Advances in medical and device therapies are opening new frontiers to the management of HF. We are moving from the end organ therapy into the autonomic nervous system control
Edoardo Gronda MD FESC FANMCO
Department of Cardiovascular Medicine
Sesto San Giovanni, Italy
Emilio Vanoli MD FESC
Department of Cardiovascular Medicine
Sesto San Giovanni, Italy;
Department of Molecular Medicine,University of Pavia, Pavia, Italy
Despite the impressive decline in the overall mortality achieved in the last three decades, heart failure (HF) remains a prominent cause of death and of hospital resource use in the western world. Since the introduction of angiotensin II converting inhibitors and beta-blockers, HF mortality dropped, on the average, by 44%. Adding appropriate use of device therapy such as implantable cardiac defibrillators and cardiac resynchronisation pacing decreased overall mortality by almost a further 20%, allowing an impressive global decrease of 60%.1 This is a result that remains unmatched in the management of most common chronic disorders that affect the national health system of economically advanced countries.
Despite this good news, recent large and long-term studies on HF patients who received the state-of-the-art device therapy in addition to optimal pharmacological treatment, revealed a prevailing mortality after about 15 years.2 Most of the reasons for such disappointing data are due to the complex pathophysiological HF mechanisms that are closely related to the mutual cardiovascular organs relationship.
Contemporary HF state-of-the-art therapy most frequently allows only a partial reversion of the clinical condition and some variable degree of cardiac dysfunction remains in place. In other words, state-of-the-art therapy is most often applied when the disease process has already caused irreversible damage and it can merely support the patient in living with the disease rather than treat it.
Indeed, cardiac dysfunction itself maintains and exacerbates, in the long run, the complex interplay of several neuro-hormonal mechanisms specifically driven by peripheral vessels and the kidneys to enhance cardiac autonomic activity in order to restore local perfusion by augmenting cardiac output.
The most prominent among these neuro-hormonal mechanisms is the adrenergic (or sympathetic) nervous system, whose activity and outflow is boosted with an immediate haemodynamic positive effect, mediated by local specific receptors stimulation that can work for a temporary need. This is at the cost of an enhanced arrhythmic risk. However, if dysfunction continues over time, increased persistent activation of receptors in end organs exceeds appropriate range, which switches the response from a positive compensatory effect to a damaging action that progressively worsens overall organ function.
The critical message is that any single organ damage will lead to a global autonomic response that, in turn, may have detrimental consequences on the all other end organs by enhancing sympathetic afferent excitatory information. As matter of fact, an excessive sympathetic response to an asymptomatic cardiac dysfunction may cause major activation of neuro-hormonal responses involving the kidney with obvious detrimental consequences. The final clinical picture will then reflect the prevailing end organ damage so that, for instance, a concealed cardiac dysfunction might eventually result in a significant kidney disease.
Of note, the increased sympathetic activation is coupled with a concomitant, proportional decrease of the counteracting vagus nerve activity. This is a pivotal point in understanding the complex interplay of neuro-hormonal rearrangement we learned since the beta-blocker saga: the autonomic disarray must be stopped and reverted, if possible.
It is also important to note that other non-cardiovascular factors, like the glycaemic hammer or insulin resistance, can elicit high sympathetic reflexes leading to progression in damaging all cardiovascular end organs, running further progression of HF haemodynamic derangement.
It is worth noting that any neuro-hormonal drug, although beneficial, as any unnatural paraphernalia, has potential important drawbacks: beta-blockers may enhance ischaemic stroke incidence in hypertensive and in HF patients.3
Recently, renin inhibition resulted in concerning results in diabetic patients,4 without forgetting moxonidine, a central pharmacological inhibitor of the autonomic system, which has negative consequences on mortality in treated HF patients.5 Based on this evidence, it is noteworthy that, in normal physiology, the autonomic system is acting by balanced activation of excitatory, pro-inflammatory sympathetic nerve action, mostly driven by catecholamine release and by the tapering of sympathetic drive run by synergic vagal activation that aims to rest organ function and to repair structural damage following over-excitation.
This crucial balancing action on the two components of the autonomic system is driven by the interaction between reflexes of cardiac origin and the cardio-circulatory control exerted by the baroreceptor system.6
The baroreceptors (also called pressoreceptor) are specific sensory nerve endings placed in the heart at the junction between left atrium wall and pulmonary veins and in the vena cava wall at the auricle junction, in the carotid sinus and in aortic arch. These sensors are sensitive to stretching of the wall due to increased pressure from within and they operate as the peripheral receptor providing information for the central mechanisms that reduce the inner pressure.
The baroreceptors serve as the primary regulators of cardiovascular function through modulation of autonomic nerve activity. Signalling from baroreceptors interacts with global afferent information coming from the heart and the periphery and is integrated in the medulla with the nucleus of the solitary tract serving as a central relay station.
Loss of baroreflex sensitivity in HF allows excess sympathetic activation to go unchecked. In the absence of inhibitory mechanisms, excitatory cardio-cardiac reflexes, first described 40 years ago7 promote remodelling and can induce sudden death.
Cumulated evidence has addressed autonomic dysfunction is a central component of the cardiac function impairment, as behaviour of all organ systems involved in HF is modulated by sympathetic and/or parasympathetic activity and their neuro-hormonal effects. Rather than a generalised state of chronic sympathetic excitation and parasympathetic withdrawal, it has become clear that HF is characterised by organ-specific changes in efferent autonomic activity, which continues to allow demand-based adaptation of outflow, although at a reduced gain.8 In this context, therapies which activate the baroreflex would be expected to modulate the input of excitatory sympathetic information originating from the damaged heart and would therefore operate physiologically in restoring autonomic balance.
Baroreceptors: a therapeutic gate into the CNS
By considering the peculiar nature of a specific baro-stimulatory action in the context of the intricate milieu of the HF syndrome environment, device therapy seems the only solution that can provide specific pathophysiologic therapies and does not create systemic side effects. More over, direct baroreceptor stimulation takes a fundamentally different approach targeting an afferent pathway, which corrects both the autonomic and the subsequent haemodynamic dysfunction characteristic of HF.
Based on these observations we recently performed a mechanistic pilot study in 11 advanced HF, NYHA f. Cl. III patients, with reduced left ventricular ejection fraction (HFrEF) of 31% (±7.3).9 In the study population we documented an elevated sympathetic activity (Muscle Sympathetic Nerve Activity, MSNA) despite optimised medical therapy coupling functional limitation with moderately impaired renal function.
After autonomic modulation via baroreflex activation therapy (BAT) using chronic electrical stimulation of the carotid baroreceptors by application of the Barostim device (CVRx, Inc. Minneapolis), a rapid sustained decrease in MSNA was observed with persistence, throughout six months observation, (from to bursts/minute). This was coupled with restoration of baroreflex sensitivity (arbitrary units 0.11±0.13 versus 1.26±0.16, p<0.001). Of note, in the 12 months follow-up, such responses were associated with an impressive decreases in the number and length of HF hospitalisations in comparison to the previous 12 months medical history (125 versus 18 days spent in hospital). Kidney function was stabilised with a trend toward improvement, while mean heart rate, blood pressure and medical therapy remained unchanged.
Impressively, in the extended 21 months follow-up, by repeating MSNA assessment in the nine surviving patients, sympathetic activation and baroreflex sensitivity was seen to be unchanged in comparison to six months control (data on file).
These data consistently correlated with a substantially decreased hospitalisation rate during BAT. In the year prior to implant, patients accumulated 155 days, whereas with BAT, total days through the six months and long-term follow-up were seven and 45, respectively. The hospitalisation rate, measured as days per month, decreased from 1.44±1.3 pre-implant to 0.13±0.33 in the six months post-activation and 0.27±0.44 between six and 21 months (p<0.01). In general, hospitalisations with BAT were much less frequent, with the highest rate observed between approximately six and 18 months post-activation.
This proof of concept study addresses a long-term inhibition of the sympathetic hyperactivity underlying HF, particularly in the lethal phenotype HFrEF. In association with its effects on an important aspect of HFrEF pathophysiology, BAT produced major clinical benefits in HFrEF. When it is administered along with optimised medical therapy it appears to last for at least 21 months. The staying power of BAT in terms of consistent clinical benefit is also noteworthy as the clinical impact of the inhibitory effects of chronic BAT on cardiac sympathetic outflow is not limited to the HF arena but extends to the hypertensive population where efficacy of BAT was documented first. Such long-term benefits of therapy reflect what has been shown in pooled data from multicentre trials in hypertensive patients. Specifically, of the 322 patients implanted, 76% (n=245) qualified as clinically significant responders. Among long-term responders receiving BAT, the mean blood pressure drop was 35/16mmHg. This blood pressure reduction was maintained over long-term follow-up of 22–53 months.10
The mechanistic HF study, together with the novel pathophysiological information on MSNA longstanding action, brings some intriguing data on clinical outcome of BAT treated patients: namely a major sparing in hospital resource utilisation suggesting a cause–effect relationship as prior to enrolment in the study, all patients were suffering a rapid progression of HFrEF.11
Normalised sympathetic and parasympathetic activity implies inhibition of catecholamine toxicity at the source rather than blockade at the end organ level, thereby inhibiting release of other neurotransmitters including substance P and neuropeptide Y that also contribute to disease progression.12 Moreover, the inhibitory effects of vagal activation on pro-inflammatory interleukins are well established.13
In the advanced HF stage, organ damage is irreversible but, evidently, autonomic balance restoration allows a dramatic and sustained attenuation of central and peripheral disease progression, with a positive recovery of overall performance even in spite of appreciable ejection fraction increase.
It is also important to recognise that BAT is advantageous in HFrEF management as it also avoids limitations encountered with medical therapies including adverse drug interaction, patient compliance, therapy intolerance or responsiveness limited by variation in genotype.
Considering the relative simplicity of the implant procedure and the excellent safety profile (only one adverse event in 11 implants performed in the HF study population that recovered without consequence), the value of BAT appears as an important piece of evidence covering the gap between understanding and treating the pathophysiology of HF.
- Mann DL, Bristow MR. Mechanisms and models in heart failure The biomechanical model and beyond. Circulation 2005;111:2837–49.
- Buber J et al. Clinical course and outcome of patients enrolled in US and non-US centres in MADIT-CRT. Eur Heart J 2011;32:2697–704.
- No authors listed. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13.
- Maggioni AP et al. Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial. Eur Heart J 2013;34:3117–31.
- Floras JS. The “unsympathetic” nervous system of heart failure. Circulation 2002;105:1753–5.
- A. Malliani A, Recordati G, Schwartz PJ. Nervous activity of afferent cardiac sympathetic fibres with atrial and ventricular endings. J Physiol 1973;229:457–69.
- Schwartz PJ et al. A cardiocardiac sympathovagal reflex in the cat. Circ Res 1973;32:215–20.
- Fu Q et al. Persistent sympathetic activation during chronic antihypertensive therapy: a potential mechanism for long term morbidity? Hypertension 2005;45:513–21.
- Gronda E et al. Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study. Eur J Heart Fail 2014;16:977–83.
- Bisognano JD et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension. Results from the double-blind, randomized, placebo-controlled Rheos Pivotal Trial. J Am Coll Cardiol 2011;58:765–73.
- Swedberg K et al. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 1990;82:1730–6.
- Brunner-La Rocca HP et al. Effect of cardiac sympathetic nervous activity on mode of death in congestive heart failure. Eur Heart J 2001;22:1136–43.
- Tracey KJ. The inflammatory reflex. Nature 2002;420:853–9.