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Chest Pain? It could be Refractory Angina

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Refractory angina pain is increased with exercise

Refractory Angina (RA) is a chronic condition (lasting more than 3 months) characterized by a feeling of pain or pressure in the chest due to myocardial ischemia and persists despite optimal medical or surgical treatments. Angina pectoris is chest discomfort that occurs when the heart muscle doesn’t receive sufficient blood supply. It can also involve the shoulders, neck, arms, or jaw and may be confused with indigestion.

Refractory angina is usually caused by the narrowing of one or more of the major coronary arteries resulting in inadequate blood supply to the heart muscle. It often occurs in association with physical activity or heightened emotion, which increases the oxygen demand of the heart. Other than vascular occlusion, arterial spasms can also cause chest pain. Risk factors for developing angina and subsequently refractory angina are obesity, smoking, high blood pressure, high cholesterol levels, and diabetes.

Although coronary artery disease (CAD) is often thought to be a prerequisite for refractory angina, RA may occur due to other cardiovascular diseases including hypertrophic cardiomyopathy, obstructive coronary artery disease, and left ventricular diastolic dysfunction. Because of the aging population and the increasing survival rate of people with coronary artery disease, the amount of people with refractory angina is expected to exponentially increase.

Signs and Symptoms

The pain of angina pectoris is usually triggered by exertion and subsides with rest. At rest, it can be provoked by stress, cold temperature, and smoking. Upon exertion, a patient with angina due to severe coronary artery blockage may have varying symptoms. The chest pain is often localized beneath the breastbone but may sometimes spread out and involve surrounding areas, mainly the left arm, jaw, neck, throat, and in some cases, even teeth. The pain may also be accompanied by other signs such as nausea, vomiting, and sweating.

Diagnosis

A chronic history of angina pectoris or chest pain unresponsive to treatment should raise suspicion of refractory angina. Demonstration of myocardial ischemia should be established and confirmation that pharmacotherapy or other appropriate treatment options such as conventional revascularization have been exhausted.

A detailed evaluation of cardiovascular status should be conducted, and other possible causes of chest pain should be ruled out such as anemia, gallbladder disease, peptic ulcer, reflux esophagitis pericarditis, pleuritis, or pneumonia. The assessment of cardiovascular status may involve electrocardiography (ECG), echocardiography, blood and stress test, coronary angiography, and chest CT or MRI.


Management of Refractory Angina

Currently, there are no pharmacotherapeutic agents approved specifically for refractory angina. However, there are plenty of approved medications for chronic stable angina. These drugs are often used for refractory angina patients and may be taken in combination or interchanged depending on efficacy. The drugs chosen are altered on an individual basis, considering drug response, tolerability, age, blood pressure, and renal function. If ineffective even at maximal dose, the medication should be discontinued, and an alternative drug is considered.

Some pharmacologic therapies for angina include beta-blockers, calcium channel blockers, anti-platelet drugs, and lipid-lowering agents. A newer anti-ischemic medication approved for chronic stable angina is Ranolazine, an inhibitor of fatty oxidation, which controls the high levels of calcium that causes myocardial ischemia by modulating sodium-dependent calcium channels.

The only other approved therapies for RA in the US are enhanced external counterpulsation (EECP) and trans myocardial laser revascularization (TMLR). EECP involves placing compressive cuffs on the calves, and upper and lower thighs. Distal cuffs are inflated first followed by more proximal cuffs during early diastole and are deflated upon systole onset. This promotes the retrograde flow of arterial blood which increases coronary perfusion. The other approved therapy, trans myocardial laser revascularization (TMLR) uses lasers to form 1mm channels in the left ventricular wall either percutaneously or surgically and the mechanism behind its efficacy is not well understood. It is thought to promote angiogenesis or denervate the myocardium hence relieving angina symptoms. TMLR has recently been subject to controversy due to inconsistent results of studies and lack of evidence detailing the therapeutic mechanism.

Newer Therapies for Refractory Angina

A new investigational treatment for refractory angina is a one-time gene therapy known as XC001 which involves intramyocardial delivery of non-replicative adenovirus-carrying vascular endothelial factor (VEGF). VEGF induces the stimulation of new blood vessel formation (angiogenesis) to restore myocardial perfusion. The treatment is still under clinical trial in the United States and initial results demonstrate improvements of exercise-induced ischemia in refractory angina patients and don’t report significant adverse effects. Initial reports claim that after a few months post-therapy, the patients were found to have increased duration of exercise before the onset of angina along with general improvement of angina symptoms.

Another potential treatment for refractory angina is the coronary sinus reducer (CSR). It is an hourglass-shaped stent inserted by a balloon catheter and causes the narrowing of the coronary sinus. The coronary sinus reducer is inserted percutaneously through one of the jugular veins while the patient is under local anesthesia. The stenting or narrowing of the coronary sinus causes stenosis and enhances retrograde pressure of the coronary veins which promotes subendocardial arteriole dilation and reduces vascular resistance. This allows the redirection of blood flow to the ischemic part of the subendocardial areas. Coronary sinus reducer therapy is now under clinical trial in Germany, Israel, and Slovenia after many studies demonstrate the effectiveness of CSR in refractory angina.

 
References:
1.         Rakhimov K, Gori T. Non-pharmacological Treatment of Refractory Angina and Microvascular Angina. Biomedicines. 2020;8(8):285. Published 2020 Aug 13. doi:10.3390/biomedicines8080285
2.         Cheng K, de Silva R. New Advances in the Management of Refractory Angina Pectoris. Eur Cardiol. 2018;13(1):70-79. doi:10.15420/ecr.2018:1:2
3.         Cheng K, Sainsbury P, Fisher M, de Silva R. Management of Refractory Angina Pectoris. Eur Cardiol. 2016;11(2):69-76. doi:10.15420/ecr.2016:26:1
4.         Grise MA, Verma A. Treatment of refractory angina. Ochsner J. 2009;9(4):220-226.
5.         UMC+ M. Maastricht UMC+. www.pijn.com. Accessed January 4, 2021. https://www.pijn.com/en/patients/cause-of-pain/diagnoses-per-body-region/upper-back-chest/cardial-chest-pain
6.         XyloCor Therapeutics Doses Patients in Phase 1/2 Trial Evaluating Novel Gene Therapy XC001 in Refractory Angina. BioSpace. Accessed January 4, 2021. https://www.biospace.com/article/releases/xylocor-therapeutics-doses-patients-in-phase-1-2-trial-evaluating-novel-gene-therapy-xc001-in-refractory-angina/
7.         Riley RF, Kereiakes DJ, Henry TD. More Data Than Options for the "No-Option" Refractory Angina Patient in the United States. Circ Res. 2019;124(12):1689-1691. doi:10.1161/CIRCRESAHA.119.315138
8.         McGillion M, Arthur HM, Cook A, et al. Management of patients with refractory angina: Canadian Cardiovascular Society/Canadian Pain Society joint guidelines. Can J Cardiol. 2012;28(2 Suppl):S20-S41. doi:10.1016/j.cjca.2011.07.007
9.         Angina | National Heart, Lung, and Blood Institute (NHLBI). Nih.gov. Published December 10, 2018. https://www.nhlbi.nih.gov/health-topics/angina
10.       Stewart DJ, Hilton JD, Arnold JM, et al. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment. Gene Ther. 2006;13(21):1503-1511. doi:10.1038/sj.gt.3302802

     

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