Neuromodulation for Refractory Angina and Heart Failure

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.