Assessment of global LV remodeling is important in evaluating the efficacy of pharmacologic and device therapies for the treatment of chronic heart failure (HF). The effects of pharmacologic or device therapies on global left atrial (LA) remodeling in HF, while also important, are not often examined. We showed that long-term therapy with the Acorn Cardiac Support Device (CSD), a passive mechanical ventricular containment device, prevents and/or reverses LV remodeling in dogs with HF. This study examined the effects of the CSD on global LA remodeling in dogs with moderate and advanced HF.
Methods and Results
Studies were performed in 24 dogs with coronary microembolization-induced HF. Of these, 12 had moderate HF (ejection fraction, EF 30% to 40%) and 12 advanced HF (EF ≤25%). In each group, the CSD was implanted in 6 dogs and the other 6 served as controls. Dogs were followed for 3 months in the moderate group and 6 months in the advanced HF group. LA maximal volume (LAVmax), LA volume at the onset of the p-wave (LAVp), LA minimal volume (LAVmin), LA active emptying volume (LAAEV) and LA active emptying fraction (LAAEF) were measured from 2-dimensional echocardiograms obtained prior to CSD implantation and at the end of the treatment period. Treatment effect (Δ) comparisons between CSD-treated dogs and controls showed that CSD therapy significantly decreased LA volumes (ΔLAVmax: 3.33 ± 0.70 vs. −2.87±1.31 ml, p=0.002; 7.77 ± 1.76 vs. −0.37 ± 0.87 ml, p=0.002) and improved LA function (ΔLAAEF: −6.00 ± 1.53 vs. 1.85 ± 1.32 %, p=0.003; −2.39 ± 1.10 vs. 3.13 ± 1.66 %, p=0.02) in the moderate HF and advanced HF groups respectively.
Progressive LA enlargement and LA functional deterioration occurs in untreated dogs with HF. Monotherapy with the CSD prevents LA enlargement and improves LA mechanical function in dogs with moderate and advanced HF indicating prevention and/or reversal of adverse LA remodeling.
Atrium; Echocardiography; Heart failure; Heart-assist device
Previous studies suggest that prolonged electrical activation of the baroreflex may reduce arterial pressure more than chronic blockade of α1-and β1,2-adrenergic receptors. To determine whether central inhibition of sympathetic outflow has appreciable effects to chronically reduce arterial pressure by actions distinct from well established mechanisms, we hypothesized that chronic baroreflex activation would lower arterial pressure substantially even during complete α1-and β1,2-adrenergic receptor blockade. This hypothesis was tested in 6 dogs during adrenergic blockade (18 days) with and without electrical activation of the carotid baroreflex (7 days). During chronic adrenergic blockade alone, there was a sustained decrease in mean arterial pressure of 21±2 mm Hg (control = 95±4 mm Hg) and nearly a 3-fold increase in plasma norepinephrine concentration (control = 138±6pg/mL), likely due to baroreceptor unloading. In comparison, during adrenergic blockade + prolonged baroreflex activation, plasma norepinephrine concentration decreased to control levels and mean arterial pressure fell an additional 10±1 mm Hg. Because of differences in plasma norepinephrine concentration, we also tested the acute blood pressure lowering effects of MK-467, a peripherally acting α2-antagonist. After administration of MK-467, there was a significantly greater fall in arterial pressure during adrenergic blockade (15±3 mm Hg) than during adrenergic blockade + prolonged baroreflex activation (7±3 mm Hg). These findings suggest that reflex-induced increases in sympathetic activity attenuate reductions in arterial pressure during chronic adrenergic blockade and that inhibition of central sympathetic outflow by prolonged baroreflex activation lowers arterial pressure further by previously undefined mechanisms, possibly by diminishing attendant activation of postjunctional α2-adrenergic receptors.
baroreflex; arterial pressure; sympathetic nervous system; α-and β-adrenergic receptors; norepinephrine; renin-angiotensin system
Chronic pressure-mediated baroreflex activation suppresses renal sympathetic nerve activity. Recent observations indicate that chronic electrical activation of the carotid baroreflex produces sustained reductions in global sympathetic activity and arterial pressure. Thus, we investigated the effects of global and renal specific suppression of sympathetic activity in dogs with sympathetically-mediated, obesity-induced hypertension by comparing the cardiovascular, renal, and neurohormonal responses to chronic baroreflex activation and bilateral surgical renal denervation. After control measurements, the diet was supplemented with beef fat while sodium intake was held constant. After 4 weeks on the high-fat, when body weight had increased ~a 50%, fat intake was reduced to a level that maintained this body weight. This weight increase was associated with an increase in mean arterial pressure from 100±2 to 117±3 mm Hg and heart rate from 86±3 to 130±4 bpm. The hypertension was associated with a marked increase in cumulative sodium balance despite ~ a 35% increase in GFR. The importance of increased tubular reabsorption to sodium retention was further reflected by ~ a 35% decrease in fractional sodium excretion. Subsequently, both chronic baroreflex activation (7 days) and renal denervation decreased plasma renin activity and abolished the hypertension. However, baroreflex activation also suppressed systemic sympathetic activity and tachycardia and reduced glomerular hyperfiltration while increasing fractional sodium excretion. In contrast, GFR increased further after renal denervation. Thus, by improving autonomic control of cardiac function and diminishing glomerular hyperfiltration, suppression of global sympathetic activity by baroreflex activation may have beneficial effects in obesity beyond simply attenuating hypertension.
obesity; hypertension; baroreflex; sympathetic nervous system; renal nerves; renal function; renin-angiotensin system
Autonomic dysregulation is a feature of heart failure (HF) characterized by sustained increase of sympathetic drive and by withdrawal of parasympathetic activity. Both maladaptations are independent predictors of poor long-term outcome in patients with HF. Considerable evidence exists that supports the use of pharmacologic agents that partially inhibit sympathetic activity as an effective long-term therapy for patients with HF; the classic example being the use of selective and non-selective beta-adrenergic receptor blockers. In contrast, modulation of parasympathetic activation as potential therapy for HF has received only limited attention. This review discusses the results of recent pre-clinical animal studies that provide support for the possible use of baroreflex electrical stimulation, also know as baroreflex activation therapy (BAT), as a long-term therapeutic approach for the treatment of patients with chronic HF. In addition to exploring the effects of chronic BAT on left ventricular (LV) function and chamber remodeling, the review will also address the effects of long-term BAT on ventricular arrhythmias and on potential modifiers of the HF state that include maladaptations of both the nitric oxide and beta-adrenergic receptor signal transduction pathways. The results of the pre-clinical studies conducted to date have shown that in dogs with advanced HF, monotherapy with BAT improves global LV systolic and diastolic function and partially reverses LV remodeling both globally and at cellular and molecular levels. In addition BAT therapy was shown to markedly increase the threshold for lethal ventricular arrhythmias in dogs with chronic HF. These benefits of BAT support the continued exploration of this therapeutic modality for treating patients with chronic HF and those with increased risk of sudden cardiac death.
Congestive heart failure; Animal models of human disease; Heart failure - basic studies; Baroreflex function; Ventricular Function; Ventricular dilation; mRNA expression; Ventricular arrhythmias; Electrophysiological testing; Plasma biomarkers; Sympathetic stimulation; Parasympathetic stimulation; Beta-adrenergic signaling; Nitric oxide; Inflammatory cytokines
Power spectral analysis of heart rate variability (HRV) has been used to indicate cardiac autonomic function. High-frequency power relates to respiratory sinus arrhythmia and therefore to parasympathetic cardiovagal tone; however, the relationship of low-frequency (LF) power to cardiac sympathetic innervation and function has been controversial. Alternatively, LF power might reflect baroreflexive modulation of autonomic outflows.
We studied normal volunteers and chronic autonomic failure syndrome patients with and without loss of cardiac noradrenergic nerves in order to examine the relationships of LF power with cardiac sympathetic innervation and baroreflex function.
We compared LF power of HRV in patients with cardiac sympathetic denervation, as indicated by low myocardial concentrations of 6-[18F] fluorodopamine-derived radioactivity or low rates of norepinephrine entry into coronary sinus plasma (cardiac norepinephrine spillover) to values in patients with intact innervation, at baseline, during infusion of yohimbine, which increases exocytotic norepinephrine release from sympathetic nerves, or during infusion of tyramine, which increases non-exocytotic release. Baroreflex-cardiovagal slope (BRS) was calculated from the cardiac interbeat interval and systolic pressure during the Valsalva maneuver.
LF power was unrelated to myocardial 6-[18F] fluorodopamine-derived radioactivity or cardiac norepinephrine spillover. In contrast, the log of LF power correlated positively with the log of BRS (r=0.72, p<0.0001). Patients with low BRS (≤ 3 msec/mm Hg) had low LF power, regardless of cardiac innervation. Tyramine and yohimbine increased LF power in subjects with normal BRS but not in those with low BRS. BRS at baseline predicted LF responses to tyramine and yohimbine.
LF power reflects baroreflex function, not cardiac sympathetic innervation.
heart rate variability; power spectral analysis; nervous system; sympathetic; fluorodopamine; baroreceptors
Chronic electrical activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as hypertension therapy for patients with resistant hypertension. However, the chronic changes in renal function associated with natural suppression of sympathetic activity are largely unknown. In normotensive dogs we investigated the integrative cardiovascular effects of chronic baroreflex activation (2 weeks) alone and in combination with the calcium channel blocker amlodipine, which is commonly used in the treatment of resistant hypertension. During baroreflex activation alone, there were sustained decreases in mean arterial pressure (17 ± 1 mm Hg) and plasma [norepinephrine] (NE, ~35%), with no change in plasma renin activity (PRA). Despite low pressure, sodium balance was achieved due to decreased tubular reabsorption, because GFR and renal blood flow decreased 10–20%. After 2 weeks of amlodipine, arterial pressure was also reduced 17 mm Hg, but with substantial increases in NE and PRA, and no change in GFR. In the presence of amlodipine, baroreflex activation greatly attenuated neurohormonal activation and pressure decreased even further (by 11 ± 2 mm Hg). Moreover, during amlodipine administration the fall in GFR with baroreflex activation was abolished. These findings suggest that the chronic blood pressure lowering effects of baroreflex activation are due, at least in part, to sustained inhibition of renal sympathetic nerve activity and attendant decreases in sodium reabsorption prior to the macula densa. Tubuloglomerular feedback constriction of the afferent arterioles may account for reduced GFR, a response abolished by amlodipine, which dilates the preglomerular vasculature.
arterial pressure; baroreflex; sympathetic nervous system; renal nerves; renal function; renin-angiotensin system
In chronic heart failure (CHF), arterial baroreflex function is impaired, in part, by activation of the central renin-angiotensin system. A metabolite of Angiotensin II (Ang II), Ang-(1–7), has been shown to exhibit cardiovascular effects that are in opposition to that of Ang II. However, the action of Ang-(1–7) on sympathetic outflow and baroreflex function is not well understood, especially in CHF. The aim of this study was to determine the effect of intracerebroventricular infusion of Ang-(1–7) on baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in conscious rabbits with CHF. We hypothesized that central Ang-(1–7) would improve baroreflex function in CHF. Ang-(1–7) (2 nmol/1 μl/hour) or artificial cerebrospinal fluid (1 μl/hour) was infused by an osmotic mini-pump for 4 days in sham and pacing-induced CHF rabbits (n=3–6/group). Ang-(1–7) treatment had no effects in sham rabbits but reduced HR and increased baroreflex gain (7.4±1.5 bpm/mm Hg vs. 2.5±0.4 bpm/mm Hg, P<0.05) in CHF rabbits. The Ang-(1–7) antagonist A779 (8 nmol/1 μl/hr) blocked the improvement in baroreflex gain in CHF. Baroreflex gain increased in CHF+Ang-(1–7) animals when only the vagus was allowed to modulate baroreflex control by acute treatment with the β-1 antagonist metoprolol, indicating increased vagal tone. Baseline RSNA was significantly lower and baroreflex control of RSNA was enhanced in CHF rabbits receiving Ang-(1–7). These data suggest that augmentation of central Ang-(1–7) inhibits sympathetic outflow and increases vagal outflow in CHF thus contributing to enhanced baroreflex gain in this disease state.
angiotensin-(1–7); heart failure; sympathetic nervous system; baroreflex; vagus nerve; blood pressure; heart rate
The arterial baroreflexes, located in the carotid sinus and along the arch of the aorta, are essential for the rapid short term autonomic regulation of blood pressure. In the past, they were believed to be inactivated during exercise because blood pressure, heart rate, and sympathetic activity were radically changed from their resting functional relationships with blood pressure. However, it was discovered that all relationships between carotid sinus pressure and either HR or sympathetic vasoconstriction maintained their curvilinear sigmoidal shape but were reset or shifted so as to best defend BP during exercise. To determine whether resetting also occurs during orthostasis, we examined the arterial baroreflexes measured supine and upright tilt. We studied the relationships between systolic BP and HR (the cardiovagal baroreflex), mean BP, and ventilation (the ventilatory baroreflex) and diastolic BP and sympathetic nerve activity (the sympathetic baroreflex). We accomplished these measurements by using the modified Oxford method in which BP was rapidly varied with bolus injections of sodium nitroprusside followed 1 min later by bolus injections of phenylephrine. Both the cardiovagal and ventilatory baroreflexes were “reset” with no change in gain or response range. In contrast, the sympathetic baroreflex was augmented as well as shifted causing an increase in peripheral resistance that improved the subjects’ defense against hypotension. This contrasts with findings during exercise in which peripheral resistance in active skeletal muscle is not increased. This difference is likely selective for exercising muscle and may represent the actions of functional sympatholysis by which exercise metabolites interfere with adrenergic vasoconstriction.
cardiovascular regulation; standing; sympathetic nerve activity; heart rate; ventilation
In the past few years, novel accomplishments have been obtained in carotid baroreflex activation therapy (BAT) for the treatment of resistant hypertension. In addition, this field is still evolving with promising results in the reduction of blood pressure and heart rate. This overview addresses the latest developments in BAT for the treatment of drug-resistant hypertension. Although not totally understood considering the working mechanisms of BAT, it appeared to be possible to achieve at least as much efficacy of single-sided as bilateral stimulation. Therefore unlike the first-generation Rheos system, the second-generation Barostim neo operates by unilateral baroreflex activation, using a completely different carotid electrode. Also significant improvements in several cardiac parameters have been shown by BAT in hypertensive patients, which set the basis for further research to evaluate BAT as a therapy for systolic heart failure. Yet important uncertainties need to be clarified to guarantee beneficial effects; hence not all participants seem to respond to BAT.
The mechanisms by which blood pressure is maintained against the orthostatic stress caused by gravity's effect on the fluid distribution within the body are important issues in physiology, especially in humans who usually adopt an upright posture. Peripheral vasoconstriction and increased heart rate (HR) are major cardiovascular adjustments to orthostatic stress and comprise part of the reflex response elicited via the carotid sinus and aortic baroreceptors (arterial baroreflex: ABR) and cardiopulmonary stretch receptors (cardiopulmonary baroreflex). In a series of studies, we have been characterizing the ABR-mediated regulation of cardiovascular hemodynamics and muscle sympathetic nerve activity (MSNA) while applying orthostatic stress in humans. We have found that under orthostatic stress, dynamic carotid baroreflex responses are modulated as exemplified by the increases in the MSNA, blood pressure, and HR responses elicited by carotid baroreflex unloading and the shorter period of MSNA suppression, comparable reduction and faster recovery of mean arterial blood pressure (MAP) and greater HR response to carotid baroreflex stimulation. Our results also show that ABR-mediated beat-to-beat control over burst incidence, burst strength and total MSNA is progressively modulated as orthostatic stress is increased until induction of syncope, and that the sensitivity of ABR control over the aforementioned MSNA variables is substantially reduced during the development of syncope. We suggest that in humans, the modulation of ABR function under orthostatic stress may be one of the mechanisms by which blood pressure is maintained and orthostatic hypotension limited, and impairment of ABR control over sympathetic vasomotor activity leads to the severe hypotension associated with orthostatic syncope.
sympathetic nervous system; lower body negative pressure; integrated circulatory regulation; blood pressure; peripheral reflexes
Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF.
Methods and Results
Electrophysiological mapping was performed in the pulmonary veins (PVs) and left atrium (LA) in 38 rapid-ventricular paced dogs (CHF group) and 39 controls under the following conditions: vagal stimulation, isoproterenol infusion, β-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor (MR) and beta-adrenergic receptor (βAR) densities, and AChE activity.
In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior LA/PVs. Sympathetic hyperinnervation was accompanied by increases in β1AR density and in sympathetic effect on ERPs and activation direction. β-adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged MR density, unchanged parasympathetic effect on activation direction, and decreased effect of vagal stimulation on ERP (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration.
In this heart failure model autonomic and electrophysiologic remodeling occurs involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.
atrial fibrillation; autonomic nervous system; heart failure
Power spectral analysis of heart rate variability is used clinically to assess cardiac autonomic function. High frequency power is related to respiratory sinus arrhythmia and therefore to parasympathetic cardiovagal tone. The relationship of low frequency (LF) power to cardiac sympathetic tone is less clear. We reported previously that LF power may reflect baroreflex function; however, in the previous study LF power was not adjusted for possible influences of respiration. In this study we assessed relationships of LF power, including respiration-adjusted LF power (LFa) using the ANSAR ANX 3.0 device, with cardiac sympathetic innervation and baroreflex function in chronic autonomic failure patients who either had or did not have neuroimaging evidence of cardiac sympathetic denervation.
Values for LF power with patients seated at baseline and during the Valsalva maneuver were compared between groups with low or normal myocardial concentrations of 6-[18F]fluorodopamine-derived radioactivity. Baroreflex-cardiovagal gain (BRS) was calculated from the slope of cardiac interbeat interval vs. systolic pressure during the Valsalva maneuver with subjects supine.
Individual values for LF and LFa were unrelated to myocardial 6-[18F]fluorodopamine-derived radioactivity. During both sitting rest and the Valsalva maneuver the logs of LF and LFa correlated positively with the log of BRS (r=0.61, p=0.0005; r=0.47, p=0.009; r=0.69, p<0.0001; r=0.60, p=0.0006). Patients with low BRS (≤3 msec/mm Hg) had low LF and LFa regardless of the status of cardiac innervation.
LF and LFa reflect baroreflex function independently of cardiac sympathetic innervation.
Power spectral analysis; Heart rate variability; Sympathetic; Parasympathetic; Autonomic
Neurohumoral disturbances characterize chronic heart failure (CHF) and are reflected, in part, as impairment of baroreflex sensitivity (BRS) and sympathetic function. However the mechanisms that trigger these neurohumoral abnormalities in CHF are not clear. We hypothesized that the BRS is blunted early in CHF and that the humoral effects occur later and contribute to progressive loss of cardiovascular control in CHF. We assessed the BRS (bpm/mmHg) and recorded renal sympathetic nerve activity (RSNA) in four groups of conscious rabbits at varying time intervals; control, one week CHF, two week CHF and three week CHF. CHF was induced by ventricular pacing at 360 bpm and was assessed by echocardiography. Arterial blood pressure and heart rate were recorded by an implanted telemetric device and RSNA through an implanted electrode. A significant fall in the ejection fraction, fractional shortening and an increase in LVESD & LVEDD was observed in all CHF groups. The BRS was significantly reduced in all the CHF groups with no significant change in the basal RSNA(% of maximum) after 1 week of pacing, a small but insignificant rise in RSNA was seen at 2 weeks and a significant rise in RSNA was observed at 3 weeks. AT1 receptor protein (Western Blot) and mRNA (RT-PCR) expression in the rostral ventrolateral medulla (RVLM) exhibited a progressive increase with the duration of CHF, reaching significance after 3 weeks, the same time point in which RSNA was significantly elevated. These data are the first to examine early changes in central AT1 receptors in CHF and suggest that the fall in BRS and hemodynamic changes occur early in the development of CHF followed by sympatho-excitation and over-expression of AT1 receptors with the progression of CHF causing further impairment of cardiovascular control.
Baroreflex; heart failure; sympathetic activity; angiotensin II receptor
β-Blockers are standard therapy for patients with heart failure (HF). This study compared the effects of chronic monotherapy with 2 different β1-selective adrenoceptor blockers, namely atenolol and metoprolol succinate, on left ventricular (LV) function and remodeling in dogs with coronary microembolization-induced HF [LV ejection fraction (EF) 30–40%].
Twenty HF dogs were randomized to 3 months of therapy with atenolol (50 mg once daily, n = 6), metoprolol succinate (100 mg, once daily, n = 7) or to no therapy (control, n = 7). LV EF and volumes were measured before initiating therapy and after 3 months of therapy. The change (Δ) in EF and volumes between measurements before and after therapy was calculated and compared among study groups.
In controls, EF decreased and end-systolic volume increased. Atenolol prevented the decrease in EF and the increase in ESV. In contrast, metoprolol succinate significantly increased EF and decreased end-systolic volume. ΔEF was significantly higher and Δend-systolic volume significantly lower in metoprolol succinate-treated dogs compared to atenolol-treated dogs (EF: 6.0 ± 0.86% vs. 0.8 ± 0.85%, p < 0.05; end-systolic volume: −4.3 ± 0.81 ml vs. −1 ± 0.52 ml, p <0.05).
In HF dogs, chronic therapy with atenolol does not elicit the same LV function and remodeling benefits as those achieved with metoprolol succinate.
Heart failure; Myocyte hypertrophy; Ventricular remodeling; Gene expression
Angiotensin-converting enzyme 2 (ACE2) has been suggested to be involved in the central regulation of autonomic function. During chronic heart failure (CHF), elevated central angiotensin II signaling contributes to the sustained increase of sympathetic outflow. This is accompanied by a downregulation of ACE2 in the brain. We hypothesized that central overexpression of ACE2 decreases sympathetic outflow and enhances baroreflex function in CHF. Transgenic mice overexpressing human ACE2 selectively in the brain (SYN-hACE2) and wild type littermates (WT) were used. CHF was induced by permanent coronary artery ligation (CAL). Four weeks after CAL, both WT and SYN-hACE2 mice exhibited a significant decrease in left ventricular ejection fraction (<40%). A slight decrease in MAP was found only in SYN-hACE2 mice. Compared with WT mice with CHF, brain-selective ACE2 overexpression attenuated left ventricular end-diastolic pressure; decreased urinary norepinephrine excretion; baseline RSNA (WT CHF: 71.6±7.6% Max vs. SYN-hACE2 CHF: 49.3±6.1% Max); and enhanced baroreflex sensitivity (Maximum Slope: WT Sham: 1.61±0.16 vs. SYN-hACE2 CHF: 1.51±0.17%/mmHg). Chronic subcutaneous blockade of mas receptor increased RSNA in SYN-hACE2 mice with CHF (A779: 67.3±5.8% vs. vehicle: 46.4±3.6% of Max). An up-regulation in angiotensin II type 1 receptor (AT1R) expression was detected in medullary nuclei in WT CHF mice, which was significantly attenuated in SYN-hACE2 mice with CHF. These data suggest that central ACE2 overexpression exerts a potential protective effect in CHF through attenuating sympathetic outflow. The mechanism for this effect involves angiotensin (1-7) mas signaling as well as a decrease in AT1R signaling in the medulla.
heart failure; angiotensin converting enzyme 2; angiotensin II; angiotensin I (1-7); autonomic function; baroreflex
Heart period constantly changes on a beat to beat basis, due to autonomic influences on the sinoatrial node, and changes can be quantified as heart rate variability (HRV). In addition, after a premature ventricular beat, there are reproducible variations in RR interval, also due to baroreflex mediated autonomic influences on the sinoatrial node, that can be measured as heart rate turbulence (HRT). Impaired autonomic function as measured by HRV and HRT has proven to predict adverse outcomes in clinical settings. The ability of reduced HRV and HRT to predict adverse outcomes has been explained by their dependency on vagal mechanisms that could reflect an increased sympathetic and a reduced vagal modulation of sinus node, thus favoring cardiac electrical instability. Analysis of non-linear dynamics of HRV has also been utilized to describe the fractal like characteristic of the variability signal and proven effective in identify patients at risk for sudden cardiac death. Despite the clinical validity of these measures, it has also been evident that the relationship between neural input and sinus node responsiveness is extremely complex and variable in different clinical conditions. Thus, abnormal HRV or HRT on a clinical Holter recordings may reflect non-neural as well as autonomic mechanisms, and this also needs to be taken into account when interpreting any findings. However, under controlled conditions, the computation of the low and high frequency components of HRV and of their normalized powers or ratio seems capable of providing valid information on sympatho-vagal balance in normal subjects, as well as in most patients with a preserved left ventricular function. Thus, analysis of HRV does provide a unique tool to specifically assess autonomic control mechanisms in association with various perturbations. In conclusion, HRV measures are of substantial utility to identify patients with an increased cardiac mortality and to evaluate autonomic control mechanisms, but their ability to capture specific levels of autonomic control may be limited to controlled laboratory studies in relatively healthy subjects.
autonomic modulation; sympathetic and vagal control; baroreflex mechanisms; spectral analysis; non-invasive evaluation of cardiac function
Adenosine (AD) elicits cardioprotection through A1-receptor (A1R) activation. Therapy with AD A1R agonists, however, is limited by undesirable actions of full agonism such as bradycardia. This study examined the effects of capadenoson (CAP), a partial AD A1R agonist, on left ventricular (LV) function and remodeling in dogs with heart failure (HF).
Methods and Results
12 dogs with microembolization-induced HF were randomized to 12 weeks oral therapy with CAP (7.5 mg Bid, n=6) or to no therapy (Control, n=6). LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), plasma norepinephrine (NE) and n-terminal pro-brain natriuretic peptide (nt-pro BNP) were measured before (PRE) and 1 and 12 weeks after therapy (POST). LV tissue obtained at POST was used to assess volume fraction of interstitial fibrosis (VFIF), SERCA-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, EDV and ESV increased and EF decreased significantly from PRE to POST (EF: 30±2 vs. 27±1 %, p<0.05). In CAP-treated dogs, EDV was unchanged; EF increased significantly after one week (36±2 vs. 27±2 %, p<0.05) with a further increase at POST (39±2 %, p<0.05) while ESV decreased. CAP significantly decreased VFIF, normalized SERCA-2a activity and expression of UCP-2 and -3, and GLUT-1 and -2 and significantly decreased NE and nt-pro BNP.
In HF dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial AD A1R agonists for the treatment of chronic HF.
Heart failure; Ventricular remodeling; Protein expression; Adenosine receptors
OBJECTIVE--To assess the influence of both sympathetic (plasma noradrenaline concentrations) and parasympathetic (baroreflex activation) tone on survival in patients with congestive heart failure. DESIGN--Invasive study with determination of parasympathetic activity and follow up for at least 4.5 years. SUBJECTS--35 patients with sinus rhythm and mild to moderate heart failure (New York Heart Association grades II-III) (mean age 53 (SD 3)). RESULTS--20 patients whose hearts survived were compared with 15 patients whose hearts did not (12 died and three received transplants). The two groups differed significantly in terms of mean arterial blood pressure (98 (3) v 90 (3) mm Hg), heart rate (82 (2) v 93 (4) beats/min), and mean pulmonary artery pressure (24 (3) v 35 (2) mm Hg) (all P < 0.05), while cardiac index, stroke volume index, and right atrial pressures were not different. The survivors had significantly lower plasma renin activities (3.6 (0.8) v 9.0 (3.6) angiotensin I/ml/h; P < 0.05) and tended to have lower noradrenaline values than non-survivors (170 (23) v 286 (74) pg/ml) at baseline. Baroreflex sensitivity was significantly lower in non- survivors than in survivors (1.3 (0.2) v 2.3 (0.3) ms/mm/Hg); P < 0.02). As the time of cardiac transplantation is dependent on complex logistical factors the three patients who received a transplant were excluded from the analysis of survival time. The risk of death in relation to baroreflex sensitivity at the median sensitivity of 1.48 ms/mm Hg was calculated. Survival was significantly different (P < 0.04) between the resulting two groups; three of the 16 subjects with high baroreflex sensitivity died compared with nine of the 16 with a baroreflex sensitivity < 1.48 ms/mm Hg. When systemic blood pressure, pulmonary artery pressure, stroke volume index, plasma noradrenaline concentrations, and baroreflex sensitivity were entered into a Cox proportional hazards regression, only systolic blood pressure and plasma noradrenaline values predicted survival (P < 0.001). CONCLUSIONS--Low vagal tone is correlated with a poor prognosis in patients with heart failure. Sympathetic tone measured as plasma noradrenaline concentration also contributed to survival. An additional contribution of vagal tone to survival could not be shown when sympathetic tone was considered simultaneously. This may be due to the inverse relation of sympathetic and parasympathetic tone and to the insensitivity of the multiple regression method to identify additional risk factors in small numbers of patients.
OBJECTIVE: To study the effect of transdermal scopolamine on heart rate variability, baroreflex sensitivity, and exercise performance in patients with heart failure and age matched healthy volunteers. DESIGN: Double blind, randomised, placebo controlled, crossover study. PATIENTS: 16 patients with chronic, stable heart failure due to ischaemic cardiomyopathy (mean (SEM) age 58 (2) years; mean (SEM) radionuclide left ventricular ejection fraction 28 (2)%; New York Heart Association class II-III) and eight age matched healthy controls. INTERVENTION: Transdermal scopolamine (500 micrograms delivered over 72 h) or a placebo patch was administered for 48 h. MAIN OUTCOME MEASURES: Indices of tonic and reflex cardiac vagal activity and exercise performance. RESULTS: In both groups scopolamine produced a reduction in the 24 h average heart rate and an increase in the time domain measures of heart rate variability. Both the incidence and severity of ventricular arrhythmias remained unchanged. Baroreflex sensitivity, evaluated by the phenylephrine technique, increased significantly (P < 0.001) with scopolamine in patients with heart failure (6.22 (2.81) ms/mm Hg) and in healthy volunteers (5.97 (2.20) ms/mm Hg) as did the amplitude of respiratory sinus arrhythmia, computed by autoregressive spectral analysis of 10 min electrocardiographic recordings (319.9 (123.5) and 657.3 (126.6) ms2 respectively, P < 0.001). While exercise performance did not change, heart rate at submaximal exercise was significantly reduced by scopolamine in each group. CONCLUSIONS: In patients with mild to moderate heart failure low doses of scopolamine increased tonic and reflex cardiac vagal activity. This was achieved without affecting exercise tolerance or the incidence and severity of ventricular arrhythmias.
Recent technical advances have renewed interest in device-based therapy for the treatment of drug-resistant hypertension. Findings from recent clinical trials regarding the efficacy of electrical stimulation of the carotid sinus for the treatment of resistant hypertension are reviewed here. The main goal of this article, however, is to summarize the preclinical studies that have provided insight into the mechanisms that account for the chronic blood pressure lowering effects of carotid baroreflex activation. Some of the mechanisms identified were predictable and confirmed by experimentation. Others have been surprising and controversial and resolution will require further investigation. Although feasibility studies have been promising, firm conclusions regarding the value of this device-based therapy for the treatment of resistant hypertension awaits the results of current multicenter trials.
We performed a pilot investigation of the cardiopulmonary baroreflex control of ventricular contractility in two conscious dogs. We specifically measured spontaneous beat-to-beat hemodynamic variability before and after the administration of propranolol. We then identified the transfer function relating beat-to-beat fluctuations in central venous pressure (CVP) to maximal ventricular elastance (Emax) to characterize the cardiopulmonary baroreflex control of ventricular contractility, while accounting for the influences of arterial blood pressure fluctuations on Emax via the arterial baroreflex and heart rate fluctuations on Emax via the force-frequency relation. Our major finding is that the cardiopulmonary baroreflex responds to an increase (decrease) in CVP by increasing (decreasing) Emax via the β-sympathetic nervous system.
In this study we describe a model predicting heart rate regulation during postural change from sitting to standing and during head-up tilt in five healthy elderly adults. The model uses blood pressure as an input to predict baroreflex firing-rate, which in turn is used to predict efferent parasympathetic and sympathetic outflows. The model also includes the combined effects of vestibular and central command stimulation of muscle sympathetic nerve activity, which is increased at the onset of postural change. Concentrations of acetylcholine and noradrenaline, predicted as functions of sympathetic and parasympathetic outflow, are then used to estimate the heart rate response. Dynamics of the heart rate and the baroreflex firing rate are modeled using a system of coupled ordinary delay differential equations with 17 parameters. We have derived sensitivity equations and ranked sensitivities of all parameters with respect to all state variables in our model. Using this model we show that during head-up tilt, the baseline firing-rate is larger than during sit-to-stand and that the combined effect of vestibular and central command stimulation of muscle sympathetic nerve activity is less pronounced during head-up tilt than during sit-to-stand.
Mathematical modeling; Heart rate regulation; Sensitivity analysis
Previous studies in experimental animals indicate an important inhibitory interaction between cardiopulmonary and arterial baroreflexes. In the dog, for example, cardiopulmonary vagal afferents modulate carotid baroreflex control of vascular resistance. On the other hand, previous studies in human subjects have not produced convincing evidence of a specific interaction between these baroreceptor reflexes. The purpose of this study was to determine whether unloading of cardiopulmonary baroreceptors in humans with nonhypotensive lower body negative pressure selectively augments the reflex vasoconstrictor responses to simulated carotid hypotension produced by neck pressure. In nine healthy subjects, we measured forearm vascular responses with plethysmography during lower body negative pressure alone (cardiopulmonary baroreflex), during neck pressure alone (carotid baroreflex), and during concomitant lower body negative pressure and neck pressure (baroreflex interaction). Lower body negative pressure produced a greater than twofold augmentation of the forearm vasoconstrictor response to neck pressure. This increase in resistance was significantly greater (P less than 0.05) than the algebraic sum of the increase in resistance from lower body negative pressure alone plus that from neck pressure alone. In contrast, lower body negative pressure did not potentiate the forearm vasoconstrictor responses either to intra-arterial norepinephrine or to the cold pressor test. Thus, the potentiation of the vasoconstrictor response to neck pressure by lower body negative pressure cannot be explained by augmented reactivity to the neurotransmitter or to a nonspecific augmentation of responses to all reflex vasoconstrictor stimuli. In conclusion, nonhypotensive lower body negative pressure selectively augments carotid baroreflex control of forearm vascular resistance. These experiments demonstrate a specific inhibitory cardiopulmonary-carotid baroreflex interaction in humans.
Baroreflex sensitivity was measured in a group of diabetic patients from the slope of the regression of pulse interval on systolic arterial pressure, during elevation of pressure induced by phenylephrine. The response to Valsalva's manoeuvre was assessed in the same subjects. There was a good correlation between the two tests in the identification of patients with a parasympathetic autonomic disturbance, but measurements of baroreflex sensitivity were more readily quantifiable than were the responses to Valsalva's manoeuvre. Furthermore, baroreflex sensitivity could be measured in patients with sympathetic nervous dysfunction in whom vagal function could not be assessed by means of the Valsalva manoeuvre. Measurement of baroreflex sensitivity is likely to be suitable for longitudinal studies of the progress of diabetic autonomic neuropathy.
We conducted this study in an effort to characterize and understand vagal abnormalities in heart failure patients whose sympathetic activity is known. We measured sympathetic (peroneal nerve muscle sympathetic recordings and antecubital vein plasma norepinephrine levels) and vagal (R-R intervals and their standard deviations) activities in eight heart failure patients and eight age-matched healthy volunteers, before and after parasympathomimetic and parasympatholytic intravenous doses of atropine sulfate. At rest, sympathetic and parasympathetic outflows were related reciprocally: heart failure patients had high sympathetic and low parasympathetic outflows, and healthy subjects had low sympathetic and high parasympathetic outflows. Low dose atropine, which is known to increase the activity of central vagal-cardiac motoneurons, significantly increased R-R intervals in healthy subjects, but did not alter R-R intervals in heart failure patients. Thus, our data document reciprocal supranormal sympathetic and subnormal parasympathetic outflows in heart failure patients and suggest that these abnormalities result in part from abnormalities within the central nervous system.