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European Review for Medical and Pharmacological Sciences 2012; 16: 1611-1636 The patient with chronic ischemic heart disease. Role of ranolazine in the management of stable angina A. DI MONACO, A. SESTITO Department of Cardiology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy Abstract. – Ischemic heart disease (IHD) is a serve is exhausted2. Symptom severity can be major cause of death in Western Countries and modulated by dynamic vasomotion at the site of accounts for very high costs worldwide. In this re- stenoses and/or by coronary microvascular dys- view we discussed the pathogenesis, symptoms, 1,2 diagnosis, prognosis and management of chronic function . IHD. In particular, we discussed about the percu- In microvascular angina transient myocardial taneous coronary interventions and coronary ischemia is caused by coronary microvascular artery bypass grafting, as well as to clinical trials dysfunction in patients with angiographically that evaluated the advantages of one approach normal epicardial coronary arteries, in the ab- versus another. Pharmacological treatment is 3,4 among major objectives of the review and for sence of any other specific cardiac disease . In each class of therapeutic agents an evaluation of vasospastic angina transient myocardial is- well-conducted clinical trials is provided. The chemia is caused by coronary spasm5. most important drug classes in IHD treatment are Furthermore, angina and transient myocardial betablockers, calcium channel blockers, nitrates, ischemia may also occur in patients with non ath- antiplatelet agents, and ACE-inhibitors. In addition to these agents, also new treatment options are erosclerotic obstructive coronary artery disease, evaluated in patients with stable IHD. Ranolazine, such as congenital abnormalities of coronary ar- in particular, is a innovative anti-anginal drug with teries, myocardial bridging, coronary arteritis in a great successful in the management of patients association with systemic vasculitis and radia- with refractory angina. A pharmacological as well tion-induced coronary disease6. as clinical profile of this drug is provided. Key Words: Pathogenesis of Myocardial Ischaemia Stable angina, Ischaemic heart disease, Diagnosis, Ischaemia is caused by an imbalance between Prognosis, Drug and surgical treatment, Ranolazine. myocardial oxygen supply and consumption. The imbalance can be caused by a primary reduction of myocardial oxygen supply which can be Introduction caused by a reduction of coronary blood flow (for instance in presence of occlusive coronary Ischaemic heart disease (IHD) is characterized thrombosis or spasm or of severe hypotension) or by stable angina symptoms over a period of by a reduction of O2-carrying capacity (for in- months, years, or even decades and it may repre- stance caused by anaemia or carbon monoxide sent the first clinical presentation of IHD, or it poisoning)1,2. The imbalance also occurs when may follow an acute coronary syndrome (ACS)1. coronary flow reserve is reduced by an increase Chronic IHD includes three different clinical pre- of coronary vascular resistance caused by critical sentations: stable angina, microvascular angina coronary stenoses, coronary microvascular dys- and vasospastic angina. Moreover, it can be function or extracoronary conditions (for in- known that myocardial ischemia may be silent in stance aortic stenosis)1-6. all anginal syndromes1. The main causes of myocardial ischemia are: In chronic IHD transient myocardial ischemia is mainly caused by obstructive coronary Stenotic atherosclerotic plaque: a progressive stenoses which reduce coronary flow reserve, impairment of tissue perfusion due to the thus preventing the matching between myocar- growth of the plaque inside the lumen of the dial oxygen supply and myocardial oxygen de- vessel causing impairment of blood flow and is- mand when subendocardial coronary flow re- chaemia which may lead to angina symptoms7. Corresponding Author: Alfonso Sestito, MD; e-mail: [email protected] 1611 A. Di Monaco, A. Sestito Occlusive spasm and dynamic stenoses: a parox- tients are affected by angina pectoris in most Eu- ysmal and intense occlusive vasoconstriction ropean Countries. The prevalence of angina in- usually involving a segment of an epicardial creases with aging in both genders. At the age of coronary artery, which results in transmural 45-54 years, indeed, it is around 2-5%, whereas myocardial ischaemia. Coronary artery spasm it is 10-20% at the age of 65-7423. may occur at the site of an obstructive coro- Interestingly, the prevalence of angina seems nary atherosclerotic plaque or in angiographi- to be slightly higher in women than in men cally normal or near normal coronary arteries. through several age decades and countries in the In some cases it may involve more segments world, with an average ratio of 1.224. However, in the same coronary artery branch or even about 10% to 30% of women with angina symp- more than one branch8-16. toms have normal or near normal coronary arter- Thrombosis: local thrombosis occurs at the site ies suggesting a prevalence of microvascular dis- of eroded or fissured plaques is central to the function in the femal gender. initiation of myocardial ischaemia in ACS17. Microvascular dysfunction: a result of either functional (e.g. endothelial and/or smooth Characteristics of Angina Pectoris muscle cell dysfunction) or structural (e.g. re- modelling of intramural coronary arteries with The most typical clinical manifestation of my- a reduced lumen to wall ratio) alterations3,4. ocardial ischaemia is represented by angina pec- Extracoronary disease: for esample hyper- toris25. The features of chest pain that should be trophic cardiomyopathy, restrictive cardiomy- investigated to diagnose and characterize angina opathy, hypertensive heart disease, aortic pectoris include type, location, irradiation and du- stenosis, pulmonary diseases, severe anaemia ration of pain, modalities of pain onset and offset, or hyperthyroidism6. and response to cessation of effort and nitrate ad- ministration. Most patients refer angina symptoms as a constrictive, aching sensation, or pressure or Epidemiology of Chronic Ischaemic tightness discomfort in the retrosternal area or in Heart Disease the anterior portion of the chest and the area of pain, indicating by the patient with a clenched fist Cardiovascular diseases remain a major cause or an open hand in the middle of the chest. of mortality and morbility in Western countries, Pain frequently radiates towards the neck, the although, after peaking in the ’60s of the previ- left shoulder and the medial side of the left arm, ous Century, a decreasing trend of their inci- and lasts no more than 10-15 minutes. Angina dence has been shown in the last decades, mainly responds promptly to cessation of effort and explained by the dramatic improvement in the short-acting nitrates. However, several variants control of cardiovascular risk factors and preven- exist to this typical presentation and pain can be tive medical therapies18-20. The exact prevalence represented by a heavy or burning sensation and and incidence of chronic stable angina in Euro- can radiate towards the epigastrium, the right pean as well as in other countries, however, is shoulder or arm, the interscapular area, the jaw poorly known in the contemporary era due to the and teeth, and, exceptionally, it can also be re- lack of recent large-scale epidemiologic studies. ferred to the upper right abdominal quadrant or In fact, the prevalence and incidence of angina to the head26. Physical efforts are often the trig- have been always difficult to be assessed ade- ger of angina, but angina symptoms may appear quately, as, in contrast with acute coronary during stressful or emotional states, exposure to events, that require hospitalization and, therefore, cold, abundant meals or hypertensive episodes. can be more easily identified, the diffusion of Angina usually subsides by removing the trig- angina in the population can be assessed only by gering cause, but short-acting nitrates may be means of surveys or questionnaires21. necessary to shorten angina duration. Finally, However, several previous studies from differ- angina can also occur at rest without any appar- ent cohorts of patients suggested an annual inci- ent triggering cause. dence of uncomplicated angina of about 0.5% in Furthermore, angina pectoris may be caused Western people with age > 40, although geo- by several non-ischaemic cardiac diseases or by graphic variations are evident22. Overall, it can be extracardiac diseases (Figure 1). In fact, somatic estimated that between 20.000 and 40.000 pa- or visceral pain signals may converge on the 1612 The patient with chronic ischemic heart disease Figure 1. Non ischaemic cause of chest pain. same neurones in the spinal dorsal horns which pattern of angina which has remained stable for also receive cardiac ischaemic pain signals, thus at least 2 months and it can be the first manifes- resulting in a pain sensation similar or indistin- tation of IHD or can appear in patients who had guishable from angina. suffered a previous acute coronary event. Typi- Furthermore, in some patients myocardial is- cally, stable angina is induced by efforts or con- chaemia is expressed by transient symptoms that ditions that increase myocardial oxygen demand are different from angina pectoris, including dys- (e.g., emotional and psychological stresses, hy- pnea, arrhythmias and presyncope or syncope pertensive

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