Controversial Question



Is targeting only stenosis sufficient to optimally improve angina?

1. P. S. Farsky, Brazil
2. L. O. Go, Philippines
3. H. Hasan-Ali, Egypt
4. H. Q. T. Ho, Vietnam
5. D. Isaza-Restrepo, Colombia
6. T. Kovarnik, Czech Republic
7. O. H. Masoli, Argentina
8. A. N. Parkhomenko and S. Gurjeva, Ukraine
9. C. K. Ponde, India
10. V. Sansoy, Turkey
11. D. Vassilev, Bulgaria

1. P. S. Farsky, Brazil

Pedro Silvio FARSKY, MD
Doutor em Ciências pela Fac Medicina USP
Fellow da European Society of Cardiology Instituto Dante Pazzanese de Cardiologia Hospital Israelita Albert Einstein São Paulo, BRAZIL
(email: farskyp@uol.com.br)

Myocardial revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) is indicated when there is significant obstruction of coronary blood flow associated with myocardial ischemia, in order to relieve symptoms or prolong survival.
Several mechanisms may explain the persistence of angina/ ischemia after a revascularization procedure, including graft or PCI failure, incomplete revascularization, and disease progression in native coronary arteries. Microvascular dysfunction may play a prominent role in the unexpected prevalence of angina after the removal of obstructions in the major coronary branches.

Graft failure and new atherosclerotic lesions

Angina may recur at any time in the first few months following apparently successful CABG surgery, and may present as stable or unstable angina. In the early postoperative period, angina is usually caused by graft closure due to a technical problem. One year after CABG, angina may occur as a result of the gradual development of graft stenosis or of the progression of new atherosclerotic lesions, either in nonbypassed vessels or distal to graft anastomosis.

After 10 years, the rate of saphenous vein graft closure is about 50%, and is associated with anatomical factors (eg, artery diameter), clinical factors (eg, male sex and aging), and risk factors for atherosclerotic cardiovascular disease.1 Using the internal thoracic artery reduces angina recurrence and prolongs survival.

Late recurrent angina after CABG can also result from progressive atherosclerosis in a native vessel. Studies performed before the widespread use of arterial grafting found that saphenous vein graft (SVG) disease was responsible for 80% of new angina symptoms, as opposed to new native artery disease, which was responsible for 54% of the cases.2 Later, an analysis from the BARI trial (Bypass Angioplasty Revascularization Investigation), which investigated the use of CABG versus PCI in patients with stable angina, showed that native coronary disease progression exceeded failed revascularization as the cause of angina after five years.3 Disease progression occurred in native untreated arteries in two-thirds of cases. In this study, the myocardial jeopardy score fell following initial revascularization, from 60% to 17% for PCI-treated patients compared with a reduction from 60% to 7% for CABG surgery patients (P<0.001), but rebounded after five years to 25% for PCI and 20% for surgery patients (P=0.01). Myocardial jeopardy increased between study entry and the fiveyear follow-up in 42% of PCI-treated patients and 51% of CABG-treated patients (P=0.06).

The MASS II trial (Medicine, Angioplasty, or Surgery Study) randomly assigned 611 patients with multivessel disease, preserved left ventricular systolic function, and stable angina to CABG, PCI, or optimal medical therapy.4 After only one year, 12% of the patients in the CABG group, 21% in the PCI group, and 54% in the medical therapy group had angina (P<0.0001). Furthermore, after 10 years, 64% of patients in the CABG group, 59% of patients in the PCI group, and 43% in the optimal medical therapy group (P<0.001) were angina free.

Incomplete coronary revascularization

In many patients with chronic stable angina, complete revascularization is not achieved at the time of PCI or CABG. Complete revascularization of all significantly obstructed coronary segments is the goal of CABG, and recent data has shown that complete revascularization following PCI has a positive effect on long-term clinical outcomes. However, incomplete coronary revascularization following CABG or PCI is associated with increased mortality as well as with an increased incidence of myocardial infarction, repeat revascularization, and major adverse cardiovascular or cerebrovascular events.5

References

1. Goldman S, Copeland J, Moritz T, et al. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study. Circulation. 1988;77:1324-1332. 
2. Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol. 1996;28:616-626. 
3. Alderman EL, Kip KE, Whitlow PL, et al. Native coronary disease progression exceeds failed revascularization as cause of angina after five years in the Bypass Angioplasty Revascularization Investigation (BARI). J Am Coll Cardiol. 2004;44: 766-774. 
4. Hueb W, Soares PR, Gersh BJ, et al. The medicine, angioplasty, or surgery study (MASS-II): a randomized, controlled clinical trial of three therapeutic strategies for multivessel coronary artery disease: one-year results. J Am Coll Cardiol. 2004; 43:1743-1751. 
5. Kereiakes DJ. Reassessing the importance of complete versus incomplete coronary revascularization. Rev Cardiovasc Med. 2014;15:24-30.

 


2. L. O. Go, Philippines

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Loewe O. GO, MD, FACC
H. B. Calleja Heart and Vascular Institute
ST. LUKE’S MEDICAL CENTER
Quezon City PHILIPPINES
(email: goloewe@yahoo.com.ph)

Back in the early 1990s, when I was a cardiology fellow in Mount Sinai Hospital in New York, coronary angioplasty was a very popular treatment for treating angina in patients with coronary artery disease. However, the director of the cardiac catheterization laboratory, Dr John Ambrose, taught us something radical at the time: patients presenting with stable and even unstable angina often have nonsignificant or no coronary stenosis during angiography. It turns out that this was a very prescient observation.
Two lines of evidence strongly suggest that targeting only coronary stenosis is NOT sufficient to optimally improve angina in patients with ischemic heart disease (IHD). First, angina actually occurs in patients in the absence of coronary stenosis. In one study of 1630 patients with typical angina, the observed prevalence of angiographically confirmed >50% stenotic coronary artery disease ranged from 38%-53% in men and 15%-29% in women over 50 years old1—which implies that the majority of these patients do not have significant coronary obstruction. And in patients with the most dramatic manifestations of IHD, namely those with ST-elevation myocardial infarction (2251 patients) or unstable angina (2406 patients), up to 7%-14% of men and 10%-30% of women have normal coronary artery angiograms.2 Second, multiple studies show that even after successful revascularization a significant number of patients still suffer from angina. The landmark COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) showed that after percutaneous coronary intervention on top of optimal medical therapy, many patients remain symptomatic—41% at three years and 26% at five years.3 A meta-analysis which included studies published from 1992-2007 (RITA-2 [Randomized Intervention Treatment of Angina 2], SWISSI II [SWiss Interventional Study on Silent Ischemia 2], MASS II [Medicine, Angioplasty, or Surgery Study 2], and COURAGE 2007) showed that angina persists in 29%-31% of revascularized patients from one to five years out.4 Despite the current technical advancements in revascularization procedures, angina is still present at 12 months of follow-up in 29.4% of percutaneous coronary intervention patients and 23.7% of coronary artery bypass graft surgery patients.5 And in the most aggressively managed IHD patient group, those with acute coronary syndrome, residual angina at one year of follow-up is found in 37% of those patients who received early invasive therapy.6

Taken together, these observations suggest that coronary stenosis or obstruction is not the only causative factor of symptomatic IHD, and hence revascularization alone cannot relieve angina in all patients. Other factors such as vasospasm, microvascular disease, endothelial dysfunction, thrombosis, inflammation and even an excessive heart rate can also provoke angina. And keep in mind that these factors are not mutually exclusive (ie, several of them can be operating simultaneously in the same patient). Thus, guidelines for IHD management emphasize global risk assessment and recommend optimizing treatment by using renin-angiotensin system– inhibitors, statins, antithrombotic agents, b-blockers, and/or other heart rate–lowering agents. But whatever the etiology of angina, the end result is a metabolic derangement in the cardiomyocytes leading to an imbalance between energy production and consumption. This imbalance produces increased lactic acid levels, which then stimulate sensory nerve fibers in the myocardium and manifest as angina. Correcting these derangements requires the use of unique agents, such as trimetazidine, which shifts mitochondrial energy production from fatty acid oxidation (more oxygen consuming) to glucose oxidation (more oxygen sparing) and thus can help to restore the balance between energy supply and demand, decrease lactic acidosis, and ultimately reduce angina.

References

1. Cheng VY, Berman DS, Rozanski A, et al. Performance of the Traditional Age, Sex, and Angina Typicality–Based Approach for Estimating Pretest Probability of Angiographically Significant Coronary Artery Disease in Patients Undergoing Coronary Computed Tomographic Angiography. Results From the Multinational Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry (CONFIRM). Circulation. 2011;124:2423-2432. 
2. Hochman JS, Tamis, JE, Thompson TD, et al. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. N Engl J Med. 1999;341:226- 232. 
3. Weintraub WS, Spertus JA, Kolm P, et al; COURAGE Trial Research Group. Effect of PCI on Quality of Life in Patients with Stable Coronary Disease. N Engl J Med. 2008;359:677-687. 
4. Wijeysundera HC, Nallamothu BK, Krumholz HM, Tu JV, Ko DT. Meta-analysis: Effects of Percutaneous Coronary Intervention Versus Medical Therapy on Angina Relief. Ann Intern Med. 2010;152:370-379. 
5. Cohen DJ, Van Hout B, Serruys PW, et al; SYNTAX Investigators. Quality of Life after PCI with Drug-Eluting Stents or Coronary-Artery Bypass Surgery. N Engl J Med. 2011;364:1016-1026.
6. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Lancet. 2002; 360:743-751.

 


3. H. Hasan-Ali, Egypt

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Hosam HASAN-ALI, MD, PhD
A Board Member of the Egyptian Society
of Cardiology
Head of Cardiovascular Medicine Department
Assiut University Cardiac Hospital
Assiut University Hospitals
Assiut Governorate, EGYPT
(e-mail: hosam_hasan@hotmail.com)

Traditionally, ischemic heart disease has been linked to the presence of obstructive epicardial coronary artery disease.1 However, extensive data have failed to show that all patients who have atherosclerotic obstructions have ischemic heart disease or, conversely, that all patients who have ischemic heart disease present with obstructive coronary atherosclerosis.2 Obstructive coronary artery disease has been reported in asymptomatic individuals and this is referred to as silent ischemia.1,3 In contrast, obstructive coronary artery disease is absent in patients with typical angina1 and in patients with positive non-invasive testing.3 This is more obvious in women than in men.3 More than half the women with stable chest pain undergoing coronary angiography do not have obstructive coronary artery disease, while this is true for only one-third of men.4

Traditionally, this was considered to be due to false positive non-invasive tests.3 Patients with stable angina and normal coronary arteries or diffuse nonobstructive coronary artery disease were thought to experience little more than a reduction in their quality of life and have a benign prognosis; however, they actually have elevated risks of major adverse cardiovascular events and all-cause mortality compared with a reference population without ischemic heart disease.4

In addition, large myocardial infarction registries have showed an absence of flow-limiting coronary pathology in 5%-25% of cases.5 This changed our view of this type of patients and the term “cardiac syndrome X” emerged to describe patients who show signs of ischemic heart disease in the absence of obstructive epicardial coronary artery disease.5 In these patients the pathophysiological mechanisms underlying ischemic heart disease are endothelial dysfunction and microvascular dysfunction, sometimes associated with coronary microvascular spam and epicardial coronary artery spasm.2,5

According to the so-called “plaque-centric” hypothesis, it was thought that removing epicardial coronary stenosis by percutaneous coronary intervention could “cure” ischemic heart disease, and therefore, angina. However, in the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation), only 66% of stable angina patients treated by percutaneous coronary intervention were free from angina at one year, and 74% at 5 years.6 The recent reports of persistent angina occurring after percutaneous coronary intervention with evidence of ischemia in the absence of residual stenosis or restenosis have showed that microvascular ischemia may coexist in patients with epicardial obstructive coronary artery disease.2,5 These findings shifted the paradigm of ischemic heart disease pathophysiology from the traditional “plaque-centric” hypothesis to a multifactorial hypothesis. This new model—which Marzilli et al 2 call the “solar system of ischemic heart disease”—is centered around myocardial ischemia, and the “orbiting planets” are the six factors that contribute to ischemia: epicardial coronary artery obstruction, endothelial dysfunction, microvascular dysfunction, coronary spasm (microvascular and epicardial), spontaneous thrombosis and platelet aggregation, and inflammation. Since epicardial coronary artery obstruction is only one of these factors, targeting epicardial coronary stenosis—when it is present—is actually only one step in the management of ischemic heart disease. A more comprehensive approach that also includes the myocardial cell and microvascular ischemia is essential to improve patient morbidity and mortality.

References

1. Cheng VY, Berman DS, Rozanski A, et al. Performance of the traditional age, sex, and angina typicality-based approach for estimating pretest probability of angiographically significant coronary artery disease in patients undergoing coronary computed tomographic angiography: Results from the multinational coronary CT angiography evaluation for clinical outcomes: An international multicenter registry (confirm). Circulation. 2011;124:2423-2432. 
2. Marzilli M, Merz CN, Boden WE, et al. Obstructive coronary atherosclerosis and ischemic heart disease: An elusive link! J Am Coll Cardiol. 2012;60:951-956. 
3. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. New Engl J Med. 2010;362:886-895. 
4. 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. 
5. Cocco G, Jerie P. Angina pectoris in patients without flow-limiting coronary artery disease (cardiac syndrome x). A forest of a variety of trees. Cardiol J. 2015; 22(6):605-612. 6. Boden WE, O'Rourke RA, Teo KK, et al; Group CTR. Optimal medical therapy with or without PCI for stable coronary disease. New Engl J Med. 2007;356:1503-1516.

 


4. H. Q. T. Ho, Vietnam

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Huynh Quang Tri HO, MD, PhD
Head of Intensive Care Unit,
Heart Institute of Hochiminh City
VIETNAM
(email: hohuynhquangtri@yahoo.com)

When treating patients with chronic stable angina, clinicians should aim at reducing anginal symptoms, which will improve their patients’ exercise capacity and quality of life. The traditional approach to symptom reduction is the prescription of hemodynamic drugs such as b-blockers, calcium antagonists, and nitrates. In case of poor response to medical therapy, coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) is often performed. The rationale for prescribing hemodynamic drugs and performing coronary revascularization as the next step in the treatment of angina is the assumption that the unique cause of angina is coronary artery stenosis.

However, numerous clinical studies have proven the shortcomings of this traditional approach. In the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation), 2287 patients with stable coronary artery disease were randomized to undergo PCI with optimal medical therapy (PCI group) or optimal medical therapy alone.1 Optimal medical therapy included antiplatelet agents, a statin, and hemodynamic antianginal drugs alone or in combination. Although antianginal drugs were widely prescribed, 21.1% of patients in the PCI group needed to undergo additional revascularization, and at the end of the study, only 74% of patients were free of angina. The design of the BARI 2D trial (Bypass Angioplasty Revascularization Investigation 2 diabetes), which was carried out in 2364 patients with coronary artery disease and type 2 diabetes, was similar to that of the COURAGE trial.2 In the group of patients who underwent prompt coronary revascularization (PCI or CABG), more than 90% needed antianginal drugs (b-blockers, calcium antagonists, and nitrates) alone or in combination to control their symptoms. Despite this extensive use of antianginal drugs, only 66% of patients were free from angina after 3 years of follow-up. The results of the COURAGE and BARI 2D trials indicate that targeting coronary artery stenosis only is far from sufficient to optimally improve angina.

On the other hand, myocardial ischemia in the absence of obstructive coronary disease is a marker of poor prognosis. In the WISE study (Women’s Ischemia Syndrome Evaluation), women with myocardial ischemia (seen on magnetic resonance spectroscopy) who did not have obstructive coronary disease had a similarly high rate of hospitalization for unstable angina than women with obstructive coronary disease.3

Trimetazidine, an antianginal drug that controls myocardial ischemia through intracellular metabolic changes, represents a useful alternative and can be used as add-on therapy to hemodynamic antianginal drugs. A growing body of evidence supports the antianginal efficacy of trimetazidine, alone or in combination.

The data described here point to the conclusion that the treatment of angina should focus on myocardial ischemia rather than solely on coronary artery stenosis. Accordingly, the latest ESC guidelines on the management of stable coronary artery disease have recognized the important role of metabolic agents like trimetazidine.4

References

1. Boden WE, O’Rourke RA, Teo KK, et al; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-1516. 
2. Dagenais GR, Lu J, Faxon DP, et al; BARI 2D Study Group. Effects of optimal medical treatment with or without coronary revascularization on angina and subsequent revascularizations in patients with type 2 diabetes mellitus and stable ischemic heart disease. Circulation. 2011;123:1492-1500. 
3. Johson BD, Shaw LJ, Buchthal SD, et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease. Results from the National Institutes of Health-National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation. 2004;109:2993- 2999. 
4. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J. 2013;34:2949-3003.

 


5. D. Isaza-Restrepo, Colombia

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Daniel ISAZA-RESTREPO, MD, FACC
Director Coronary Care Unit
Fundación Cardioinfantil
Director of Cardiology Fellowship program
Universidad del Rosario, and Universidad
del Bosque at Fundación Cardioinfantil
Bogotá, COLOMBIA
(email: disaza@cardioinfantil.org)

Cardiac energy metabolism alterations are the main pathophysiological factor involved in many heart conditions, such as ischemic heart disease, where oxygen delivery is impaired by the presence of stenosis.1 Oxygen is required to produce enough energy to maintain cardiac function using substrates such as glucose, free fatty acids (FFAs), and proteins. The lack of oxygen caused by ischemic heart disease alters the metabolic pathways of individual cells. Current data show that even after successful revascularization a third of angina patients still suffer from pain. Reasons for this include: mechanical aspects such as neointimal hyperplasia/ restenosis, incomplete revascularization, atherosclerotic plaque progression, microvascular dysfunction, or coronary vasospasm. However, the diffuse nature of angina and the fact that ischemia affects the metabolism of every cardiomyocyte may perpetuate this condition.

Modifying the energy substrate supply has been proposed as a way to improve the metabolic performance of cardiomyocytes. Initially, studies that used an infusion of glucose-insulinpotassium to increase the rate of glycolysis and decrease the bioavailability of FFAs to potentiate cardiac metabolism were not conclusive in showing clinical benefit.2 Other drugs, such as fibrates, niacin, and nicotinic acid—which act as PPAR ligand– activated nuclear hormone receptor agonists and decrease triglyceride levels, and therefore FFA levels, thereby reducing the rate of b-oxidation—showed benefits but their side effects casted doubt about their clinical usefulness.3

Modifying enzyme expression should theoretically be beneficial, but more clinical evidence is needed to support the use of etomoxir, oxfenicine, and perhexiline. These drugs inhibit the action of malonyl-CoA decarboxylase, an enzyme in the fatty acid synthesis pathway, which degrades malonyl- CoA. In turn, malonyl-CoA acts as an inhibitor of carnitine palmitoyltransferase-1 (CPT-1), a key enzyme involved in b-oxidation. This prevents the use of FFAs as an energy substrate, thereby optimizing energy production in cardiomyocytes.4 The effects of dichloroacetate, a drug that increases glucose oxidation by stimulating pyruvate dehydrogenase, have been studied in patients with ischemic heart disease.5 However, some pharmacokinetic and pharmacodynamic issues need to be clarified before its real clinical benefit can be determined.5 As mentioned above, these methods either require further evidence or are not used because of concerns regarding their safety.

Taking into account these issues, trimetazidine appears to be the best evidence-based option to optimize metabolism in ischemic heart disease. It competitively inhibits long-chain 3-ketoacyl CoA thiolase, and therefore inhibits b-oxidation and stimulates glucose oxidation. Meta-analyses have proven its clinical benefit in patients suffering from angina pectoris secondary to ischemic heart disease, and have suggested that it may be beneficial in patients with heart failure.6,7

As exposed previously, we can be sure that modifying the cardiomyocytes’ metabolic machinery in patients with coronary artery disease improves ischemic symptoms further than mechanical coronary interventions alone. This knowledge opens up a broad range of possibilities for improving the quality of life of our patients. The results of the ongoing ATPCI clinical trial (efficAcy and safety of Trimetazidine in Patients with angina pectoris having been treated by percutaneous Coronary Intervention), which is currently enrolling patients with angina pectoris undergoing PCI who are then randomized to trimetazidine or placebo and treated for 2 to 4 years, are expected to further our knowledge in this area.

References

1. Taegtmeyer H, Young ME, Lopaschuk GD, et al. Assessing Cardiac Metabolism: A Scientific Statement From the American Heart Association. Circ Res. 2016; 118(10):1659-1701. 
2. Selker HP, Beshansky JR, Sheehan PR, et al. Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. JAMA. 2012;307: 1925-1933. 
3. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245- 1255. 
4. Cole PL, Beamer AD, McGowan N, et al. Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation. 1990;81:1260-1270. 
5. Wargovich TJ, MacDonald RG, Hill JA, Feldman RL, Stacpoole PW, Pepine CJ. Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease. Am J Cardiol. 1988;61:65-70. 
6. Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Database Syst Rev. 2005;CD003614. 
7. Gao D, Ning N, Niu X, Hao G, Meng Z. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 2011;97:278-286.

 


6. T. Kovarnik, Czech Republic

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Tomas KOVARNIK, MD, PhD
Associate Professor of Internal Medicine
Charles University Hospital
Prague, CZECH REPUBLIC
(email: Tomas.Kovarnik@vfn.cz)

Angina pectoris (AP) refers to chest pain caused by myocardial ischemia and is actually only a symptom. Myocardial ischemia can develop either gradually— and cause clinical manifestations known as stable angina pectoris (SAP)—or suddenly—with the development of acute coronary syndrome (ACS).

In both clinical scenarios the extent of myocardial ischemia is the strongest predictor of prognosis. Myocardial ischemia can be treated by (i) improving blood flow to the myocardium (revascularization), (ii) decreasing myocardial demand on blood flow (eg, with b-blockers, calcium channel blockers, and ivabradine—a drug that lowers oxygen consumption and increases blood flow to the myocardium by decreasing the heart rate), and (iii) increasing myocardial metabolic efficiency when blood supply is limited (eg, with trimetazidine, a drug that improves the efficiency of energy production in myocardial cells suffering from ischemia by shifting their metabolism from free-fatty-acid b-oxidation back to glycolysis). Nitrates fall somewhere between revascularization and the latter two “conservative” strategies, because they can enlarge coronary arteries and increase blood flow, while at the same time decreasing preload (by venous dilatation). This action, in turn, decreases oxygen consumption.

The greater the extent of myocardial ischemia, the greater the benefit of revascularization will be. Revascularization not only limits AP better than conservative therapy, but it also improves the prognosis in patients with significant stenosis located in the left main coronary artery; significant stenosis located in a proximal part of the left anterior descending artery; significant stenosis located in two or three major vessels together with systolic dysfunction of the left ventricle (ejection fraction <45%); myocardial ischemia affecting a large area (>10%); and significant stenosis located in the last patent coronary artery.1

However, about 30% patients suffer from AP after successful revascularization, which significantly impairs their quality of life.2 Post-revascularization AP occurs when:
(i) Revascularization is inappropriately indicated. The only unquestionable indication for coronary revascularization in stable patients is the presence of significant ischemia with (SAP) or without (silent ischemia) angina pectoris. Revascularization simply cannot overcome the inherent risk of complications (in-stent restenosis, periprocedural myocardial necrosis, instent thrombosis, bleeding during antithrombotic treatment, potential wound infection, and many others) in patients without significant ischemia. Moreover, in patients without evidence of ischemia, chest pain may have other causes, and its recurrence after revascularization cannot be considered as treatment failure.
(ii) There is a coronary etiology. In this case, AP recurs after appropriately indicated and well-performed revascularization. This relapse can be caused by target lesion failure (in-stent restenosis, in-stent thrombosis) or the progression of a lesion that was not significant at the time of revascularization. Revascularization itself does not affect the process of atherosclerosis, which can continue unless appropriate medication is prescribed. These conditions must be treated according to the underlying causes.
(iii) AP persists despite appropriately indicated revascularization, which may be due to incomplete revascularization (another significant stenosis that has been left untreated), the presence of microvessel disease, a technical complication during PCI (peripheral embolization, untreated dissection), or “stretch” pain (probably due to extension of vessel adventitia).

Several smaller studies have suggested that the incidence of chest pain is lower after implantation of fully biodegradable stents rather than metallic stents. However, the large randomized controlled trial ABSORB 3 did not confirm this finding. 3 In this trial, AP occurred in 18% of patients, both in the biodegradable and drug-eluting stent groups.

Conclusion

For every patient it is necessary to determine whether chest pain is caused by ischemia, and if it is, to what extent. Based on this information, the treatment can be properly tailored to each patient to avoid unnecessary revascularization, which would not only without any benefit, but could actually be harmful.

References

1. Windecker S, Kolh P, Alfonso F. 2014 ESC/EACTS Guidelines on myocardial Revascularization. Eur Heart J. 2014;35:2541-2619. 
2. Abbate A, Biondi-Zoccai G, Agostoni P, Lipinski M, Vetrovec G. Recurrent angina after coronary revascularization: a clinical challenge. Eur Heart J. 2007;28: 1057-1065. 
3. Kereiakes D. ABSORB 3 trial. Presented at: TCT 2015; October 2015; San Francisco, CA.

 


7. O. H. Masoli, Argentina

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Osvaldo H. MASOLI, MD, FACC, FESC
Chief of Cardiac Imaging
Image Department of TCba Salguero
Buenos Aires, ARGENTINA
(email: ohmasoli@fibertel.com.ar)

The coronary circulation is composed of the epicardial coronary arteries, which are of large caliber, and the resistance vessels, which are less than 300 μm in diameter. Whereas the epicardial vessels exert little or no flow resistance, flow resistance in the resistance vessels increases gradually as the vessel diameter decreases to less than 100 μm (eg, in arterioles). Exchange of substances between blood and tissue occurs at the capillary level.

In the myocardium, blood flow largely depends on the pressure gradient between the aortic root and the left atrium (“coronary pressure”). Under normal conditions, coronary pressure is fully maintained in the epicardial vessels, with minimal or no loss of pressure in the distal epicardial arteries. In contrast, intracoronary pressure decreases along the microvasculature to a pressure of 20-30 mm Hg (with most of the pressure dissipating in vessels with a diameter of 100-300 μm).

As a result of a decrease in microvascular resistance caused by metabolic changes—possibly involving adenosine, a metabolite of adenosine monophosphate which induces vascular muscle relaxation—work-related myocardial flow increases.

The resulting flow increase is augmented by endothelium-dependent factors, and this faster flow exerts more shear stress on the endothelium, stimulates the enzyme nitric oxide synthase (eNOS), triggering the release of nitric oxide, which relaxes smooth muscles. In this scenario, endothelial cells and smooth muscle cells interact closely, which helps the vessels adjust their diameter according to changes in flow rate in the microvascular and epicardial vessels.

Coronary reserve

A good understanding of the physiology of the coronary circulation is necessary to understand the concept of coronary reserve. In a nutshell, coronary reserve refers to the ability of the vascular circuits to adapt to myocardial oxygen consumption by vasodilation. Dependingon the levelof endothelial health and on the extent of the mechanical obstruction present in the epicardial arteries as a result of the atherosclerotic process, an adaptive process called vascular remodelingmay takeplace. This process initially leads to an increase in vessel diameter. When atherosclerosis involves the lumen, the percentage of obstruction will affect the coronary reserve capacity, ie, the ability to lower vascular resistance, and thus increase flow, so that the arterial blood can reach peripheral tissues without altering cellular metabolism. But this compensation mechanism is limited. Unless we try to stop the progress of atherosclerosis or remove the obstruction, with medication and/or invasive treatments such as myocardial revascularization procedures, the damage may be irreversible and permanently alter the affected vessel, and thus tissue function.

Conclusion

The mechanisms involved in the genesis of myocardial ischemia and its manifestation as angina are very complex and go beyond the epicardial arteries. Therefore, efforts aiming to normalize the lumen of the arteries or bypass the obstruction only act on part of the problem. Fortunately, we now have drugs that can improve cell metabolism, such as trimetazidine, or new drugs that can reduce the heart rate, such as ivabradine, a drug whose pleiotropic effects lead to vasodilatation and the release of nitric oxide, and thus improve endothelium function. But we should not forget all the other drugs that have been shown to have a beneficial effect on the outcome of patients with coronary heart disease, nor the positive effects of healthy eating and physical activity.

References

1. Masoli O, Baliño NP, Sabaté D, et al. Effect of endothelial dysfunction on regional dysfunction on regional perfusion in myocardial territories supplied by normal and diseased vessels in patients with coronary artery disease. J Nucl Cardiol. 2000;7:199-204.
2. Schelbert HR. Anatomy and physiology of coronary blood flow. J Nucl Cardiol. 2010;4:545-554.

 


8. A. N. Parkhomenko and O. S. Gurjeva, Ukraine

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Alexander N. PARKHOMENKO, MD, PhD
Olga S. GURJEVA, MD, PhD, MH
Ukrainian Institute of Cardiology – Kiev, UKRAINE
(e-mail: aparkhomenko@yahoo.com)

Microvascular angina (MVA) is found in about onethird of patients undergoing coronary angiography for angina who have no significant obstructive coronary lesions, and is strongly associated with adverse longterm prognosis.1 In patients with normal, “near-normal,” or restored epicardial flow, several factors contributing to an imbalance between oxygen demand and supply may coexist. About half the patients with coronary artery disease (CAD) have concomitant hypertension, and a growing proportion of elderly patients may present with aortic stenosis (AS). In this group of patients, increased oxygen demand is the result of increased left ventricular end-systolic pressure, left ventricular hypertrophy, impaired diastolic function, increased heart rate, and increased wall stress. As left ventricular hypertrophy progresses, coronary flow reserve may be affected by increased diastolic filling pressure, which compresses the endocardium, impairs perfusion, and reduces capillary distribution.2 In patients with AS, MVA has been attributed to preexisting abnormal resting arteriolar vasodilation in patchily distributed microvasculature preserving myocardial perfusion and abnormally constricted prearteriolar vessels preventing distal pressure overload.3

MVA may follow an endothelium-dependent or an endothelium- independent pattern. According to the current in-depth understanding of the pathways underlying angina symptoms, there is a close correlation between the ratio of oxygen demand to oxygen supply and cardiac energy metabolism (substrate utilization, production of ATP by oxidative phosphorylation, and ATP transfer and utilization).4 The cardiac metabolic system is very flexible, and can switch from one energy source to another. However, its adaptive capacity decreases in states associated with increased oxygen demand or steadily decreased coronary blood flow, triggering metabolic remodeling. Prolonged energy deficit triggers the expression of fetal genes and a switch from fat to glucose metabolism, stimulates glycogen accumulation and changes in cell signaling, increases the number of dysfunctional mitochondria, leads to collagen deposition, macrophage infiltration, fibrosis, depletion of sarcomeres, and activates apoptosis. More profound changes occur in stunned myocardium and result from inhibition of Na-K-ATPase, increased intracellular Na+ level, Ca2+ overload, stimulation of reactive oxygen species (ROS) production, and depression of contractile function in near normal coronary flow. Revascularization partially attenuates these changes, but patients may still experience coronary microembolization and microvascular obstruction, which may lead to abnormal gene expression and apoptosis.5 Apoptosis occurs in low-flow states and may be triggered by reperfusion injury and severe energy depletion and follows either intrinsic mitochondria-mediated or extrinsic membrane-mediated pathways. The intrinsic pathway involves mechanisms that impact the functioning of mitochondrial permeability transition pores (mPTPs). The extrinsic pathway is receptor-mediated and may be activated by oxidative stress late after reperfusion. Reperfusion injury and slow-reflow states contribute to necrosis, increased mitochondrial membrane permeability, cell swelling, lysis, fragmentation of cellular structures, activation of inflammatory pathways, and leukocyte infiltration.

These maladaptive cascades often partially persist after epicardial flow is restored and should be addressed medically. Metabolic agents such as trimetazidine counteract the effect of myocardial ischemia on mitochondrial membrane permeability by diminishing oxidative stress and inhibiting mPTP opening, and also reduce caspase 3 activity and apoptosis.6 The mechanisms that underlie angina are so complex that it cannot be resolved by relying on revascularization only; other nonmechanistic approaches are therefore needed to manage patients after revascularization.

References

1. Jespersen L, Hvelplund A, Abildstrøm S, 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(6):734-744. 2. Rajappan K, Rimoldi OE, Camici PG, et al. Functional changes in coronary microcirculation after valve replacement in patients with aortic stenosis. Circulation. 2003;107:3170-3175. 
3. Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol. 2012;59:655-662. 
4. Neubauer S. The failing heart—an engine out of fuel. N Engl J Med. 2007;356 (11):1140-1151. 
5. Reffelmann T, Kloner RA. The "no-reflow" phenomenon: basic science and clinical correlates. Heart. 2002;87(2):162-168. 
6. Hu B, Li W, Xu T, Chen T, Guo J. Evaluation of trimetazidine in angina pectoris by echocardiography and radionuclide angiography: a meta-analysis of randomized, controlled trials. Clin Cardiol. 2011;34(6):395-400.

 


9. C. K. Ponde, India

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C. K. PONDE, MD, DM(Card), DNB (Card),
FACC, FSCAI, FCSI, FIAE, FISE, FICC
Consultant cardiologist
Head, Department of Cardiology
P.D. Hinduja National Hospital
Mumbai, INDIA
(email: ckpshekhar@yahoo.co.in)

The number of percutaneous coronary angioplasty procedures (PCI) performed in patients with chronic stable angina (CSA) has increased tremendously in the last two decades.1 In a series of 2000 patients with CSA (of whom 39% underwent PCI and 28% CABG) almost a third had multiple episodes of angina per week after 6 months of follow-up.2 Moreover, the Euro Heart Survey reports that 60% of patients with persistent angina post-PCI are moderately/severely disabled.

The most common causes of persistent/recurrent angina post- PCI are either structural (“stretch pain,” in-stent restenosis, in-stent thrombosis, incomplete revascularization, or progression of coronary atherosclerosis) or functional (microvascular dysfunction or epicardial coronary spasm). A recent metaanalysis of randomized clinical trials comparing PCI versus optimal medical therapy (OMT) in patients withCSA has shown that PCI does not reduce the risk of mortality, cardiovascular death, nonfatal myocardial infarction, or revascularization procedures; however, it provides greater relief from angina compared with OMT, at least in the first year.3 Most international guidelines recommend revascularization procedures in CSA only when symptoms are not controlled by OMT.

In-stent restenosis usually manifests between 4 and 8 months after PCI and is associated with angina and objective evidence of myocardial ischemia on provocative testing.4 If OMT fails to control it, repeat revascularization is usually required. However, the use of drug-eluting stents (DESs) has substantially reduced its occurrence.

Inappropriate vasoconstrictionof small vessels in thedistal coronary bed of the target vessel is a frequent cause of positive stress tests after successful angioplasty.5 Stent implantation also induces distal coronary endothelial dysfunction. Exerciseinduced spasm of a large epicardial coronary artery in the distal post-stent segment has been documented and reported. The two most frequent causes of early post-CABG angina are anastomotic site lesions and rapid venous graft degeneration/ thrombosis. A thorough clinical evaluation is crucial in such patients. In those with established angina, direct coronary angiography should be performed, while non-invasive stress tests (vs myocardial scintigraphy/stress echocardiography) are appropriate in those whose probability of having angina is intermediate. Estimation of coronary flow reserve is a boon for those in whom angiography shows borderline stenosis (≤70%). A fractional flow reserve (FFR) of 0.75 or less is usually considered to be a good indication for PCI. The DEFER trial has shown that performing PCI for lesions with a FFR of 0.75 or more does not improve symptoms nor prognosis.6

Achieving and maintaining an optimal body weight and following a graded exercise training program are known to improve exercise capacity in patients with CSA. Achieving an optimal hematocrit and excellent blood pressure control, and lowering LDL-C levels to below 70 mg/dL are all extremely important ways to improve the prognosis of these patients. Post-PCI stretch pain is usually treated with analgesics and is, thankfully, self-limiting. The functional causes of recurrent angina (microvascular dysfunction/epicardial coronary spasm) respond best to diltiazem and long-acting nitrates. Trimetazidine (an inhibitor of fatty acid oxidation), which improves angina by shifting myocardial metabolism toward glucose oxidation (TRIMPOL II study)7 has also been found to be useful in such patients. b-Blockers should be prescribed to all post-PCI patients unless contraindicated. Statins and angiotensin-converting enzyme (ACE) inhibitors should also be part of OMT in most patients. High compliance rates with OMT, such as those obtained in the COURAGE trial, (90% at 5 years) are not easy to obtain in clinical practice unless combinations are used to reduce the number of pills patients are prescribed. Thankfully in India various combinations are freely available. Recently, the BEAUTIFUL and ASSOCIATE trials have shown some promising results for the use of ivabradine as an add-on therapy or in those in whom b-blockers are contraindicated to reduce the frequency of angina attacks and the number of cardiac events.

References

1. Ko DT, Tu JV, Samadashvili Z, et al. Temporal trends in the use of percutaneous coronary intervention and coronary artery bypass surgery in New York State and Ontario. Circulation. 2010;121:2635-2644. 
2. Vetrovec GW, Watson J, Chaitman B, Cody R, Wenger N. Symptoms persist in patients with chronic angina despite frequent antianginal use and prior revascularization. J Am Coll Cardiol. 2004;43(Suppl. II):A281. 
3. Pursnani S, Korley F, Gopaul R, et al. Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease, a systematic review and meta-analysis of randomized clinical trials. Circ Cardiovasc Interv. 2012; 5:476-490. 
4. Holmes DR Jr. In-stent restenosis. Rev Cardiovasc Med. 2001;2:115-119. 
5. Ito S, Nakasuka K, Morimoto K, et al. Angiographic and clinical characteristics of patients with acetylcholine-induced coronary vasospasm on follow-up coronary angiography following drug-eluting stent implantation. J Invasive Cardiol. 2011; 23:57-64. 
6. Pijls NH, Van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol. 2007;49:2105-2111. 
7. Szwed H, Sadowski Z, Elikowski W. Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J. 2001;22: 2267-2274.

 


10. V. Sansoy, Turkey

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Vedat SANSOY, MD, FESC
Professor of Cardiology
Institute of Cardiology
University of Istanbul
Istanbul, TURKEY
(email: vedat.sansoy@gmail.com)

Despite the progress made by the various therapeutic methods used in cardiology in the last decades, coronary artery disease remains the leading cause of mortality and morbidity worldwide. Percutaneous coronary intervention is an effective and safe treatment to relieve severe stenosis in patients with coronary artery disease, but studies have shown that many patients still suffer from recurrent angina or silent myocardial ischemia after revascularization.1

Traditional antianginal agents for the treatment of stable angina pectoris include nitrates, calcium antagonists, and b-blockers, which reduce angina attacks either by reducing ATP consumption via a reduction in the heart rate and blood pressure or by increasing ATP production through an increase in coronary blood flow.2 Optimizing myocardial metabolism with metabolic agents is a new strategy that can be used in patients with stenotic coronary artery disease. These drugs represent a new class in the treatment of ischemic heart disease. Trimetazidine is a metabolic agent, and unlike conventional antianginal drugs, it restores the balance between myocardial oxygen supply and demand by selectively inhibiting the longchain 3-ketoacyl coenzyme A thiolase, thus partially suppressing the b-oxidation of fatty acids, stimulating glucose metabolism, and increasing myocardial ischemic tolerance.3,4 Xu et al 5 have showed that adjunctive therapy with trimetazidine after drug-eluting stent implantation reduces the incidence and the severity of angina pectoris as well as that of silent ischemia in elderly patients with multivessel coronary artery disease and diabetes mellitus. In addition, pretreatment or concomitant treatment with trimetazidine seems to have a cardioprotective effect in patients undergoing percutaneous coronary intervention. These studies have shown that trimetazidine treatment results in an improvement in several ischemic parameters, such as a reduction in the frequency of angina pectoris attacks and of myocardial damage during percutaneous coronary intervention and coronary artery bypass graft surgery. These benefits are achieved because trimetazidine protects the heart from ischemic damage and oxidative stress. In addition, trimetazidine has also been shown to improve left ventricular function in the follow-up period after percutaneous angioplasty.6

References

1. Hueb W, Soares PR, Gersh BJ, et al. The Medicine, Angioplasty, or Surgery trial (MASS-II): a randomized, controlled, clinical trial of three therapeutic strategies for multivessel coronary artery disease. One-year results. J Am Coll Cardiol. 2004;43:1743-1751. 
2. Kolh P, Windecker S, Alfonso F, et al; Task Force on Myocardial Revascularization of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery; European Association of Percutaneous Cardiovascular Interventions. 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur J Cardiothorac Surg. 2014;46:517-592. 
3. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000;86:580-588. 
4. Desideri A, Celegon L. Metabolic management of ischemic heart disease: clinical data with trimetazidine. Am J Cardiol. 1998;82:50K-53K. 
5. Xu X, Zhang W, Zhou Y, et al. Effect of trimetazidine on recurrent angina pectoris and left ventricular structure in elderly multivessel coronary heart disease patients with diabetes mellitus after drug-eluting stent implantation: a single-centre, prospective, randomized, double-blind study at 2-year follow-up. Clin Drug Investig. 2014;34:251-258. 
6. Bonello L, Sbragia P, Amabile N, et al. Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary intervention. Heart. 2007;93:703-707.

 


D. Vassilev, Bulgaria

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Dobrin VASSILEV, PhD
Head of cardiology department
Medical University of Sofia
Sofia, BULGARIA
(email: dobrinv@gmail.com)

Ischemic heart disease is a diffuse disease encompassing not only the epicardial compartment, but also the microvascular compartment. This is one of the reasons for continuing chest pain even after complete mechanical epicardial revascularization: about 40% of all bypassed or stented patients still have angina one year after the procedure.1 We present a case in which the patient had residual ischemia despite complete revascularization with the use of last-generation drug-eluting stents. In cases such as this one—in which further revascularization is impossible—a metabolic drug that can reduce ischemia may improve symptoms.

A fifty-two year-old male smoker, with a history of hypertension and dyslipidemia, was admitted to our clinic with stable angina triggered by low-level physical activity, which he had started to experience approximately one year earlier (class III CCS). His ECG at rest was normal, and did not show any signs of ischemia. Echocardiography did not show any kinetic dysfunction at rest; the ejection fraction was 53%, the left ventricle was not dilated, and there were no significant valvular lesions. In addition, the cardiac markers of myocardial necrosis were normal.

Coronary angiography, which was performed through right radial access, showed 80% stenosis in the distal left main (LM) artery. There was 70% stenosis in the proximal and middle segments of the left anterior descending (LAD) artery, where there were two Medina 110 bifurcation stenotic lesions in the first and second diagonal branches, respectively. The SYNTAX score was 28. According to the ESC Guidelines for Myocardial Revascularization, the patient had left main artery disease with a SYNTAX score of 23-32, which corresponds to class I and level of evidence B for coronary artery bypass graft surgery (CABG).2 Treatment with percutaneous coronary intervention is class IIa with a level B of evidence. However, the Heart Team decided that percutaneous coronary intervention was an option as the patient was reluctant to go through CABG surgery.

Before the procedure, the patient was preloaded with clopidogrel 600 mg and 500 mg aspirin. The procedure was performed through radial access, and a JL 4, 6F guiding catheter was used to canulate the LM. Two wires were placed in the LAD and LCX. First, we predilated the LM-LAD with a balloon, after which two overlapping stents (Biofreedom 3.0×28 mm and 3.5×24 mm) were implanted into the LAD. There was no significant stenosis in the diagonal ostia (grade III TIMI flow). Another overlapping stent was placed in the LM and ostioproximal part of the LAD (Biofreedom 3.5×24 mm). We then dilated the stented region (LM and LAD) with noncompliant (NC) balloons. Because there was 70% stenosis in the LCX ostium we performed a balloon dilation of the LAD and LCX ostia. The final angiographic result showed no dissection and no residual stenosis, and normal flow was restored in all treated vessels. A final intravascular ultrasound (IVUS) was performed in the LAD, LCX and left main artery, and showed no signs of dissection and stent strut malposition. The circumflex artery ostium was not compromised, so there was no need for additional stenting.

The patient was discharged 2 days after the procedure; he had no angina symptoms, nor any elevation of the markers of myocardial necrosis, and there were no adverse events. He was prescribed rosuvastatin, ramipril, bisoprolol, clopidogrel, and acetylsalicylic acid.

At 1 month of follow-up, there were no adverse events, but the patient still had intermittent episodes of chest pain. The stress test at 11 METs (metabolic equivalents) was ECG negative, with slight chest discomfort. For this reason we decided to add trimetazidine to his treatment. At the next visit—the following month—the patient was completely asymptomatic. This case clearly illustrates the fact that even after complete mechanical revascularization microvascular dysfunction can still cause discomfort. Increasing hemodynamic therapy provides no additional benefit in this kind of situation and the only option is to directly alter the ischemic threshold by adding a metabolic drug (eg, trimetazidine) according to the currently proposed algorithm for the treatment of angina.3

References

1. Cohen DJ, Van Hout B, Serruys PW, et al. Quality of life after PCI with drug-eluting stents or coronary-artery bypass surgery. N Engl J Med. 2011;17;364(11): 1016-1026. 
2. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio- Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35(37):2541-2619. 
3. Task Force Members; 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(38):2949-3003.