Angina is often portrayed as a reflection of myocardial ischemia resulting from an imbalance between oxygen supply and demand. Refractory angina on the other hand encompasses neurological, psychogenic and mitochondrial dysfunctions that, in addition to tissue ischemia, are responsible for a persistent cardiac pain syndrome. A growing number of treatment options are becoming available that target these dysfunctions and help relieve severe angina [Figure 1]. Decision support tools have been developed in order to help patients suffering from refractory angina make well-informed decisions about their healthcare and guide them in choosing a treatment that best suits their situation.¹ The following text presents new and emerging treatment options that appear particularly promising to help patients with refractory angina.

FIGURE 1

REDUCTION OF THE CORONARY SINUS

The percutaneous narrowing of cardiac venous system is the modern adaptation of a surgery originally performed by Beck and Leighninger in the 1950's to restrict the venous drainage of the heart.^2,3 In response to stress, the healthy subendocardium remains adequately perfused due to the adaptive vasoconstriction of the subepicardial arterioles. In the presence of advanced coronary artery disease (CAD), this adaptive vasoconstriction becomes insufficient due to the inadequate increase in blood flow secondary to the abnormally high resistance at the level of the large conductance coronary arteries, and subendocardial ischemia ensues. The reduction of the coronary sinus creates a trans-sinusal pressure gradient which is thought to unbalance regional capillary pressure and to force a redistribution of coronary arterial blood from the epicardium to the underperfused endocardium.

The phase II COSIRA (coronary sinus reducer for treatment of refractory angina) sham-controlled trial enrolled participants with advanced CAD unsuitable for revascularization and refractory CCS III or IV angina.⁴ In COSIRA, a greater proportion of patients assigned to a device that narrowed their coronary sinus experienced an improvement of at least two CCS angina classes at six months compared to patients assigned to a sham implantation (35% vs. 15%, p = 0.02) (see Figure 2).⁵ The total exercise duration measured by stress test and the angina-related quality of life improved concordantly. While invasive, the procedure was deemed safe. At six months, one patient (2%) in the treatment group compared to three patients (6%) in the control group experienced a myocardial infarction. One death occurred in the control group. At this moment, the narrowing of the coronary sinus is thought to be efficient for myocardial ischemia originating from the left coronary system, as the right coronary system does not drain by the coronary sinus. A confirmatory phase III trial will be necessary before this treatment can be broadly recommended. This treatment is currently not approved in the Unites States or Canada but is available in some European countries.

FIGURE 2 – A Device to Narrow the Coronary Sinus

CELL THERAPY

In refractory angina, the transplant of exogenous cells is thought to promote angiogenesis and improve blood supply to the ischemic myocardium. Thus far, no finding from a phase III clinical trial has lived up to this promise. However, a meta-analysis of five phase I-II randomized controlled trials with a total of 381 patients has suggested that autologous CD34+ cells or bone marrow mononuclear cells are better than a sham delivery at reducing angina frequency (by 7.3 episodes per week; 95% confidence interval [CI], 1.2 to 13.4; p = 0.02), at increasing exercise tolerance (by 61 seconds; 95% CI, 18 s to 104 s; p= 0.005) and at lowering the risk of myocardial infarction (odds ratio = 0.37; 95% CI, 0.14 to 0.95; P = 0.04).⁶ Concordant findings were also seen in a broader meta-analysis which included patients with chronic ischemic cardiomyopathy.⁷

CD34+ endothelial progenitor cells have been most frequently studied in refractory angina. Wang et al. compared the intracoronary transfusion of bone-marrow derived CD34+ cells (mean 5.6 x10⁷ cells) to placebo in 112 patients with refractory angina. After six months, CD34+ cells significantly reduced the weekly angina count (–15.6 ± 4.0) compared with placebo (–3.0 ± 1.2; p<0.01).⁸ Similarly, Lee et al. found that the intracoronary transfusion of granulocyte colony-stimulating factor (GCSF)-mobilized CD34+ cells was significantly better than a sham delivery at improving left ventricular function. A cardiac MRI sub-study suggested that CD34+ cells improved neovascularization. However, the change in exercise tolerance and symptoms were similar in both groups.⁹ In the largest trial to date, GCSF-mobilized CD34+ (1 x 10⁵ cells per kg) injected directly into the myocardium were found superior to a placebo at improving weekly angina count (6.8 ± 1.1 vs. 10.9 ± 1.2; p = 0.02), with a significant improvement in exercise time (139 s ± 115 s versus 69 s ± 122 s; p = 0.01).¹⁰ These favorable results prompted the launch of the phase III RENEW trial¹¹ which was stopped prematurely in 2014.

Autologous mesenchymal stromal cells (MSCs) have been tested in an open-label, uncontrolled study of patients with advanced CAD and refractory angina. MSCs injected directly into the ischemic myocardium significantly improved total exercise duration and angina class up to three years after implantation.¹² In a phase I-II randomized, controlled trial, the intramyocardial (IM) injection of CD133 cells significantly reduced the number of angina episodes per month (median absolute difference, –8.5; 95%CI, –15.0 to –4.0) and the angina functional class compared to the medical control group.¹³ More recently, a small mechanistic study suggested that the repeated intramyocardial injection of bone marrow mononuclear cells further improved myocardial perfusion and relieved angina in patients who previously responded to cell therapy but who nonetheless had residual or recurrent myocardial ischemia.¹⁴

Cell therapy for refractory angina remains controversial at this moment, especially given the lack a safety information from large phase III trials.

CARDIAC REHABILITATION

While cardiac rehabilitation has been shown to reduce the symptoms of depression and to improve the quality of life of patients with ischemic heart disease, it has infrequently been studied in patients with advanced CAD. In clinical practice, cardiac rehabilitation is rarely prescribed to patients with severe angina by fear of adverse coronary events, even if symptoms have been stable for a long time. Likewise, cardiac rehabilitation is not addressed in practice guidelines for refractory angina.^15,16

In a pilot trial, 42 patients with refractory angina were randomly assigned to either an eight-week outpatient cardiac rehabilitation exercise program or no exercise program.¹⁷ The program was designed to improve aerobic conditioning, functional capacity, and muscular strength through classes in a dedicated center combined with home exercises. Patients randomized to the rehabilitation program were asked to exercise at 60 to 75% of their age-predicted heart rate reserve (when their left ventricular ejection fraction (LVEF) was preserved), or at a target of 40 to 60% (when their LVEF was inferior to 40%). Patients assigned to cardiac rehabilitation improved their total distance walked by about 50 m (on the progressive Shuttle Walk level attainment test), with no significant deterioration of their angina frequency and severity. However, the severity and frequency of angina frequency remained unchanged in both groups, possibly due to a type II error. Cardiac rehabilitation for refractory angina has not been validated in an independent study nor has it been tested in a trial appropriately powered to assess its effect on symptoms improvement.

MENTAL STRESS-INDUCED MYOCARDIAL ISCHEMIA

The treatment of angina typically emphasises on the relief of myocardial ischemia by reducing oxygen demand or increasing offer. Beyond ischemia, angina is also a pain signal that can be modulated by the brain and the emotions. The mental stress-induced myocardial ischemia (MSIMI) is a term coined to describe objective signs of myocardial ischemia (such as ST-segment depression on an electrocardiogram) during a mental stress task. MSIMI is rarely investigated properly in clinical practice. However, experienced cardiologists will not deny that emotional distress can trigger angina episodes,¹⁸ even to the point of inducing myocardial necrosis and failure.¹⁹

MSIMI has been associated with death and cardiovascular events.²⁰ In the REMIT trial (Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment), a greater proportion of patients treated with the selective serotonin-reuptake inhibitor (SSRI) escitalopram (5mg daily for six weeks) were free of MSIMI compared to patients treated with a placebo (17.5% vs. 34.2%, odds ratio 2.62, p = 0.04). Escitalopram had no effect on exercise-induced ischemia but rather improved anxiety and emotional reactions to mental stress.²¹ SSRIs have been hypothesized to down modulate the inappropriate effect that the central nervous system and the hypothalamic–pituitary–adrenal axis system have on the coronary microcirculation, but the exact mechanism of action remains uncertain. Escitalopram should be used cautiously in the concomitant presence of major depression, as it has been associated with increased suicidal risk in subsets of patients. Escitalopram is not to be confused with citalopram, which has been associated with QT interval prolongation.

References

1. McGillion MH, Carroll SL, Metcalfe K, et al. Development of a patient decision aid for people with refractory angina: protocol for a three-phase pilot study. Health and quality of life outcomes 2014;12:93.
2. BECK CS, LEIGHNINGER DS. Operations for coronary artery disease. J Am Med Assoc 1954;156:1226-33.
3. BECK CS, LEIGHNINGER DS. Scientific basis for the surgical treatment of coronary artery disease. J Am Med Assoc 1955;159:1264-71.
4. Jolicoeur EM, Banai S, Henry TD, et al. A phase II, sham-controlled, double-blinded study testing the safety and efficacy of the coronary sinus reducer in patients with refractory angina: study protocol for a randomized controlled trial. Trials 2013;14:46.
5. Verheye S, Jolicoeur EM, Behan MW, et al. Efficacy of a device to narrow the coronary sinus in refractory angina. N Engl J Med 2015;372:519-27.
6. Li N, Yang YJ, Zhang Q, Jin C, Wang H, Qian HY. Stem cell therapy is a promising tool for refractory angina: a meta-analysis of randomized controlled trials. The Canadian journal of cardiology 2013;29:908-14.
7. Kandala J, Upadhyay GA, Pokushalov E, Wu S, Drachman DE, Singh JP. Meta-analysis of stem cell therapy in chronic ischemic cardiomyopathy. Am J Cardiol 2013;112:217-25.
8. Wang S FAU - Cui J, Cui JF, Peng WF, Lu M. Intracoronary autologous CD34+ stem cell therapy for intractable angina.
9. Lee FY, Chen YL, Sung PH, et al. Intracoronary Transfusion of Circulation-Derived CD34+ Cells Improves Left Ventricular Function in Patients With End-Stage Diffuse Coronary Artery Disease Unsuitable for Coronary Intervention. Critical care medicine 2015.
10. Losordo DW, Henry TD, Davidson C, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res 2011;109:428-36.
11. Povsic TJ, Junge C, Nada A, et al. A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study. Am Heart J 2013;165:854-61.e2.
12. Mathiasen AB, Haack-Sorensen M, Jorgensen E, Kastrup J. Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina--final 3-year follow-up. International journal of cardiology 2013;170:246-51.
13. Jimenez-Quevedo P, Gonzalez-Ferrer JJ, Sabate M, et al. Selected CD133(+) progenitor cells to promote angiogenesis in patients with refractory angina: final results of the PROGENITOR randomized trial. Circulation research 2014;115:950-60.
14. Mann I, Rodrigo SF, van Ramshorst J, et al. Repeated Intramyocardial Bone Marrow Cell Injection in Previously Responding Patients With Refractory Angina Again Improves Myocardial Perfusion, Anginal Complaints, and Quality of Life. Circ Cardiovasc Interv 2015;8.
15. McGillion M, Arthur HM, Cook A, et al. Management of patients with refractory angina: canadian cardiovascular society/canadian pain society joint guidelines. CanJ Cardiol 2012;28 Suppl A:S20-S41.
16. National Clinical Guidelines C. National Institute for Health and Clinical Excellence: Guidance. Stable Angina: Methods, Evidence & Guidance. London: Royal College of Physicians (UK) National Clinical Guidelines Centre.; 2011.
17. Asbury EA, Webb CM, Probert H, et al. Cardiac rehabilitation to improve physical functioning in refractory angina: a pilot study. Cardiology 2012;122:170-7.
18. Dimsdale JE. Psychological stress and cardiovascular disease. J Am Coll Cardiol 2008;51:1237-46.
19. Prasad A, Dangas G, Srinivasan M, et al. Incidence and angiographic characteristics of patients with apical ballooning syndrome (takotsubo/stress cardiomyopathy) in the HORIZONS-AMI trial: an analysis from a multicenter, international study of ST-elevation myocardial infarction. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions 2014;83:343-8.
20. Wei J, Rooks C, Ramadan R, et al. Meta-analysis of mental stress-induced myocardial ischemia and subsequent cardiac events in patients with coronary artery disease. Am J Cardiol 2014;114:187-92.
21. Jiang W, Velazquez EJ, Kuchibhatla M, et al. Effect of escitalopram on mental stress-induced myocardial ischemia: results of the REMIT trial. JAMA 2013;309:2139-49.

Keywords: Angina Pectoris, Angina, Stable, Anxiety, Arterioles, Brain, Bone Marrow, Capillaries, Cardiomyopathies, Cell- and Tissue-Based Therapy, Citalopram, Citrus sinensis, Confidence Intervals, Control Groups, Coronary Artery Disease, Coronary Sinus, Counterpulsation, Depression, Depressive Disorder, Major, Drainage, Electrocardiography, Emotions, Endocardium, Endothelial Cells, Exercise Test, Exercise Tolerance, Granulocyte Colony-Stimulating Factor, Heart, Heart Rate, High-Energy Shock Waves, Mesenchymal Stem Cells, Microcirculation, Myocardial Infarction, Myocardial Ischemia, Myocardium, Neoplasms, Nervous System, Odds Ratio, Outpatients, Oxygen, Percutaneous Coronary Intervention, Pericardium, Quality of Life, Randomized Controlled Trials as Topic, Risk Factors, Serotonin, Societies, Medical, Stents, Stress, Psychological, Stroke Volume, Transmyocardial Laser Revascularization, Vasoconstriction, Ventricular Function, Left

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