Definition, Pathology, and Symptomatology of Angina Pectoris

Angina pectoris, first described by William Heberden in the 18th century, is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back, or arm. described angina pectoris as a sense of strangling and anxiety in the chest, especially associated with exercise. The cardiac origin was not established until a few years later when Parry, during necropsy of patients who had experienced the symptoms, demonstrated coronary artery disease (CAD), i.e., atherosclerosis in the coronary arteries with a subsequent reduction of the inner lumen of the artery ( ). The connection between angina pectoris and myocardial ischemia was not established until the 20th century ( ).

To date, stable CAD is described as episodes of reversible myocardial demand/supply mismatch, which is related to ischemia or hypoxia. It is usually reproducible and induced by exercise, emotion, or other stress, but the episodes may also occur spontaneously ( ). Such episodes of ischemia/hypoxia are commonly associated with transient chest discomfort, i.e., angina pectoris, which can be relieved by rest or nitrates.

In stable CAD, myocardial ischemia is caused by a transient imbalance between blood supply and metabolic demand of oxygen. Under normal physiological conditions during exercise, the increased oxygen demand in the myocardium is met by increased coronary blood flow (CBF), usually not by increased oxygen extraction. In patients with stable CAD during physical or mental stress, the oxygen supply becomes insufficient for myocardial needs since the stenotic coronary arteries are not able to dilate sufficiently in order to meet the increased oxygen demand. Thus, due to insufficient blood flow, normal aerobic metabolism cannot be maintained during these conditions and ischemia with reduced supply of oxygen and nutrients and accumulation of metabolic residual products occurs in the myocardium.

In modern medicine, the term angina pectoris is used to describe chest discomfort due to myocardial ischemia that is associated with CAD. The severity of anginal symptoms is commonly graded according the Canadian Cardiovascular Society’s (CCS) classification ( ). Severe angina is usually defined as CCS 3–4, i.e., “Marked limitations of ordinary physical activity” and “Inability to carry on any physical activity without discomfort,” respectively.

Lifestyle Modification and Pharmacological Treatment

Conventional treatment of angina pectoris encompasses both prevention of CAD and symptom relief. Lifestyle modification such as smoking cessation, increased physical activity, and weight loss in overweight or obese individuals decrease morbidity and mortality in patients with CAD ( ).

The basic treatment effect desired from antianginal therapy is a reduction of myocardial ischemia by either increasing the oxygen supply (increased CBF) or by reducing the demand for oxygen (decrease in oxygen consumption). Conventional, symptom-relieving, pharmacological treatment in angina pectoris consists of nitrates, beta blockers, and calcium antagonists. To date, there are additional pharmacological agents available such as nicorandil, ranolazine, and ivabradine, which are used for symptomatic second-line treatment of angina pectoris ( ).

For event prevention in patients with angina pectoris and stable CAD, pharmacological treatment with antiplatelet agents and lipid-lowering agents is recommended. In addition, renin-angiotensin-aldosterone system (RAAS) blockers should be considered for patients with stable CAD with coexisting hypertension, HF, diabetes, or chronic kidney disease, unless contraindicated.

Revascularization

For patients suffering from severe angina pectoris (CCS 3–4), especially patients reporting limited effects from antianginal treatment, revascularization for symptom relief might be indicated. Depending on the extent of the CAD, i.e., the degree of visualized stenosis in the coronary arteries using coronary angiography, and the amount of related ischemia, revascularization in terms of coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) is considered for symptom relief. The functional severity of a coronary stenosis is usually assessed by measuring the intracoronary artery pressure differences across a coronary artery stenosis (Fractional Flow Reserve, FFR) to determine the likelihood that the stenosis impedes oxygen delivery to the heart muscle. FFR provides guidance for the clinician in situations when it is unclear whether or not a lesion of intermediate angiographic severity causes ischemia, i.e., whether the stenosis is flow-limiting or not. If the stenosis significantly impairs the myocardial blood flow, CABG and PCI are both effective in reducing anginal symptoms by reestablishing the blood and oxygen supply to the affected myocardium.

Definition

According to the European Society of Cardiology (ESC) joint study group on the treatment of RA pectoris ( ) RA pectoris is defined as “a chronic condition characterized by the presence of angina caused by coronary insufficiency in the presence of CAD which cannot be controlled by a combination of medical therapy, angioplasty and coronary bypass surgery. The presence of reversible myocardial ischemia should be clinically established to be the cause of the symptoms. Chronic is defined as duration of more than 3 months . ”

The definition is based on the ESC guidelines for management of stable angina pectoris and the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines for the management of patients with chronic stable angina ( ).

Incidence and Prevalence

The number of patients suffering from refractory angina (RA) is unknown ( ) but the global prevalence of RA is believed to be increasing ( ). According to a study by , 6.7% of all patients undergoing coronary angiography have CAD (with stenosis >70% on their coronary angiography) and are on optimal medical therapy with no revascularization options. These results are in line with an epidemiological study from Sweden, reporting an incidence of 2.5–3/100,000 persons/year ( ). RA pectoris has been suggested to affect between 600,000 and 1.8 million people in the United States ( ; ). The incidence has been estimated to be 30,000–50,000 per year in Europe and 50,000 new cases each year in the United States ( ).

Patient Characteristics

The average age of patients with refractory angina pectoris is 64–70 years and approximately 67%–77% of the patients with RA are men ( ). The majority of patients had previously suffered a myocardial infarction (MI) (64%–71%) and had previously undergone a revascularization procedure (64%–88%). The patients had usually suffered from angina approximately 7–8 years before being considered to have RA. Studies show that patients with RA have surprisingly well preserved, left ventricular ejection fraction (LVEF), with only a subgroup of patients showing an LVEF <40% (16%–24%). Previous reports have indicated that patients with RA have a cardiac annual mortality of approximately 5% ( ).

Treatment of Refractory Angina Pectoris

Patients with RA are greatly limited in daily function by severe symptoms of chest discomfort and/or chest pain at slight effort or even at rest. Patients with RA are frequently hospitalized and have severely impaired QOL ( ). Effective and comprehensive care of patients with RA requires the collaboration of cardiologists and experts in pain medicine, and the aim of the treatment should be improving symptom relief and QOL ( ). To date, there are several symptomatic adjuvant therapies available. Since the treatment aim is symptomatic improvement, it is of utmost importance that the treatment modality is effective, safe, and associated with only minor (reversible) complications.

In the aforementioned 2002 report by the ESC joint study group on the treatment of refractory angina pectoris, neuromodulation techniques, transcutaneous electrical nerve stimulation (TENS) and spinal cord stimulation (SCS) are recommended as the first line of treatment in RA, since these treatment modalities have the most extensive documentation of efficacy and safety in RA ( ). In the 2013 ESC guidelines for the management of stable CAD and in the 2012 ACCF/AHA guidelines for the diagnosis and management of patients with stable ischemic heart disease, SCS, and TENS are given class IIb recommendation for RA pectoris. Other adjuvant therapies for the treatment of RA include enhanced external counterpulsation, transmyocardial revascularization, percutaneous myocardial revascularization, self-management training, thoracic epidural anesthesia, endoscopic thoracoscopic sympathectomy, shock wave therapy, and stem cell therapy for angiogenesis ( ). In summary, SCS is a therapeutic alternative in patients with RA according to international guidelines for management of patients with stable CAD.

Implant Procedure

During SCS implantation, the patient is awake and placed in the prone position. An incision is made at the midthoracic level after the administration of local anesthesia. The epidural space is identified and punctured using a Touhy needle. The electrode is introduced through the needle lumen into the epidural space and is guided to the level of the Th1–Th2 vertebrae using fluoroscopic monitoring. The electrode is placed at the midline and during intraoperative test stimulation the patient experiences paresthesia. It is important to adjust the position of the electrode so that the paresthesia felt by the patient in the chest covers the area in which the patient feels anginal pain. This procedure is to ensure that the area of the spinal cord innervating the heart is stimulated. When adequate paresthesia is obtained, the electrode is fixed to the ligaments with a manufacturer provided anchor and an extension wire is tunneled subcutaneously to below the left costal arch, where it is connected to a subcutaneous IPG ( ).

Stimulation Regime

After implantation, the device is programmed and the patient obtains a patient programmer for adjusting stimulation intensity. The stimulation settings are programmed at the hospital. Previously, concordant paresthesia, i.e., the patient’s perception of the stimulation paresthesia concordant to the area of the perceived anginal pain, was considered a prerequisite for effective SCS treatment. In a study by , it was demonstrated that both conventional (paresthesia perceived) and subliminal stimulation (below perceived threshold and not felt by the patient) had positive effects on angina symptoms and exercise when compared to “placebo SCS,” using a low-output (0.1 V) stimulation (no effects). In clinical practice at our pain center in Gothenburg, Sweden, we generally use bipolar conventional stimulation (paresthesia perceived). For patients who experience the paresthesia as uncomfortable or in patients with frequent, nightly anginal attacks, subliminal stimulation can be considered as an option. According to our expert opinion, we advise the patient to use the stimulation regime as presented in Fig. 106.1 .

Recommended stimulation regime for patients with RA treated with spinal cord stimulation (SCS).

At other centers, a stimulation regime of “stimulation on” for 1 h, 3 times per day or continuous stimulation is used. To date, it is not clear which stimulation regime is more optimum. However, the use of long-term stimulation, and not only stimulation for angina attacks, seems to be beneficial for controlling the angina burden. This antianginal effect is described as poststimulation analgesia or “carry over effect” ( ).

Safety and Preclinical Studies of Neuromodulation for Myocardial Ischemia

When neuromodulation was first introduced, safety of the treatment was of major concern. One concern was that the electrical stimulation in the vicinity of the heart would induce arrhythmias. This was shown not to be the case as long-term ECG studies (Holter monitoring) demonstrated that arrhythmias were not increased during stimulation ( ).

Another major concern was that neuromodulation might conceal symptoms of ischemia and thus deprive the patient of the angina “warning” signal by solely inhibiting the pain signal. A clinical study by showed that SCS does not mask symptoms of MI. Since 1982, several studies have been published from different centers on the short-term effect of TENS, SENS, and SCS on the relationship between myocardial ischemia and anginal pain ( ). Irrespective of the stress method used, the relationship between anginal pain and myocardial ischemia is unchanged. In summary, the results from these studies indicate that stimulation does not induce changes in coronary hemodynamics or myocardial metabolism at rest. At comparable stress levels during stimulation, myocardial ischemia and anginal pain disappears ( Fig. 106.2 ). However, at maximum stress levels, myocardial ischemia and anginal pain reoccurs. Thus, myocardial ischemia, during stimulation, induces anginal pain and the patient is not deprived of this very important warning signal. In summary, the pain-relieving effect of SCS in RA is secondary to an antiischemic effect.

“Ischemic shift.” Spinal cord stimulation elevates the ischemic threshold. The patients are able to be more physically active without experiencing angina due to myocardial ischemia.

Long-term ECG studies of SCS show that neuromodulation reduces the number of ischemic attacks and several, short-term, experimental studies show that the mechanism of action (MOA) of neuromodulation is its effect on ischemia rather than a pain inhibiting effect ( ). Furthermore, TENS has been demonstrated to reduce the number of episodes of silent ischemia in unstable angina pectoris ( ).

Results from preclinical work have suggested that SCS might even have a protective effect on cardiomyocytes (for example, a decrease in oxygen-dependent metabolism) as there are indications that SCS may induce protective effects in tissues totally deprived of oxygen supply ( ). In addition, there are data implying that SCS might induce modulation of neuronal activity within the heart, which, in turn, would protect the heart against arrhythmias and thus lead to less generalized ischemic threat to the heart ( ).

A preclinical study using a rabbit model for ischemia-induced MI indicates that preemptive SCS reduces infarction size ( ). Beneficial effects of SCS have also been demonstrated in a porcine model for coronary ischemia-reperfusion ( ). Preemptive SCS reduces signs of myocardial ischemia on three-dimensional (3D) vectorcardiography and the accumulated incidence of spontaneous ventricular arrhythmias during ischemia-reperfusion was reduced by SCS. However, in the porcine model preemptive SCS showed no effect on infarction size ( ).

The MOA of the antiischemic effect of SCS is still debated. According to experimental studies, the antiischemic effect of TENS and SCS, at comparable stress levels, seems to be secondary to decreased myocardial oxygen consumption rather than an increase in myocardial blood flow ( ). The mechanism behind the reduced oxygen consumption during stimulation has not yet been fully elucidated. Animal studies have indicated the existence of local opioid receptors in the myocardium. Agonistic effects on the opioid receptors give rise to decreased myocardial oxygen consumption ( ). In one report, it was shown that myocardial extraction of beta-endorphin, a highly selective, endogenous μ-agonist, during a control session, was turned into release during SCS stimulation, indicating that this release of beta-endorphin might contribute to the decreased myocardial oxygen consumption via agonistic effects on the μ-receptor ( ).

Studies on heart rate variability from the 1990s and invasive studies on catecholamine release from the coronary circulation indicate that SCS does not have an effect on local sympathetic activity in the myocardium ( ). In contrast, a recent placebo-controlled trial of heart rate variability suggests that SCS affects sympathetic/parasympathetic balance, thereby reducing sympathetic activation ( ). General sympathetic activity seems to decrease during stimulation, which might be beneficial in terms of reducing oxygen demand ( ).

Another possible explanation for the rise in the anginal threshold by neuromodulation may be related to redistribution of CBF from normally perfused (nonischemic) to impaired perfused (ischemic) myocardial regions, causing a homogenization of myocardial perfusion, even in the absence of increased total blood flow ( ).

Furthermore, results from preclinical work also suggest that SCS might induce effects that are similar to preconditioning ( ). Ischemic preconditioning is the metabolic adaptation of the heart to ischemic stress that follows a brief episode of nonlethal, myocardial ischemia, resulting in an increased resistance to prolonged myocardial ischemia.

In summary, SCS seems to act by inducing a shift of the ischemic threshold to higher levels of myocardial performance. This phenomenon is referred to as “ischemic shift” ( Fig. 106.2 ). The mechanism is not fully elucidated but seems to depend mainly on a reduction of myocardial oxygen consumption, although several mechanisms might contribute to the effect and likely involves changes in myocardial blood flow and neurohormonal mechanisms.

Long-Term Effects of Spinal Cord Stimulation

Several reports of the long-term effects of SCS in angina pectoris have been published. They have shown positive effects on symptoms in terms of decreased frequency of anginal attacks, improved QOL as well as beneficial effects on myocardial ischemia ( ). Furthermore, patients report high treatment satisfaction with SCS ( ). The effectiveness of SCS in RA has been demonstrated in several studies using different designs.

Placebo-Controlled Trials

Two randomized studies of SCS have compared conventional, paresthesia producing SCS to low-out put stimulation (0.1 V and 0.05 mV respectively), which is considered placebo stimulation ( ). In both studies, stimulation with conventional, paresthesia producing SCS was superior to placebo stimulation with regard to anginal symptoms, short-acting nitrate consumption, and QOL. In the study by Eddicks et al. conventional stimulation was also superior to placebo with regard to functional status (6 min walk test). This finding was not repeated in the study by Lanza et al.

Randomized Trials of Spinal Cord Stimulation Versus Other Treatment Modalities

In the Electrical Stimulation vs. Coronary Artery Bypass Surgery for Severe Angina Pectoris (ESBY) trial, 104 patients with severe angina pectoris and increased surgical risk were randomized to either SCS or CABG. Both treatment modalities improved anginal symptoms, consumption of short-acting nitrates and QOL after 6 months and after 4.8 years, with no differences between the groups ( ). Nor were there any differences with regard to mortality after 4.8 years.

In the SPiRiT trial, 68 patients with RA pectoris were randomized to either SCS or percutaneous myocardial revascularization. After 12 months, there were no differences seen between the groups with regard to anginal symptoms, mean total exercise time or QOL ( ).

Registry Studies

Two registry studies have followed-up patients with RA pectoris. In the Prospective Italian Registry, 104 patients with RA were included and followed for 13.2 months ( ). A significant improvement of anginal symptoms was reported and the CCS angina class ascribed to patients improved by >1 class in 80% and by >2 classes in 42% of patients. Furthermore, there was a reduction in the rate of hospital admissions and days spent in the hospital because of angina. In the European Angina Registry Link (EARL) study, 121 patients from 10 European centers were followed for 12.1 months after implantation ( ). SCS treatment resulted in improved anginal symptoms, decreased consumption of short-acting nitrates and improved QOL.

Systematic Reviews

One systematic review has been published and one combined systematic review and meta-analysis on the subject of SCS for the treatment of RA ( ). Both reviews concluded that there is (1) strong evidence that SCS gives rise to symptomatic benefits in terms of decreased frequency of anginal attacks and improved QOL in patients with angina pectoris, (2) strong evidence that SCS improves the functional status in patients with angina pectoris, as illustrated by improved exercise time on treadmill or longer walking distance without angina, and (3) SCS does not seem to have negative effects on mortality in these patients (limited scientific evidence), and the complication rate is low.