Spinal Cord Stimulation for Refractory Angina and Peripheral Vascular Disease

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Chapter 11 Spinal Cord Stimulation for Refractory Angina and Peripheral Vascular Disease

Chapter Overview

Chapter Synopsis: Electrical stimulation of the spinal cord (SCS) can provide pain relief and improve the underlying ischemic condition in certain indications, including angina and peripheral vascular disease (PVD). This chapter examines the ways that SCS can improve these conditions, which affect people in staggering numbers that are likely to climb in the coming years. SCS is indicated for angina that is refractory (i.e., it does not respond to pharmacological or mechanical therapies). Although SCS can improve cardiac vascularization and relieve the underlying ischemia, it is not a treatment for advanced cardiovascular disease. Evidence of success of SCS in patients with angina include a decreased need for short-acting oral nitrates, improved cardiac function, and improved quality of life. SCS reduces angina pain as it does in other indications according to the gate theory: by increasing stimulation of Aβ fibers, competing pain signaling from nociceptors is reduced. It also appears that SCS causes release of several biologically active substances in the periphery that can decrease pain and reduce the underlying ischemia, notably including β-endorphin. SCS also seems to improve ischemic conditions by affecting microcirculation within the heart, although these mechanisms have not been entirely elucidated. This may be achieved by redirecting blood flow or oxygen demand via manipulation of intracardiac neurons (ICNs). Patient selection and technical considerations can improve the chances of success of SCS in treatment of refractory angina. The chapter provides further considerations for SCS in the treatment of PVD.

Important Points:

Clinical Pearls:

Clinical Pitfalls:

Introduction

As technologies and research into the treatment of cardiovascular disease and peripheral vascular disease (PVD) advance, applications of treatment regimens not only reduce morbidity and mortality, but they also can lead to undesirable, unintentional consequences—the development of a population of patients who no longer respond to the therapies that initially prolonged their lives, increased their functional capacity, or increased their quality of life. Neuromodulation via spinal cord stimulation (SCS) may be a partial answer to the challenge being faced for patients with refractory angina (RA) or irreparable PVD. It has not been Food and Drug Administration (FDA)–approved for use in either RA or PVD as of yet in the United States. Originally used to treat a patient with cancer pain by Shealy, Mortimer, and Reswick in 1967,1 SCS therapy has been extended to many other areas with varying amounts of success. Not everyone is a candidate for this technique. But appropriately screened patients who meet appropriate diagnostic and psychological criteria may benefit from SCS, which may alleviate chronic pain while adding an anti-ischemic benefit so patients’ quality of life and functional capacity improve.

This chapter discusses RA in its first section and PVD in its second. After the section on epidemiology, each section contains these parts: establishing diagnosis, anatomy, indications, basic science mechanisms, guidelines, equipment and techniques, outcomes, and complications. Ideally this chapter will provoke further thought and research into this novel application of neuromodulation, leading to eventual FDA approval for using SCS in RA and expanded use in PVD.

Epidemiology: Coronary Artery Disease and Peripheral Vascular Disease

Coronary artery disease (CAD) remains the number one cause of morbidity and mortality in the United States, yet the prevalence of RA in the population has not been well-defined in the literature. Several estimates have been proposed. According to the American Heart Association’s Heart Disease and Stroke Statistics—2010 Update, approximately 10.2 million people suffer from angina pectoris. Currently the annual incidence is estimated to be approximately 500,000.2 In 1999 Mukherjee and associates3 attempted to estimate the incidence of RA. Their approximation of 12% of the total population of those with angina is based on the percentage of people undergoing angiography at tertiary referral centers who ultimately are not eligible for percutaneous or coronary artery bypass graft (CABG) revascularization procedures.3 This percentage is also endorsed by Mannheimer and associates,4 who remarked on the paucity of data but noted that one study they reviewed had a prevalence of 5% to 15% of the population as having RA. In 2002 Holmes5 noted that approximately 2.4 million people in the United States suffer from CAD untreatable by either percutaneous revascularization or CABG. With a large and ever-expanding population, the demand for novel treatments will certainly climb. This demand will undoubtedly be mirrored in the population that suffers from PVD.

PVD likely affects more than 10 million people in the United States according to Vallejo et al estimates in 2006, and it affects 12% to 20% of the population aged 65 and older.6 Of the people who develop PVD with signs of intermittent claudication, approximately 20% are believed to develop chronic critical limb ischemia (CLI); 25% of CLI sufferers require an amputation.7 The mortality for this population also is quite high, ranging from 25% to 30% at 2 years and increasing to 50% to 75% at 5 years after the onset of CLI. Although the amputation rate and mortality are significant in this subpopulation, the implementation of SCS shows promise in alleviating some of the suffering and morbidity and mortality of this disease.

Establishing Diagnosis: Angina and Role of Spinal Cord Stimulation

An imbalance between myocardial oxygen delivery and its consumption rapidly results in ischemic conditions within the heart that may progress to infarction if not corrected. This imbalance may or may not be associated with symptoms of angina pectoris because some patients develop silent ischemia. Besides being a harbinger of a potentially serious condition, angina not only presents significant acute or chronic discomfort, but it also typically causes psychological stress that may impact a person’s quality of life and functionality.

As defined by the American Heart Association in 1999,8 angina comprises a clinical syndrome of pain and discomfort in the chest, jaw, shoulder, back, or arm that may be exacerbated by physical exertion or emotional stress. Although angina typically is associated with CAD involving the epicardial vessels and subsequent ischemia, a more robust differential diagnosis of angina must be considered from both a cardiac and noncardiac standpoint. Cardiovascular origins of angina may also include valvular heart disease, severe hypertension, hypertrophic cardiomyopathies, acute aortic dissection, acute pericarditis, severe aortic stenosis, coronary vasospasm, and cardiac syndrome X (CSX).810 CSX patients present similarly to those with CAD-related angina. Although patients with CSX tend to feel pain with exertion and their electrocardiograms (ECGs) may show ST-segment depression during exercise stress tests that induce angina, these patients do not have signs of obvious CAD on angiography; in fact, in some patients, evidence suggests that ischemia may not be a causative factor.11 Proposed mechanisms for CSX include estrogen deficiency, abnormal function and distribution of adenosine receptors, and coronary microvascular dysfunction.9,11,12 Noncardiac origins of chest pain include trauma and esophageal conditions, including reflux and motility disorders, biliary colic, costochondritis, and pulmonary embolism or pulmonary hypertension.

In addition, angina may be classified as stable or unstable. Stable angina typically arises during physical or emotional stress secondary to severe stenotic lesions affecting more than 70% of the affected coronary artery lumen of one or more arteries that causes myocardial ischemia.13 Conversely, unstable angina involves acute formation of a thrombosis within an already stenotic coronary vessel, which may or may not immediately lead to a myocardial infarction (MI). Unstable angina is of greatest concern since it predicts an elevated short-term risk of a cardiac event8 and necessitates immediate coronary revascularization to alleviate. Unstable angina is beyond the scope of this chapter; however, episodes of unstable angina pain manifest even in patients with spinal cord stimulators for RA, as discussed in the following paragraphs.

To improve clinical classification of angina, the Canadian Cardiovascular Society (CCS)8,14 modified the New York Heart Association’s (NYHA) Functional Classification (Box 11-1). Campeau and Letter14 developed four classes—I through IV. In class I angina patients perceive angina only with strenuous activity. Class II patients experience only slight limitation of activity secondary to angina. Class III patients experience marked limitation of normal activity, and in class IV they experience angina with any activity, including being at rest. MI falls within classes III and IV.

RA is marked by severe chronic chest pain for more than 3 months secondary to coronary insufficiency; it occurs in patients who have failed to obtain or undergo appropriate control via other modalities, including medical therapy, percutaneous revascularization, and CABG, yet who continue to have a reversible ischemia.9,15,16 RA occurs when all reversible causes for ischemia have been ruled out. SCS has been used successfully to target RA—decreasing the frequency and severity of the episodes and improving patient functionality and quality of life.

Anatomy: Pain Pathway for Angina

Signals for angina pain are initiated at both the chemosensitive and mechanoreceptive nociceptors in the adventitia of the coronary arteries and myocardium.16 Because the majority of these nerves are slow-conducting C fibers, the predominant pain experienced is of a dull, aching, heavy, and squeezing type.8 Aδ fibers that carry stabbing and sharp pain are typically not involved in angina. On their activation these nociceptors release a variety of chemical mediators, including adenosine, bradykinin, prostaglandins, and others, which initiate signals in the sympathetic and parasympathetic (vagal) afferent pathways to dorsal spinal cord and parasympathetic ganglia located from C7 to T5.17,18 The pain experienced by the patient during an episode of angina is related to the convergence of common pathways at the dorsal spinal cord between C7 and T5, where afferent myocardial inputs and cutaneous nociceptors converge on the same interneurons at the same level within the spinal cord.16 Thus the pain perceived by the patient is distributed within the dermatome from where the cutaneous afferents converge on the same spinal segment as from the heart.

Indications: Spinal Cord Stimulation and the Alternative Therapies Available for Refractory Angina

As previously mentioned, neuromodulation has treated RA successfully; however, before choosing SCS as a treatment modality, the patient must be properly assessed, and all other modalities pursued. SCS provides analgesia and anti-ischemic effects, but it does not cure advanced cardiovascular disease. This section briefly reviews therapies for angina and establishes a framework within which SCS should be considered as an alternative.

As medical, interventional, and operative treatment modalities for angina and occlusive vascular disease have developed along with an aging population, so has the portion of the population with angina that lacks viable options for further improvement, despite optimization from one of the novel or improved therapies. This subgroup contains patients with RA who typically have failed either percutaneous coronary interventions (PCIs) or CABG, or who have not been candidates for either procedure because of poor coronary anatomy, prior surgical repairs not amenable to further manipulation, impaired left ventricular function, co-morbid noncardiac disease compounding their cardiovascular status, or advanced age.19,20 Jolicoeur and associates19 also mentioned that a person with RA may fall into the category of “nonrevascularization” secondary to either their geographical location where practitioners may not have the expertise or the patients lack of interest in pursuing a particular therapeutic path.

Multiple pharmacological and nonpharmacological (mechanical intervention) therapies for RA are reviewed in the following paragraphs. The reviews are based primarily on Jolicoeur and colleagues’ report of the working group on clinical and research issues regarding chronic advanced CAD.19 Although their reviews are not comprehensive, they highlight the current management options for RA.

Pharmacological agents mitigate angina symptoms by a variety of mechanisms so the patient has reduced myocardial oxygen demand and increased supply via a reduction in heart rate (HR), decreased afterload, and decreased contractility. Agents with antianginal properties that are helpful in accomplishing these changes include β-blockers, nitrates, calcium channel blockers, and opioids. Each provides angina relief via different mechanisms, but each is not without side effects that lead to dose limitation or intolerance. Antithromboembolic agents such as aspirin and clopidogrel (Plavix) target the platelets; whereas antihyperlipidemics such as statins promote vessel patency, thus decreasing risk for myocardial ischemia and resultant angina. Ranolazine (Ranexa) is a relatively new drug with direct antianginal and anti-ischemic properties. A debate as to its mechanism of action exists; however, it permits an increase in exercise performance without changing HR or blood pressure.21 In addition, ranolazine improves angina and exercise threshold when used as a monotherapy and in combination with more traditional therapies listed previously.21,22

Mechanical interventions are also available for RA: percutaneous stent placement, transmyocardial laser revascularization, and CABG. Despite these interventions, people continue to have angina symptoms, and some people are not candidates for such therapies. Chronic total occlusion (CTO) recanalization via the percutaneous approach has been conducted after the development of chronic occlusions (greater than 3 months) with a substantial improvement in 10-year survival.19 The reported success of revascularization achieved by CTO recanalization remains a stable 71% despite attempts at canalizing longer lesions, whereas reported complications of the procedure range from 3.8% to 5.1%.2325 Technical advances may eventually make this technique more effective and safe.19

Another mechanical technique sometimes used is enhanced external counterpulsation (EECP), approved by the FDA in 1995 for angina. In EECP three bilateral lower extremity cuffs are inflated sequentially during diastole to provide increased venous return and diastolic augmentation.26 Currently this technique requires 35 consecutive days of 1-hour sessions to show some lasting benefit of decreased angina symptoms and a longer time to greater-than–1-mm ST depression on an exercise stress test.26 EECP has not been studied in a large, randomized controlled setting; and it has side effects, including edema, bruising, and pain in the lower extremities. According to Soran and associates,27 patients undergoing EECP noted a substantial improvement in the quality of life; 72% improved from severe to mild or moderate angina, 52% stopped nitroglycerin use, and at 2 years 55% of the patients reported a maintained decrease in their angina.

Before choosing SCS as a treatment modality for RA, the patient must be properly assessed according to various diagnostic algorithms, ideally ones that have been standardized. One such algorithm for assessing a person’s appropriateness for SCS was proposed by the European Society of Cardiology.20 First a team of cardiologists and cardiac surgeons should determine if a patient’s angina is of ischemic origin and evaluate him or her for revascularization. A recent angiogram should be used to rule out newly treatable coronary pathology. In addition, all other forms of chest pain should be eliminated. For example, the differential diagnosis of chest pain should include noncardiac origins of chest pain, including esophageal pain, gastroesophageal reflux, musculoskeletal pain, costochondritis, anemia, uncontrolled hypertension, atrial fibrillation, and thyroid disorder.19,20 Once these criteria have been met, the patient’s medical therapy must be optimized. After an appropriate diagnosis has been established and subsequent medical and surgical optimization has occurred, the focus shifts to psychological evaluation to determine if the patient’s perception of pain has a significant co-morbidity of depression or anxiety that should be treated before SCS implantation or if the person should be evaluated on the basis of compliance with other treatments. Finally, risk factor management and cardiac rehabilitation must continue.

Basic Science: Mechanism of Action of SCS for Angina

SCS for angina enables both antianginal and anti-ischemic effects to be integrated to achieve pain relief. The severity of the angina decreases; and cardiac function improves, as evidenced by the following: decreased need for short-acting oral nitrates and 24-hour cardiac monitoring and markers of functional status and increased perceived quality of life.28 Multiple mechanisms have been proposed to explain these effects, a number of which are outlined here. note: What follows is not an exhaustive review of the literature on this topic.

Given the benefits of the antianginal and anti-ischemic effects of SCS, one should also consider its safety for patients with RA. An early concern was that SCS could mask angina pain associated with myocardial ischemia and eliminate a patient’s subjective sensation of RA. This concern has not been borne out in several studies.28 Instead, SCS merely raises the patient’s threshold for sensing angina, thus permitting the patient to increase exercise capacity. Investigators have not noted any resultant increase in morbidity and mortality with SCS.

The following mechanisms have been suggested.

Direct Suppression of Pain

The antianginal effect of the SCS may be caused by direct suppression of pain. According to the gate control theory proposed by Melzack and Wall in 1965,29 fast-conducting myelinated A fibers modulate slow-conducting unmyelinated C fibers via a negative feedback mechanism at the level of the dorsal horn of the spinal cord. Thus applying neuromodulation techniques to the dorsal column of the spinal cord at the level where input from nociceptors occurs inhibits signals ultimately responsible for achieving the decreased sensation of pain. The electricity of the SCS provides a continuous, selective, low-level activation of the sensitive afferent A fibers, which in turn inhibits the Aδ and C fibers of nociception presynaptically.9 Chandler and associates’30 support of this mechanism comes in their studies of SCS on anesthetized monkeys. They demonstrated that SCS of the dorsal column decreased the output of spinothalamic tract neurons that were triggered by electrical stimulation of cardiac sympathetic afferent fibers with sensory endings in the ventricles. These spinothalamic tract cells also received somatic input from the chest and upper extremities; this type of input is also blocked with SCS. Chandler and associates30 also demonstrated that intracardiac injection of bradykinin, which duplicates the effects of either cardiac sympathetic or somatic nociception, is blocked by the use of an SCS.30 What was not resolved was whether suppression of the spinothalamic tract is a direct effect or a decrease in information from nociceptive afferent.31

Molecular Mechanism

More recently a molecular mechanism leading to reduced angina has been investigated. Excitatory amino acids involved in transmitting signals within the dorsal horn include glutamate and aspartate. The release of these neurotransmitters has been shown to decrease in the presence of elevated gamma aminobutyric acid (GABA) that occurs during neuromodulation of the dorsal horn.32 Cui and associates32 further pointed out that this observed effect was transiently reversed with the addition of a GABA β-receptor antagonist placed at the dorsal horn. In addition, Oldroyd and colleagues33 found that β-endorphins are released from the pituitary in response to myocardial ischemia.33 The significance of these findings is that β-endorphins may participate in pain reduction through their action as endogenous opioids. In addition, β-endorphins may affect the regulation locally at the level of the myocardium by directly aiding in decreased oxygen consumption.34 According to Eliasson and associates,34 β-endorphin release at the myocardium increased with the use of SCS during conditions of rest and during pacing to angina in humans. They suggest that the data be interpreted cautiously since they conducted their study by applying an accepted method of evaluation of myocardial ischemia involving the myocardial lactate extraction ratio and using it to look at myocardial turnover of peptides. While conducting the study, they derived a wide range of individual values.34 Thus one current hypothesis suggests that SCS promotes release of biologically active molecules that may have both direct and indirect effects on angina pain and myocardial ischemia.

Central Nervous System Mechanism

A central mechanism of pain control may be triggered by the use of neuromodulation. According to Eckert and Horstkotte,16 functional neuroimaging has been used to examine areas of cerebral blood flow in patients with known CAD. In such patients angina and ECG changes are elicited by dobutamine infusion. According to Hautvast and colleagues,35 dynamic positron emission tomography (PET) scans during such periods of chemically induced ischemia demonstrated areas of varying regional cerebral blood flow. When using SCS, Zonenshayn and associates36 noticed corresponding changes of increase and decrease in cerebral blood flow during periods with and without stimulation, respectively. Eckert and Horstkotte16 pointed out that, when they examined the two groups, they saw similarities in increased cerebral blood flow to the hypothalamus bilaterally and the periaqueductal grey area, and decreased cerebral blood flow in the posterior insular cortex that modulates sympathetic nervous system (SNS) activity. Thus SCS may be influencing pain perception and processing in the central nervous system. These findings suggest that the thalamus may be acting as a filter for afferent pain signals.

Anti-Ischemic Mechanisms

It is important to recognize that the antianginal benefits of SCS are enhanced by its anti-ischemic effect as demonstrated by improvements in patients’ ECGs during stress testing and 24-hour Holter monitoring. In addition, by decreasing their subjective experience of angina, patients can exercise more, thus improving cardiac conditioning. This suggestively leads to the benefits of improved functionality and quality of life. As with antianginal mechanisms, several mechanisms have been proposed for anti-ischemic effects as well.

One hypothesis to explain this decreased ischemia suggests that coronary blood flow (CBF) is redistributed to areas of poor perfusion, likely secondary to collateral flow.28 It has been suggested that SCS improves myocardial perfusion via vasodilation of microvessels within the myocardium, alleviating angina pain in patients who continue to have a small amount of coronary reserve, despite the ischemia. SCS may eliminate this reserve. Many techniques (i.e., intracoronary pressure and flow measurements, stress echo, myocardial scintigraphy, and PET scanning) have been attempted to evaluate possible mechanisms to explain why the SCS has an anti-ischemic effect, but they have not been entirely successful in elucidating such mechanisms. These techniques may not be able to fully identify the changes in microcirculation that result in decreased angina symptoms.16

The ability of neuromodulation to promote blood flow change remains controversial since evidence is lacking and somewhat contradictory. Mobilia and associates37 used PET to evaluate CBF and suggested that the SCS promoted increased CBF and allowed for redistribution from areas of high and low flow.37 SCS promotion of increased CBF was contradicted by Norrsell and colleagues38 who demonstrated an anti-ischemic effect independent of CBF velocity. Studies on dogs with normal hearts did not show an increase in local flow or a redistribution.39 Wu, Linderoth, and Foreman31 also point out that long-term use of SCS has been shown to decrease myocardial ischemia, perhaps because of better coronary collateralization secondary to increased physical activity of the patients.31

Remodeled Neural Pathways

The myocardium contains intracardiac neurons (ICNs) that are the primary integrators of the nervous system within the heart.40 Neuromodulation with an SCS has been suggested to “remodel the neural pathways” by altering the firing rate of the intracardiac neurons and stabilizing their activity during ischemia.41 Hypothetically decreases in angina secondary to SCS allow patients to increase and prolong their exercise. Initially SCS was believed to modulate the sympathetic branch of the SNS with respect to the perception of pain; however, this is likely not the case because there is no change in HR variability or in epinephrine and norepinephrine metabolism.28 Instead it is hypothesized that SCS acts on the myocardium via the ICNs to permit a redistribution of blood flow from the areas of normal perfusion to areas of ischemia.42 Speculation exists as to how this blood flow redistribution occurs. Possibilities include angiogenesis, collaterals, and preconditioning.

Intrinsic Cardiac Nervous System

Another working hypothesis suggests that the SCS neuromodulates the intrinsic cardiac nervous system. Wu, Linderoth, and Foreman31 witnessed decreased magnitude of ST-changes in the ECG and decreased risk for development of arrhythmias secondary to ischemia in patients with functioning SCSs.31 The intrinsic cardiac nervous system is comprised of parasympathetic and sympathetic efferent nerves, sensory afferents, and interconnecting local neurons. It resides in the cardiac ganglion plexi of the pericardial fat pads near and within the myocardium.43

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