Editorial N° 130

Look beyond the obvious:
the continuing dilemma
of angina pectoris

by D. del Val and J. L. Zamorano, Spain


University Hospital Ramon y Cajal
Madrid, SPAIN


There is a disorder of the breast marked with strong and peculiar symptoms, considerable for the kind of danger belonging to it, and not extremely rare, which deserves to be mentioned more at length and of which I do not recollect any mention among medical authors. The seat of it, and sense of strangling, and anxiety with which it is attended, may make it not improperly be called angina pectoris.1

Since the publication of William Heberden’s brilliant paper entitled “Some Account of the Disorder of the Breast”1—which he presented in the Royal College of Physicians in London—and Edward Jenner’s subsequent theory on “the importance of the coronary arteries” at the end of the 18th century, the link between obstructive coronary artery disease and angina has been widely accepted.2 This concept, which linked angina with obstructive coronary artery stenosis caused by atherosclerosis, remained in force for a long time and was supported by the exponential growth of coronary angiography in the 20th century, which highlighted the relief of angina symptoms that follows revascularization of flow-limiting stenosis.

In 1967, however, Link off et al first introduced the “paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease.”3</sup< Since then, several studies have described patients that exhibit angina-like symptoms even though their coronary angiograms do not show significant flow obstruction in the epicardial coronary arteries.4 As a consequence, considerable efforts have recently been directed toward identifying an alternative etiological theory for those patients who experience chest pain but have normal coronary angiograms and structurally normal hearts.

Why should we care?

Although mortality from cardiovascular disease in developed countries has declined slightly in recent years due to advances in both pharmacological and interventional therapies, cardiovascular disease remains a leading cause of death in these countries. Moreover, they are one of the main sources of health care expenditure and one of the principal determinants of disability. According to recent data from the United States, direct and indirect costs associated with cardiovascular disease are estimated at over $312 billion per year. While the real prevalence of stable angina pectoris is unknown and differs widely among major population studies, angina remains highly prevalent and is the most common initial symptomatic presentation of cardiovascular disease.5,6

In the past decades, research into the mechanisms underlying angina has gained interest, and a considerable number of studies have suggested that angina may be the consequence of various clinical conditions, which include not only obstructive atherosclerosis of the epicardial coronary arteries, but also functional and structural abnormalities of the coronary microcirculation.

Are we doing enough?

It is relatively common in daily practice to see patients who suffer from chest pain in the absence of obstructive coronary artery disease and of any other clinical condition that might either limit myocardial oxygen delivery or increase myocardial metabolic demand, such as severe aortic stenosis, anemia, or hypertrophic cardiomyopathy. Furthermore, it has been reported that in up to half of patients presenting with signs and symptoms of angina pectoris, coronary angiography does not show any obstructive coronary artery disease.

Interestingly, many features of this patient population are consistent among various studies: onset of symptoms in middle age, a markedly higher prevalence in women, severe and disabling chest pain, and inconsistent responses to conventional anti-ischemic therapy.

These patients were often disregarded as their prognosis was perceived to be benign and their long-term cardiovascular risk was thought to be low, and as a result no specific treatment beyond reassurance was offered to them. This was wrong, and it should be noted that several recent large studies with a long-term follow-up have shown that, compared with an asymptomatic reference population, these patients have a higher mortality and a greater risk of cardiovascular events.7 Therefore, these patients need answers, and these answers should be given by clinicians and investigators.

Until recently, the management of angina pectoris was based on a combination of lifestyle changes—especially dietary changes, weight loss in overweight or obese patients, and smoking cessation—and pharmacological and/or interventional therapies. Increased scientific awareness about this pathological entity has led to considerable efforts being made in order to improve diagnostic accuracy and develop effective therapies beyond the standard antianginal therapies based on β-blockers, calcium channel blockers, and long-acting nitrates. As a result, alternative antianginal therapies have rapidly emerged in clinical practice as promising complementary therapies that may be used when symptoms are insufficiently controlled.

These emerging therapies include ranolazine, a metabolic antianginal agent, and ivabradine, a selective heart-rate–lowering agent whose use is supported by preliminary outcomes from registries and randomized clinical trials.8-11 There is a lot of evidence showing the benefit of ivabradine in patients with chronic angina; furthermore, the CLARIFY multinational registry (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) has demonstrated the importance of heart rate as a risk marker in these patients.

Despite the efforts of many over the past decades, the pathogenesis of angina and the mechanisms that contribute to its development in patients without flow-limiting stenosis remain undefined, and it can often be difficult to establish an accurate diagnosis. Basically, the most widely recognized etiological mechanisms include a functional disorder of the epicardial coronary arteries, with either endothelial dysfunction or reduced nitric oxide bioavailability, and a microcirculatory abnormality in endothelium-independent vasodilation in the absence of structural or functional epicardial coronary artery disease.

The diagnosis and management of chronic stable angina is complex, and this complexity is illustrated by the fact that the European Society of Cardiology (ESC) Guideline on the Management of Stable Coronary Artery Disease and the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease differ in several ways, despite sharing many common approaches.12,13

Is there anything on the horizon?

Although the development of novel therapeutic strategies in the field of cardiology has led to a decline in the incidence of some pathologies, the prevalence of angina continues to be high. More than two hundred years after its elegant description and its inherent association with flow-limiting stenosis of the epicardial coronary arteries, critically important aspects of angina pectoris remain unclear, and as a result, its diagnosis and management are challenging. It is clear, however, that the coronary microcirculation and the endothelium are involved and play an essential role.

We are convinced that in the next few years our understanding of the etiology of angina pectoris will have improved and that we will then be in a position to give answers to the non-negligible proportion of patients who have ongoing symptoms and a long-term adverse prognosis despite adequate full classic anti-ischemic therapy. Renewed efforts should be made to identify the underlying pathophysiological mechanisms by delving into the idea that stable angina can occur in the absence of flow-limiting stenosis in the coronary arteries and, likewise, that severe stenosis does not necessarily cause angina.

This issue of Medicographia aims to review all the scientific aspects of the management of angina pectoris, focusing on novel therapies and alternative etiological mechanisms beyond the “classic” etiology described several years ago. ■

1. Heberden W. Some account of a disorder in the breast. Med Trans Coll Phys London. 1772;2:59-67.
2. Baron J. The life of Edward Jenner, M.D. London, United Kingdom: Henry Colburn, 1827.
3. Likoff W, Segal B, Kasparian H. Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med. 1967;276:1063-1066.
4. Gulati M, Cooper-DeHoff RM, McClure C, et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med. 2009;169:843-850.
5. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics-2013 update: a report from the American Heart Association. Circulation. 2015;127:143-152.
6. World Health Organization. World Health Statistics 2013. Geneva, Switzerland: WHO, 2013.
7. Jespersen L, Hvelplund A, Abildstrom SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012;33:734-744.
8. Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and longterm survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375-1382.
9. Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol. 2013;61:2038- 2045.
10. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371:1091-1099.
11. Steg PG, Greenlaw N, Tardif JC, et al; CLARIFY Registry Investigators. Women and men with stable coronary artery disease have similar clinical outcomes: insights from the international prospective CLARIFY registry. Eur Heart J. 2012; 33:2831-2840.
12. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/ SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164.
13. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949-3003.

Keywords: angina pectoris; coronary artery disease; etiology