Outline
Assessment of Human Sympathetic and Parasympathetic Nervous System Activity, 181
Catecholamines, 181
Microneurography, 182
Arterial Baroreflex Sensitivity, 183
Heart Rate Variability, 183
Cross-Spectral Analysis, 184
Tracer Imaging With Catecholamine Analogues, 184
Sympathetic Activation and Parasympathetic Withdrawal in Human Heart Failure, 184
Heart Failure With Reduced Systolic Function, 184
Heart Failure With Preserved Ejection Fraction, 185
Clinical Consequences of Autonomic Imbalance, 185
Mechanisms Disturbing Autonomic Equilibrium, 187
Afferent Influences, 187
Central Integration and Interactions, 193
Efferent Mechanisms, 194
Ganglionic Neurotransmission, 194
Prejunctional Mechanisms and Efferent Sympathovagal Interactions, 194
Therapeutic Implications, 195
Pharmacological Interventions, 195
Nonpharmacological Interventions, 196
Cardiac Resynchronization Therapy, 196
Cardiac Sympathetic Denervation, 196
Carotid Baroreceptor Stimulation, 196
Carotid Body Denervation, 196
Diet, 197
Exercise Training, 197
Positive Airway Pressure, 197
Renal Denervation, 197
Spinal Cord Stimulation, 198
Vagal Nerve Stimulation, 198
Summary and Future Directions, 198
Despite substantive advances in medical and device therapy of heart failure, symptom burden and rates of hospitalization and death remain high. Increased plasma norepinephrine (NE) concentration, its rate of appearance in coronary sinus efflux, and diminished tonic and reflex heart rate modulation were among the first characteristics of heart failure with reduced ejection fraction (HFrEF) that were shown to identify individuals at particular risk of premature death. This chapter, which focuses on the autonomic disturbances of heart failure, will review mechanisms responsible for between-patient variation in their magnitude and the relevance of altered sympathetic and vagal regulation of the heart and circulation to the pathophysiology and management of this condition. The autonomic phenotype of heart failure patients with preserved ejection fraction (HFpEF) is less well characterized ( see also Chapter 11, Chapter 39 ), but extant knowledge will be summarized. Reference to animal models will be limited to concepts as yet unstudied in humans. Disturbances of autonomic thermoregulatory mechanisms in heart failure will not be discussed.
Assessment of Human Sympathetic and Parasympathetic Nervous System Activity
A range of distinct yet complementary invasive and noninvasive methods are available for this purpose ( see also Chapter 42 ). Their application has yielded important insights into mechanisms of autonomic dysregulation in heart failure but, as highlighted in Table 13.1 , each has specific shortcomings as well as utility. None, thus far, has an established role in clinical practice.
| Vagal | Sympathetic | Comment | Research Utility | Clinical Utility | |
|---|---|---|---|---|---|
| Heart rate (HR) at rest | Yes | Yes | + | ++ | |
| HR response to Valsalva maneuver | Yes | Yes | + | + | |
| HRV: time domain | Yes | If with BP | Quantitation of spontaneous blood pressure (BP) → HR relationship to estimate arterial baroreflex regulation of sinoatrial deceleration (vagal) or acceleration (sympathetic) | ++ | +++ |
| HRV: frequency domain | Yes | Yes | High-frequency spectral power reflects vagal HR modulation; spectral power at lower frequencies primarily sympathetic HR modulation; Concurrent BP → HR spectral power transfer function to estimate arterial baroreflex regulation of HR | ++ | + |
| HR responses to drug stimuli | Yes | Yes | Arterial baroreceptor stimulation by phenylephrine elicits immediate vagal response; unloading by vasodilators elicits reflex sympathetic response | +++ | ++ |
| HR response to mechanical stimuli | Yes | Yes | Responses to lower body negative or positive pressure primarily sympathetic; to negative or positive neck pressure primarily vagal | ++ | ? |
| Blood pressure (BP) variability | ? | ? | Time or frequency domain measures not specific to autonomic regulation; Principal utility when evaluated in conjunction with HRV spectrum | ? | ? |
| Arterial/venous norepinephrine (NE) | No | Yes | Global nonspecific index | + | ++ |
| Urinary NE excretion | No | Yes | Global nonspecific index | + | ++ |
| NE spillover to plasma | No | Yes | Total body or organ-specific (heart, kidney, limb muscle, brain) data | +++ | + |
| Sympathetic nerve recordings | No | Yes | Multi-unit or single-unit efferent muscle sympathetic nerve activity (MSNA); Sympathetic reflex response to baroreceptor, chemoreceptor, muscle mechanoreflex and metaboreflex, and other reflex simulation or inhibition can be estimated in time domain; Concurrent BP → MSNA spectral power transfer function estimates arterial baroreflex efferent sympathetic regulation in frequency domain | +++ | + |
| Sympathetic nerve imaging | No | Yes | Nuclear tracers or PET ligands to assess principally cardiac sympathetic innervation and NE uptake | ++ | ++ |
Catecholamines
Venous plasma NE concentrations, acquired at rest, reflect primarily neurotransmitter release from upstream forearm skeletal muscle and provide little insight into the magnitude and duration of other sympathetic nerve or adrenal responses to emotional stimuli or exercise. Moreover, the effect of heart failure or its therapies on neurotransmitter release cannot be deduced definitively solely from changes in plasma catecholamine concentrations. The majority of NE released from sympathetic vesicles is subject to neuronal or extraneuronal uptake; only a small fraction either acts on postjunctional adrenoceptors or appears in plasma. Low cardiac output reduces neuronal and extraneuronal clearance, causing plasma NE concentrations to rise.
The isotopic method addresses such limitations but at increased complexity and cost. Total body NE spillover into plasma is determined from the dilution of tritium-labeled NE during its steady-state infusion in tracer concentrations. If venous effluent from an organ, such as the heart, kidney, or brain, is collected simultaneously with an arterial sample, the difference in tritium-labeled NE between vein and artery can be used to calculate its local extraction (Extr) by neuronal and extraneuronal transport mechanisms. Organ-specific NE spillover (NES) can then be determined by the equation:
NES=[(NEv−NEa)+(NEa×E×tr)]×PF
Microneurography
Multifiber or single-unit recordings from postganglionic nerves supplying muscular or cutaneous vascular beds capture the dynamic nature of sympathetic nerve firing and illustrate its reflex control ( Fig. 13.1 ). Skin sympathetic nerve activity is not modulated by input from high- or low-pressure baroreceptor reflexes. It responds preferentially to alerting stimuli or cold with burst firing occurrence independent of the cardiac cycle, whereas sympathetic discharge directed at skeletal muscle resistance vessels is entrained by input from arterial and cardiopulmonary mechanoreceptors. Muscle sympathetic nerve activity (MSNA) exhibits distinctive pulse-synchronicity, with multiunit bursts appearing 1.1 to 1.3 seconds after the preceding R wave of the electrocardiogram. In healthy subjects, MSNA is activated by reductions in diastolic or cardiac filling pressure, exercise, hypoxia, hypercapnia, and arousal from sleep, and is inhibited by lung inflation. In healthy resting individuals, the magnitude of MSNA correlates with both renal and cardiac NE spillover. Isometric exercise elicits proportionately similar increases in MSNA and cardiac norepinephrine spillover (CNES). In HFrEF, however, such concordance is lost.
Arterial Baroreflex Sensitivity
Because cardiac cycle length responds more rapidly to the release and metabolism of acetylcholine than of NE, the normally brisk sinus node response to an acute perturbation in blood pressure is mediated primarily by arterial baroreceptor reflex-mediated vagal activation or withdrawal. One method of determining the strength, or gain, of reflex vagal heart rate regulation is to quantify the bradycardic response to a bolus of a vasoconstrictor drug, such as phenylephrine, or the tachycardic response to nitroprusside- or nitroglycerin-induced hypotension. Longer (“steady state”) infusions of these vasoactive agents elicit competing sympathetic influence. The use of such drugs for this purpose has several limitations. Nitrate donors affect sino-atrial discharge directly. By causing sustained vasoconstriction or dilation, these drugs mechanically distort baroreceptor nerve endings. Their action is nonspecific, affecting also mechanoreceptors situated in the atria and pulmonary vasculature. Heart rate responses to carotid sinus baroreceptor stimulation by neck suction or unloading by neck pressure have been studied, but aortic arch baroreceptors will elicit counter-regulatory reflex responses to any arterial pressure changes these maneuvers induce.
Algorithms have been developed to track spontaneous fluctuations in blood pressure and heart rate from continuous noninvasive or invasive recordings, and to identify, within such time periods, brief sequences with concordant changes in systolic blood pressure and the subsequent R-R intervals (inverse of heart rate).
Common to such methods is the construction of regression equations relating changes in output (pulse interval; in milliseconds) to changes in input (systolic blood pressure; mm Hg) from antecedent cardiac cycles. The slope of this estimates the gain of the arterial baroreflex control of heart rate. Values obtained by this spontaneous sequence method are qualitatively similar to those derived using vasoactive drugs.
Reflex regulation of central sympathetic outflow can be evaluated similarly by relating changes in MSNA to changes in arterial pressure during graded infusions of pressors and vasodilators, or by constructing, under resting drug-free conditions, regression equations relating spontaneous changes in MSNA to preceding diastolic blood pressures. By their nature, such methods cannot establish if any reduction in the arterial baroreflex gain of either heart rate or sympathetic nerve firing accrues from conduit artery inelasticity, diminished neural transduction of baroreceptor stretch, central neuroplastic adaptation, or efferent nerve dysfunction.
Heart Rate Variability
The half-life of acetylcholine is too brief and its actions too local to permit assay. Instead, tonic vagal heart rate modulation is estimated indirectly, most often and best validated by determining beat-to-beat variation either within the time domain (e.g., the standard deviation of all nonectopic pulse intervals occurring within a specified period) or within the frequency domain, using spectral analysis. A complimentary method, termed heart rate turbulence analysis, evaluates beat-to-beat variations in heart rate that follow a premature ventricular complex. Algorithms commonly employed to derive heart rate power spectra include Fast Fourier Transformation, autoregression, and coarse-graining spectral analysis (CGSA). The complexity of the heart rate variation is such that a range of additional analytic methods, both linear and nonlinear, have been proposed to characterize the information contained more fully, but few have been adopted broadly for research, clinical, or prognostic purposes.
Because atropine abolishes high-frequency (0.15–0.5 Hz) spectral power, oscillations in heart rate within this band have been attributed to parasympathetic activity, with respiration as its primary rhythmic stimulus. Conversely, because maneuvers known to increase central sympathetic outflow, such as standing, tilt, and exercise, increase low-frequency (0.05–0.15 Hz) spectral power, whereas decreases are observed during sleep or after β-blockade or central sympatholysis with clonidine, heart rate fluctuations within these frequencies initially were considered specific representations of sympathetic neural modulation. However, parasympathetic oscillatory input also influences power spectral frequencies below 0.15 Hz. For this reason, a (contentious) ratio between low- and high-frequency power has been proposed as an estimate of “sympathovagal balance.”
Oscillatory autonomic contributions to heart rate variability are superimposed on a broadband nonharmonic fractal signal, most prominent between 0.00003 and 0.1 Hz (i.e., at very low and low frequencies). Using CGSA, this nonharmonic power can be quantified by plotting the log of spectral power as a function of the log of frequency (l/f β plot) then extracted, yielding more precise estimates of residual harmonic contributions to low- and high-frequency (0.15–0.50 Hz) power. For this reason, CGSA becomes particularly useful when evaluating autonomic contributions to heart rate variability in patients with heart failure, whose harmonic spectral power is both concentrated within the very low- and low-frequency ranges and are markedly diminished relative to the nonharmonic signal.
Frequency domain analysis should be appreciated primarily for the insight it allows into mechanisms responsible for short- and long-term heart rate oscillations and for its prognostic value in populations with cardiovascular disease. At best, it provides an estimate of the extent to which parasympathetic and cardiac sympathetic discharge and neurotransmitter release modulate heart rate within these specific frequency bands, but not of the intensity of such neural discharge or the magnitude of sympathetic outflow directed elsewhere, for example, to the ventricle, kidney, or regional vascular beds.
Cross-Spectral Analysis
Algorithms used to derive power spectra for heart rate can also be applied to blood pressure, respiratory signals, and MSNA. Cross-spectral analysis between two such variables can establish their coherence, the influence of input on output, and the phase delay between these signals. For example, the gain of the transfer function between systolic blood pressure (input) and pulse interval (output) oscillations within the low- or high-frequency regions (α coefficient) estimates arterial baroreceptor reflex control of heart rate (although agreement with values obtained using vasoactive drug methods is poor), and the gain of the transfer function between blood pressure (input) and MSNA (output) estimates arterial baroreflex modulation of central sympathetic outflow.
Tracer Imaging With Catecholamine Analogues
Nuclear iodine-123 metaiodobenzylguanidine ( 123 I-MIBG) or 11 C-metahydroxyephredrine ( 11 C-HED) positron emission tomographic (PET) imaging infer the integrity and homogeneity of cardiac sympathetic innervation and NE transport and indirectly, by calculating tracer uptake and washout, an approximation of its neural release. PET imaging provides superior spatial resolution. PET tracer analogues of β-adreno-, muscarinic, and nicotinic receptors are being evaluated for potential clinical application.
Sympathetic Activation and Parasympathetic Withdrawal in Human Heart Failure (see also Chapter 42 , Chapter 6 )
Heart Failure With Reduced Systolic Function
The onset of HFrEF is characterized by a cardiac-specific autonomic “signature,” with the loss of tonic and reflex vagal heart rate modulation and selective increase in cardiac NE spillover; total body or renal NE spillover and MSNA are not elevated. Indeed, in many patients with asymptomatic or mild to moderate symptomatic HFrEF, plasma NE concentrations and sympathetic nerve firing rates are similar to those of age-matched healthy subjects ( Figs. 13.2 and 13.3 ).
Sympathetic Activation
Relative to the unaffected population, cohort-mean plasma NE concentration increases as asymptomatic HFrEF progresses to overt congestion. In more advanced HFrEF, heightened adrenal sympathetic nerve activity stimulates medullary epinephrine and NE release into plasma.
In health, approximately 25% of total body NE spillover arises from the kidney and about 2% from the heart. In patients with left ventricular dysfunction and congestion, studied before the advent of contemporary therapies, calculated NE clearance was one-third lower, and total body NE spillover double that of control subjects. Approximately 60% of this increase resulted from a 5- to 20-fold elevation in cardiac and a 2- to 3-fold greater renal NE spillover into plasma. Mental stress and cycling exercise elicit further increases in cardiac neurotransmitter release, indicating preservation of myocardial adrenergic reserve. Preferential activation of cardiac sympathetic nerve traffic also is evident in the paced-ovine HFrEF model.
Microneurographic recordings provided definitive evidence that the majority of this increase in total body NE spillover can be attributed to greater central sympathetic outflow rather than altered neurotransmitter reuptake or clearance. Single-unit recordings from patients with HFrEF in sinus rhythm display both higher firing probability and recruitment of previously silent efferent neurons, but no increase in the proportion of cardiac cycles associated with multiple discharges; whereas those who develop atrial fibrillation exhibit a significantly greater incidence of multiple firing, which would evoke more NE release and consequently greater vasoconstriction. In contrast, sympathetic discharge to skin is not increased.
There is little or no correlation, in patients with HFrEF, between left ventricular ejection fraction (LVEF) and MSNA burst incidence. Indeed, if oxygen uptake at maximum exercise capacity (peak VO 2 )is relatively preserved, resting MSNA can remain within the range of age-matched control subjects, despite profound left ventricular systolic dysfunction. However, their sympathoneural response to exercise is exaggerated ( Fig. 13.4 ).
In the frequency domain, heart failure and age-matched control subjects display similar total MSNA power, harmonic power, nonharmonic power between 0 and 0.5 Hz, and spectral density within the very low (0–0.05 Hz) and high (0.15–0.5 Hz) frequency bands. However, low-frequency oscillations in the mean voltage neurogram are diminished markedly or absent, despite near-maximal sympathetic burst incidence, indicating loss of central or reflex modulation of efferent sympathetic traffic proportional to heart failure severity.
Parasympathetic Withdrawal
Responses to infusions of both phenylephrine and sodium nitroprusside (expressed either as msec/mm Hg or as beats/min/mm Hg) and to carotid sinus baroreceptor stimulation by neck suction diminish in proportion to the resting heart rate, the left ventricular systolic dysfunction, the New York Heart Association (NYHA) functional symptom class, mitral regurgitation severity, blood urea nitrogen, and the standard deviation of all normal-to-normal pulse intervals (SDNN), a time domain index of tonic vagal heart rate modulation.
In NYHA Class II patients, the low-frequency component of the heart rate power spectrum predominates, but as heart failure progresses, saturation or downregulation of cardiac postjunctional β-adrenoceptors and impairment of postsynaptic β-adrenoreceptor signal transduction decreases sinoatrial responsiveness to neurally released NE. There is less variation in the heart rate. Low-frequency spectral power is attenuated more often than augmented and relates inversely rather than directly to both the discharge frequency of muscle sympathetic nerves or the cardiac NE spillover.
Heart Failure With Preserved Ejection Fraction (see also Chapter 11 , Chapter 39 )
Our understanding of this phenotype would benefit from more extensive and rigorous investigation. To date, HFpEF cohort sizes have been small, the definitions of HFpEF inconsistent (some conflate hypertension plus impaired relaxation with HFpEF), the quality of studies published often have been suboptimal, and few have considered the confounding excitatory influences of age and left ventricular hypertrophy, with blunted stimulation of inhibitory ventricular afferents, on sympathetic activity. Although long-standing hypertension is a well-recognized risk factor for HFpEF and itself is often accompanied by chronic sympathetic excitation, no prospective studies have as yet determined whether such long-term autonomic imbalance increases the risk of incident HFrEF.
In the Studies of Left Ventricular Dysfunction (SOLVD) registry, mean plasma NE concentrations of patients with pulmonary congestion and LVEF greater than 45% were not increased. In general, heart rate variability is diminished, the sympathetic nervous system appears less activated than in patients with HFrEF, and cardiac NE transport function, as assessed using 123 I-MIBG imaging, not as defective. A series of 15 patients with restrictive cardiomyopathy due to endomyocardial fibrosis and a LVEF greater than 50 who were studied at least 6 months after endocardial resection surgery described increases in MSNA burst frequency and incidence, sympathetic contributions to heart rate variation, and decreases in indices of tonic and reflex vagal heart rate modulation that were comparable to those observed concurrently in a matched cohort of patients with dilated cardiomyopathy. The recent discovery of an excitatory reflex engaged by high atrial pressure (vide infra) identifies a potential causal mechanism that could elicit sympathoexcitation in both HFrEF and HFpEF.
Clinical Consequences of Autonomic Imbalance
Cardiac
Fractional shortening is diminished in mice with defective vesicular acetylcholine transport; deficient neurotransmitter release is accompanied by more extensive fibrosis in response to exogenous angiotensin II. The impact of impaired vagal tone in human heart failure on heart rate modulation, inflammatory pathways, the regulation of left ventricular performance, and the progression of HFrEF have been reviewed in detail.
The combination of early vagal withdrawal plus a selective increase in cardiac NE spillover constitute adaptive autonomic responses, which are engaged to maintain peripheral tissue perfusion in the face of compromised ventricular performance. However, once congestion becomes manifest, the heart is subject to the greatest proportional increase in regional NE spillover, and thus, the failing heart is the organ exposed for the longest duration to the greatest magnitude of sympathetic activation. The direct adverse myocardial consequences of such intense cardiac adrenergic drive, which are reviewed in Chapter 6, Chapter 10 , include: an increase in heart rate; induction of myocyte necrosis and apoptosis; fibrosis; decreased β 1 -adrenergic receptor density; diminished β 1 -adrenoceptor responsiveness to catecholamines and altered β 1 -adrenergic receptor signal transduction with upregulation of G-protein-coupled receptor kinase 2; defective calcium regulation by the sarcoplasmic reticulum; induction of proinflammatory cytokine expression, greater oxidative stress; increased muscarinic M2 receptor expression; destruction of sympathetic nerve terminals; and depletion of myocardial NE content—all of which contribute to the relentless progression of cardiac dysfunction. Nonuniform NE depletion and sympathetic denervation disturb the temporal coordination of right and left ventricular contraction and relaxation and alter the dispersion of refractoriness, leading to ventricular dyssynergy and promoting arrhythmogenesis. In human experiments, muscarinic stimulation was found to exert a negative lusitropic effect and to antagonize the effect of beta-adrenergic stimulation in patients with HFrEF.
Peripheral
Sympathetically mediated constriction of capacitance and resistance vessels increases both preload and afterload; diminished conduit artery compliance impairs ventricular-vascular coupling. Stimulation of renal sympathetic nerves activates the renin-angiotensin-aldosterone axis ( see also Chapter 15 ), promotes tubular absorption of sodium and water, increases renal vascular resistance, and blunts the renal responsiveness to atrial natriuretic peptide. Angiotensin II–mediated efferent arteriolar vasoconstriction and atrial natriuretic peptide–mediated afferent arteriolar vasodilation strive to maintain glomerular filtration in the face of renal hypoperfusion.
Exercise
Exercise constrained by dyspnea or fatigue is a common heart failure symptom indicative of decreased oxygen delivery (central) or utilization (peripheral). Limiting central mechanisms include heart failure–associated reductions in ventilation, diffusion, chronotropic competence, and cardiac output. Also, β 2 -adrenoceptor polymorphisms associated with impaired exercise performance have been identified. Proposed peripheral limiting mechanisms include sarcopenia, impaired mitochondrial respiration, and diminished oxygen transport due to augmented neurogenic vasoconstriction. In heart failure patients (but not in healthy age-matched controls) maximal oxygen uptake (peak VO 2 ) during exercise correlates inversely to resting MSNA but not cardiac NE spillover.
In recent experiments, fibular MSNA was recorded continuously while subjects performed contralateral one-leg cycling without and against resistance. In contrast to healthy controls, whose burst incidence fell, exercise increased MSNA in those with HFrEF; overall there was a significant inverse relationship between the maximum MSNA elicited by one-leg exercise and subjects’ peak VO 2 ( Fig. 13.5 ). Sympathetically mediated reductions in blood flow below levels required to meet local metabolic demands during exercise could attenuate endothelium-mediated vasodilatation and stimulate metaboreceptor afferents in skeletal muscle. Consequent reflexive increases in central sympathetic outflow could further diminish exercise capacity.
Mortality
Before widespread clinical adoption of angiotensin-converting enzyme inhibitors and β-adrenoceptor antagonists, the prognostic weight of a single resting plasma NE concentration was superior to that of heart rate, plasma renin activity, serum sodium or stroke index; if this exceeded 800 pg/mL, life expectancy was less than 1 year. In the pre β-blocker era, survival of transplant candidates was inversely proportional to cardiac NE spillover. In those treated chronically with β-adrenoceptor antagonists, renal has proven superior to cardiac NE spillover for the prediction of death or transplantation. However, cardiac NE content can also predict the mode of death: in a cohort of 116 patients (mean LVEF, 19%), followed on average for 18 months, the risk of sudden death was two- to threefold greater if estimated cardiac NE stores and cardiac NE spillover exceeded median values. By contrast, individuals with depleted myocardial NE stores and high cardiac NE spillover (reflecting chronically increased neurotransmitter turnover and reduced reuptake and storage) had a two- to fourfold greater risk of death from progressive pump failure.
Each of MSNA, diminished baroreflex sensitivity, loss of heart rate variability, abnormal heart rate turbulence, and augmented chemosensitivity to both hypoxia and hypercapnia have been linked to premature death, whether due to progressive myocardial failure or arrhythmia. An attenuated reflex heart rate response to phenylephrine has similar prognostic implications in patients treated or not treated with beta-adrenoceptor antagonists. Loss of both complexity in the heart rate signal, as estimated by nonharmonic power-law regression parameters, and low-frequency harmonic power, appears to be the most sensitive frequency domain predictors of sudden death. Abnormal 11 C-HED or 123 I-MIBG uptake by ventricular sympathetic nerves can also identify HFrEF patients at increased risk of sudden cardiac arrest or premature death ( Fig. 13.6 ).
Mechanisms Disturbing Autonomic Equilibrium
Alterations in the neurogenic control of the circulation stimulated by the onset and progression of heart failure can arise from one or more regulatory components, such as those participating in the generation and conveyance of inhibitory and excitatory input to brainstem vasomotor neurons, the cortical modulation of central nervous system integration and catecholamine turnover, or the determination of release and receptor responsiveness to neurotransmitters ( Fig. 13.7 ).
Afferent Influences
In healthy resting subjects, the reflex effect of sympathoinhibitory input from carotid sinus and aortic arch “arterial high-pressure” and the cardiopulmonary “low-pressure” mechanoreceptors outweighs any excitatory contributions from arterial chemoreceptors, muscle mechanoreceptors or metaboreceptors, or renal afferent nerves. The efferent vagal component of the baroreceptor heart rate reflex is also subject to arterial baroreceptor afferent input. Consequently, healthy resting individuals display low sympathetic nerve firing and high heart rate variability. Reflex vagal and sympathoneural responses to acute perturbations in blood pressure are brisk.
Arterial Baroreceptor Reflexes
Arterial baroreceptor nerve discharge is activated by the pressure wave of systole and diminishes or falls silent during diastole. Systolic stimulation of baroreceptor discharge increases parasympathetic and decreases efferent sympathetic outflow reflexively. When arterial pressure falls below mechanoreceptor stimulation threshold, release of baroreceptor restraint on sympathetic motor neurons permits efferent sympathetic fiber discharge.
Because arterial baroreceptor modulation of heart rate is diminished in patients with HFrEF and baroreceptor afferent nerve discharge is less responsive to changes in local distending pressure in experimental models of ventricular systolic dysfunction, it had been concluded that the arterial baroreflex regulation of vagal and sympathetic outflow in human HFrEF are impaired in parallel. However, assessment of the baroreceptor–heart rate reflex in humans relies upon the indirect estimation of sinoatrial responsiveness to two distinct and differentially regulated autonomic inputs. In experimental canine heart failure, it is impaired vagal ganglionic neurotransmission that diminishes parasympathetic responsiveness to baroreceptor stimulation; sinoatrial acetylcholinesterase is reduced, and muscarinic receptors are upregulated. By contrast, cardiac-specific sympathetic neural modulation is attenuated by downregulation or desensitization of β-adrenoceptors rendering the sinoatrial node less responsive to reflexively elicited changes in neurally released NE. In patients with HFrEF the variability and complexity of heart rate are attenuated, but the variability of blood pressure is similar to that of age-matched healthy subjects.
In patients with HFrEF, reports of significant inverse relationships between stroke work index and MSNA and between cardiac output and cardiac NE spillover suggest the arterial baroreflex regulation of efferent sympathetic discharge responds appropriately to the altered hemodynamics of heart failure. Two challenges to any interpretation of experiments in HFrEF involving vasoactive drugs are: (1) muscle sympathetic burst firing is pulse synchronous, with an incidence (i.e., bursts/100 cardiac cycles) approaching 100%; and (2) heart rate responses to arterial baroreceptor perturbation by phenylephrine or nitroprusside are markedly attenuated. Consequently, there is little opportunity, arithmetically, to modify a cardiac frequency–dependent multiunit representation of sympathetic nerve firing. If the reported effect of these drug interventions on MSNA burst frequency is re-expressed relative to cardiac frequency (or as changes in absolute units, rather than as a percentage of baseline values), then the gain of the arterial baroreflex regulation of MSNA is not appreciably impaired.
Several lines of evidence, obtained using different approaches and summarized in Table 13.2 , reveal relatively intact arterial baroreflex modulation of efferent sympathetic outflow in human heart failure. An instructive illustration is the rapidity with which MSNA responds to the initiation and termination of ventricular bigeminy (see Fig. 13.1 ). Further evidence for preserved arterial baroreflex function is provided by experimental heart failure models. Brandle et al., who found no differences in the time course of changes in hemodynamics and plasma NE concentrations during the development of heart failure in dogs with and without sinoaortic baroreceptor denervation, concluded that impairment of the arterial baroreflex could not be responsible for sustaining the increase in sympathetic outflow observed in this experimental model. In sheep, cardiac sympathetic nerve activity (CSNA), recorded directly, was significantly increased and the baroreceptor regulation of heart rate was profoundly impaired, but the arterial baroreflex control of both CSNA and renal sympathetic nerve traffic did not differ from that of control animals.
| Concept | Observation |
|---|---|
| MSNA pulse synchronicity lost after sinoaortic baroreceptor denervation | Pulse synchronicity preserved, even in end-stage HF |
| Pause with decay in DBP after premature beat increases reflexively MSNA burst amplitude, duration, and area; rise in DBP after postextrasystolic beat inhibits MSNA | Extrasystolic augmentation of MSNA amplitude, duration and area and postextrasystolic suppression replicated in HF; duration or suppression proportional to magnitude of diastolic overshoot |
| MSNA bursts track previous DBP with 1.2–1.3 s lag | Synchronization of sympathetic neural alternans with pulsus alternans |
| Frequency domain estimate of arterial BR gain derived by cross-spectral analysis with BP oscillations as stimulus and MSNA oscillations as response | Transfer function gain in HF and healthy subjects similar across all frequency bands; calculated gain highest in high-frequency range |
| Arterial BR unloading with SNP elicits reflex increase in TNES | Similar reflex increase in TNES in HF and healthy subjects |
| LV pacing in HF increases DBP | Acute inverse DBP–MSNA relationship immediately from RV to LV pacing |
| Muller maneuver increases acutely intrathoracic aortic and LV transmural pressures | MSNA inhibited similarly in HF and control subjects |
Human cardiac and renal efferent responses to arterial baroreceptor unloading are dissimilar. In one study, nitroprusside-induced hypotension (to offload low- as well as high-pressure mechanoreceptors) elicited, as anticipated, an 85% increase in renal NE spillover in healthy control subjects, but no net change in heart failure subjects (albeit from a nearly threefold higher baseline). In a subsequent experiment, a hypotensive dose of nitroglycerin lowered renal NE spillover in individuals with systolic dysfunction but not in healthy control subjects. These data point to the emergence, in HFrEF, of an important inhibitory effect of cardiopulmonary baroreceptor unloading on the arterial baroreflex regulation of renal NE spillover.
Cardiopulmonary Reflexes
In healthy subjects, reflexes arising from afferent nerve endings situated in the heart and pulmonary veins elicit sympathoinhibition and forearm vasodilation when stimulated by increases in cardiac filling pressure or volume, or by inotropic force. Conversely, phlebotomy or nonhypotensive lower body negative pressure (LBNP) provoke sympathoexcitation. After observing similar gains in the arterial baroreflex control of MSNA in healthy and HFrEF subjects, but in the latter attenuated responses to stimuli that increased or decreased cardiac filling pressure without affecting systemic blood pressure, Dibner-Dunlap and colleagues concluded that the cardiopulmonary, rather than the arterial, baroreflex was impaired in human heart failure (see Fig. 13.7 ). Subsequently, nonhypotensive LBNP was shown to significantly increase total body NE spillover in control subjects with normal LVEF but not in individuals with impaired ventricular systolic function. In a more recent study, low-dose nitroglycerin selectively reduced pulmonary artery pressures, yet did not alter renal NE spillover in either HFrEF or healthy subjects.
However, such selective impairment of inhibitory cardiopulmonary reflex responses does not explain the direct correlations seen, in more advanced heart failure, between MSNA and pulmonary artery or capillary wedge pressure, nor accounts for the selective augmentation in cardiac NE spillover in mild to moderate heart failure, which is apparent before any concomitant increase in total body or renal NE spillover or in MSNA. Those observations suggest that a second, independent and cardiac-specific sympathoexcitatory reflex, responsive to pathological increases in cardiopulmonary blood volume or pressure, may become operative in human heart failure. Indeed, in dogs with pacing-induced congestion, Wang and Zucker documented sensitization of cardiac sympathetic afferents responsive to chemical stimulation; this reflex was potentiated by acute volume expansion.
Several observations in individuals with HFrEF support the concept of activation, by increased filling pressure, of a cardiac-specific sympathoexcitatory reflex. These include detection of a positive relationship between pulmonary capillary wedge pressure and cardiac NE spillover and reductions in cardiac NE spillover when atrial, pulmonary, and systemic arterial pressures are reduced concomitantly by sodium nitroprusside infusion, or when positive airway pressure is applied acutely to reduce atrial and pulmonary venous transmural pressure (consequent reductions in intrathoracic aortic and left ventricular transmural pressure should increase sympathetic outflow reflexively). Importantly, nonhypotensive LBNP, applied to reduce selectively cardiac filling and pulmonary pressures, decreases cardiac NE spillover in HFrEF, but not in control subjects with normal left ventricular systolic function ( Fig. 13.8 ). Conversely, increasing the intensity of LBNP to induce systemic hypotension elicits a significant increase in cardiac NE spillover in control subjects only (see Fig. 13.8 ). The most plausible interpretation of these findings is that a physiological increase in cardiac NE spillover evoked reflexively by the unloading of high- and low-pressure mechanoreceptors when both atrial and systemic blood pressures are reduced is countered, in HFrEF, by concurrent withdrawal of a second stimulus arising from myelinated mechanoreceptor afferents, situated within the venous–atrial junctions that reflexively and selectively excite cardiac adrenergic drive when distended (see Fig. 13.7 ).
