Neuromodulation in Heart Failure

Anatomy of the Autonomic Nervous System

The principle regions of ANS control are located within the medulla oblongata, which in turn is subject to control by the hypothalamus and the cerebral cortex. The medulla receives afferent fibers from the glossopharyngeal nerve and the vagus nerve ( Fig. 42.1 ), which terminates in the nucleus tractus solitarius (NTS). From here, neurons project to the rostral ventrolateral medulla (RVLM) and the nucleus ambiguous in the brainstem. Sympathetic preganglionic neurons of the intermediolateral cell column of the spinal cord arise in the RVLM and may have either inhibitory or excitatory effects on the sympathetic preganglionic neurons. The balance of stimulation in the fibers descending from the medulla and local spinal inputs determines the nature of the effect of the activity of the sympathetic preganglionic neurons. Sympathetic preganglionic neurons travel via the ventral roots of the spinal cord to the sympathetic chain, where most synapse with the cell bodies of the sympathetic postganglionic fibers. Some extend further and may terminate directly in target organs, such as the adrenal medulla. Axons from postganglionic cell bodies are nonmyelinated and travel in mixed peripheral nerves where they terminate in the outer parts of the tunica media. Arteries and larger arterioles have a rich supply of sympathetic vasoconstrictor fibers, with less dense innervation of veins and smaller arterioles. Noradrenaline released by sympathetic postganglionic neurons act on alpha-adrenoreceptors, leading to vasoconstriction ( see also Chapter 6, Chapter 13 ). Cardiac sympathetic fibers travel subepicardially along the main coronary arteries.

Parasympathetic preganglionic fibers leave the CNS via the cranial and sacral spinal outflows. In comparison with the SNS, they terminate on the postganglionic neurons situated in the end-organs themselves, such as the heart. Below the atrioventricular groove, the parasympathetic fibers penetrate the myocardium and are subendocardial in their distribution. There is a greater density of parasympathetic innervation in the atria compared with the ventricles.

Cardiac Reflexes

Sympathetic outflow to the heart and peripheral tissues is regulated by cardiovascular reflexes. Increasingly these reflexes have served as the primary targets for ANS modulation as a therapy for the treatment of heart failure. Autonomic fibers carry afferent arms of these reflexes, whereas efferent limbs are formed by either somatic or autonomic nerves.

Baroreceptors are high pressure mechanoreceptors located in high pressure areas, such as the wall of the aortic arch and the carotid body (see Fig. 42.1 ). Afferent fibers of these receptors relay information regarding arterial pressure to the brainstem, where they terminate in the NTS. Afferents from the aortic arch travel within the vagus, whereas those from the carotid sinus are carried initially by the carotid sinus nerves, which then merge with the glossopharyngeal. The baroreceptors are dynamic receptors that respond to changes in pressure. At normal levels of blood pressure (MAP 90–100 mm Hg), there is only a modest degree of activity in the afferent nerves, which is in phase with the arterial pulse wave. A steep incline in activity occurs as pressure increases between 60 and 180 mm Hg. This afferent information leads to an increase in vagal activity and a decrease in cardiac sympathetic activity. The vagal activity causes a resultant bradycardia, while the reduction in sympathetic vasoconstriction leads to vasodilatation.

The venous mechanoreceptors that are located in the junction of the atria and the pulmonary arteries send their signals via unmyelinated fibers of the vagus nerve as a part of the Bainbridge reflex. The Bainbridge reflex responds to increases of blood volume in venous circulation by increasing heart rate and ventricular contractility via inhibition of efferent vagal fibers. These cardiovascular reflex arcs are intimately related to each other with the Bainbridge reflex serving to counterbalance the baroreceptor reflex; the Bainbridge reflex is dominant when blood volume is increased, and the baroreceptor reflex is dominant when blood volume is decreased.

In the setting of a failing heart, a range of compensatory functions attempt to preserve cardiac function ( Fig. 42.2 ). The ANS and renin-angiotensin-aldosterone system (RAAS) are the chief curators of cardiovascular homeostasis. Reduced cardiac output increases afferent stimuli from baroreceptors to the CNS cardioregulatory regions, with subsequent activation of the SNS. Though acutely advantageous, the compensatory mechanisms to maintain cardiac output, which are brought about by the SNS activation, in conjunction with vasoconstriction and sodium and water retention brought about by the RAAS system, are detrimental in chronic cardiac dysfunction. It is now established that alterations of the sympathovagal balance with diminished vagal activity and accelerated sympathetic activity is a predictor of increased mortality in heart failure ( see also Chapter 13 ). In addition to being a proarrhythmic state, a shift in the ANS balance toward heightened SNS activity is associated with nitric oxide (NO) dysregulation, excess cytokine release, and adverse cardiac remodeling.

Measurement of Autonomic Nervous System Activity

Measurement of autonomic activity has been demonstrated to correlate with prognosis in HF. The activity of the SNS can be measured in different ways. Examples are measurement of heart rate, plasma or urinary norepinephrine (NE) level, assessment of local tissue NE spillover, muscle sympathetic nerve activity (MSNA), iodine ¹²³ I-metaiodobenzylguanidine ( ¹²³ I-mIBG), or heart rate variability (HRV; Fig. 42.3 ). The simplest assessment of overall ANS function is resting heart rate, which is a marker of SNS activation and PNS withdrawal. The SHIFT trial assessed the efficacy of ivabradine in patients with HF and found that the lowest risk of mortality was in patients with a heart rate of less than 60 beats/min. Guideline documents for the treatment of HF patients recommend treatment the use of β-blockers and ivabradine to reduce heart rate to this target ( see also Chapter 37 ).

Reduced HRV is a marker of increased mortality in HF patients. The ANS and PNS effect the beat-to-beat variability in different frequency bands. The SNS regulates the low-frequency component of HRV, in contrast to the vagal effects, which modulates the high frequency variance. ANS balance may be assessed by computation of the low frequency/high frequency ratio. Therefore, it may be possible to assess the different contributions of each limb of the ANS. HRV can easily be assessed, requiring just simple measurement of consecutive RR intervals. However, it has a number of limitations. First, the most appropriate technique for HRV measurement remains ill-defined. It can be collected in short (10 minutes) intervals with short-segment electrocardiography or over 24 hours with cardiac monitoring. Secondly, HRV does not correlate specifically with SNS function. It measures both PNS and SNS activity, including both postsynaptic and presynaptic pathways. Finally, the development of atrial fibrillation, increased ectopy, and the use of biventricular pacing as heart failure advances restricts the measurement of HRV.

Quantification of NE spillover was one of the earliest attempts at assessing ANS activity. Radiotracer techniques that involve measuring radioisotopes dilution with plasma concentration of NE can be used to calculate regional NE spillover. However, there is considerable variability in the way that circulating NE is metabolized by different tissues, contributing to limitations in the use of NE spillover. In addition, NE increases may be related to decreased regional clearance rather than increased secretion. Microneurography facilitates measurement of nerve firing within the skin and local vasculature, but its clinical use has been precluded by low reliability.

The radiotracers iodine-labeled metaiodobenzylguanidine ( ¹²³ I-mIBG), which is used for planar and single-photon emission computed topography (SPECT) imaging, and ¹¹ C-hydroxyephedrine, which is used for positron emission topography (PET) imaging, can be used to image local SNS activity. Increased LV function has been seen in HF patients with increased sympathetic innervation as assessed by mIBG scan. The heart-to-mediastinal (H/M) ratio is the most accepted measure used to image cardiac ANS activity. Reduced H/M ratio correlates with increased risk of arrhythmia and mortality. The AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) study enrolled 961 HF patients. ADMIRE-HF demonstrated that an abnormal mIBG H/M ratio was associated with major adverse cardiovascular events and ventricular arrhythmia. However, other investigators have not been able to demonstrate a clear relationship between mIBG studies and arrhythmia inducibility at during electrophysiology studies.