Cardiac Denervation

Denervation can be divided into two categories: pregangli-onic and postganglionic. Preganglionic denervation is caused primarily by disease or injury of the vasomotor centers in the brain or spinal cord above Tj0; it leaves intact the postgangli-onic nerve fiber and many reflexes that occur at the ganglionic level. Preganglionic denervation not only results in loss of centrally mediated cardiac reflexes, but also leads to dysfunctions in the control of peripheral vascular tone and inability to control blood pressure with changes in position. Shy-Drager syndrome is a classic example of preganglionic denervation affecting the cardiovascular system (13).

Postganglionic denervation can occur as the result of several neurodegenerative processes, after certain types of cardiac surgery, or after cardiac transplantation. Loss of the postganglionic nerve cell body results in Wallerian degeneration of the distal nerve, with loss of axonal integrity and neurotransmitter availability. Loss of neurotransmitters at the neural junction with the distal target (e.g., cardiac conduction tissue or cardiac myocytes) leads to an increase in neurotransmitter receptor numbers and densities. This, combined with a loss of neurotransmitter metabolism by the degenerated neuron, makes both the cardiac conduction system and muscle hypersensitive to circulating catecholamines (so-called denervation hypersensitivity).

Cardiac transplantation is the most complete form of cardiac denervation, resulting in loss of both sympathetic and parasym-pathetic innervation, with Wallerian degeneration of the intra-cardiac nerve fibers (14). Yet, diabetes is the most common cause of partial cardiac denervation in humans (15). Diabetic

Fig. 8. The heart rate response to treadmill exercise is shown for normally innervated subjects (solid line) and patients with cardiac denervation after heart transplantation (dashed line). The denervated patients have higher resting heart rates, but heart rates rise more slowly with exercise because the increase in heart rates depends primarily on circulating catecholamines. After cessation of exercise, heart rates in the denervated patients continue to rise briefly and then fall slowly as circulating catecholamines are metabolized.

Fig. 8. The heart rate response to treadmill exercise is shown for normally innervated subjects (solid line) and patients with cardiac denervation after heart transplantation (dashed line). The denervated patients have higher resting heart rates, but heart rates rise more slowly with exercise because the increase in heart rates depends primarily on circulating catecholamines. After cessation of exercise, heart rates in the denervated patients continue to rise briefly and then fall slowly as circulating catecholamines are metabolized.

neuropathy can result in losses of both sympathetic and parasympathetic efferent and afferent pathways. As with other neurodegenerative diseases, neuronal loss is typically patchy and permanent. Other diseases leading to cardiac denervation include infiltrative diseases such as amyloidosis.

10.1. Effects of Denervation on Basal Cardiac Function

The loss of tonic parasympathetic vagal inhibition of sinus node depolarization causes a rise in basal heart rate and loss of heart rate fluctuation with respiration. The resting heart rates of patients with a heart transplant typically are in the range of 95100 beats/min. A number of reflexes, mediated primarily through the vagal nerves, are absent, including carotid sinus slowing of heart rate, the pulmonary inflation reflex, and the Bezold-Jarisch reflex.

In contrast, the resting inotropic state of the cardiac muscle and myocardial blood flow are normal after denervation. Basal ventricular function is changed minimally by denervation. Measures of systolic contraction (such as dP/dt, ejection fraction, and cardiac output) are usually preserved. Preservation of pump function after denervation may be related in part to an upregulation of ^-catecholamine receptors on myocytes and the conduction system, leading to an amplification of the response to blood-borne catecholamines (16).

Coronary blood flow in the denervated heart is unchanged at rest and increases normally with exercise. Coronary flow reserve (a measure of maximal coronary blood flow) is typically normal; although in animals the response to ischemia is blunted (17,18).

Afferent sensation to pain (e.g., from ischemia), chemore-ceptor stimulation (e.g., from ischemia, hyperosmolar contrast media), and stretch receptor stimulation (e.g., from pressure overload) are absent in the recently transplanted heart. This aspect of denervation is important because coronary occlusion because of transplant-related coronary arteriopathy is common, and the absence of anginal pain removes an important warning symptom.

10.2. Effects of Denervation on Exercise Hemodynamics

Cardiac denervation results in a blunting of the chronotropic response to exercise. With exercise, heart rate increases because of an increase in plasma catecholamines (released primarily from the adrenal glands) rather than from direct sympathetic stimulation of the sinus node. Thus, heart rate increase is delayed; the heart rate peaks well after cessation of exertion and remains elevated until the circulating catecholamines can be metabolized (Fig. 8).

Exercise or stress also will both result in a delayed increase in inotropic status, similar to the changes in chronotropic response. Unlike status, resting ventricular function, peak inotropic states and ejection fractions are typically reduced.

10.3. Reinnervation

Sympathetic neural reinnervation of the heart occurs in nearly all animals undergoing auto-transplantation and in most patients undergoing orthotropic transplantation. Reinnervation typically occurs over both the aortic and atrial suture lines (left more than right), extending from the base of the heart to the apex. The rate of reinnervation is slow (years), and in humans, it is patchy and considered incomplete. The anterior wall typically reinnervates earlier and more densely than the rest of the left ventricle (19). The sinus node reinnervates to some degree in over 75-80% of patients.

Reinnervation results in partial normalization of the chronotropic and inotropic responses to exercise (20,21). Thus, the reinnervated patients can exercise longer and have higher maximal oxygen consumptions. In addition, cardiac pain sensation (i.e., angina) can return, although the regional nature of reinnervation results in reduced or patchy sensation to ischemia in most transplant recipients (22). Parasympathetic reinnervation has been reported in a small number of transplant recipients; it is accompanied by return of respiratory-mediated fluctuation in heart rate and carotid sinus slowing of heart rate.

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