been extensively used to investigate circulatory homeostatic mechanisms. However, the nature of very low-frequency (VLF) fluctuations remains unclear. Because we previously observed enhanced VLF fluctuations in blood pressure (BP) in the sympathectomized rat (a model characterized by markedly increased plasma epinephrine levels), the aims of our study were to assess whether the genesis of VLF fluctuations in BP depends on circulating catecholamines and to determine which adrenergic receptor(s) and which membrane ion channel(s) are involved. We used continuous intra-arterial BP recordings from unanesthetized unrestrained rats to compute the power of VLF fluctuations in BP in the intact condition, during acute ganglionic blockade with hexamethonium, and after restoration of BP levels by infusion (in addition to hexamethonium) of adrenergic agonists (epinephrine, norepinephrine, and clonidine) or nonadrenergic vasoconstrictors (vasopressin). Effects of infusion of specific adrenergic receptor blockers (propranolol, prazosin, and yohimbine) with hexamethonium and catecholamines and infusion of various membrane ion channel blockers on VLF fluctuations in BP were also evaluated. Our results are as follows. 1) Ganglionic blockade drastically reduced BP levels and VLF fluctuations. 2) All vasoconstrictors restored BP levels, but only adrenergic vasoconstrictors generated striking VLF fluctuations in BP. 3) Catecholamine-induced fluctuations were abolished by alpha2-, but not alpha1- or beta-, adrenergic receptor blockade and by Ba2+-sensitive K+ channel or L-type Ca2+ channel, but not by other ion channel, blockers. We conclude that, in the conscious, unrestrained ganglion-blocked rat, catecholamine infusion generates VLF fluctuations in BP through stimulation of alpha2-receptors and activation of Ba2+-sensitive K+ channels. These fluctuations may have (patho)physiological relevance under conditions of disrupted circulatory homeostasis.

Effects of slow, controlled breathing on baroreceptor control of heart rate and blood pressure in healthy men.

BACKGROUND: Slow, controlled breathing has been shown by cross-spectral techniques to potentiate arterial baroreflex control of heart rate. However, crucial aspects of the effects of slow breathing on the arterial baroreflex remain unsettled, namely whether the major function of the arterial baroreflex (i.e. the control of blood pressure) is also potentiated and whether baroreflex function is differentially modulated according to the age of the individual. OBJECTIVE: To examine the bradycardic and depressor responses to selective carotid baroreceptor stimulation by the neck chamber technique (-15 and -30 mmHg neck suction) and the cross-spectral R-R interval/systolic blood pressure relationship (alpha index). METHODS: In 24 resting, supine healthy male volunteers (aged 19-66 years, mean +/-SEM 37.5 +/- 3.19 years), blood pressure (Finapres), R-R interval (electrocardiogram) and ventilation (impedance) were recorded continuously. Both assessments were performed during spontaneous breathing and during 6 cycles/min controlled ventilation in random order. RESULTS: The depressor and bradycardic responses to neck suction were significantly larger during slow breathing than in spontaneous breathing (+32 and +85%, respectively; both P < 0.01). The alpha index was also significantly larger during slow breathing (+62%; P < 0.01). Even after the volunteers were divided into older (> 50 years, n = 9) and younger (< 30 years, n = 9) groups, the baroreflex potentiation related to slow breathing was clearcut and significant for both the depressor (+46 and +24% older and younger volunteers; both P < 0.01) and the bradycardic (+130 and +73% older and younger volunteers; both P < 0.01) responses. When the assessment was made by computing the cross-spectral alpha index, a marked potentiation related to slow breathing was observed in younger volunteers (+99%; P < 0.01), whereas in older volunteers only a trend to an enhancement (by 32%; P < 0.055) was observed. CONCLUSIONS: Slow controlled breathing is associated with potentiation of both the depressor and the cardio-inhibitory components of the arterial baroreflex, the potentiation being largely similar regardless of the age of the individual.

Invited review: aging and the cardiovascular system.

Aging is associated with complex and diversified changes of cardiovascular structure and function. The heart becomes slightly hypertrophic and hyporesponsive to sympathetic (but not parasympathetic) stimuli, so that the exercise-induced increases in heart rate and myocardial contractility are blunted in older hearts. The aorta and major elastic arteries become elongated and stiffer, with increased pulse wave velocity, evidence of endothelial dysfunction, and biochemical patterns resembling early atherosclerosis. The arterial baroreflex is sizably altered in aging, but different components are differentially affected: there is a definite impairment of arterial baroreceptor control of the heart but much better preserved baroreceptor control of peripheral vascular resistance. Alterations at the afferent, central neural, efferent, and effector organ portions of the reflex arch have been claimed to account for age-related baroreflex changes, but no conclusive evidence is available on this mechanistic aspect. Reflexes arising from cardiopulmonary vagal afferents are also blunted in aged individuals. The cardiovascular and reflex changes brought about by aging may have significant implications for circulatory homeostasis in health and disease.

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.