Kounis syndrome

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Kounis syndrome
Other namesAllergic acute coronary syndrome
Specialty Cardiology

Kounis syndrome is defined as acute coronary syndrome (symptoms such as chest pain relating to reduced blood flow to the heart) caused by an allergic reaction or a strong immune reaction to a drug or other substance. [1] It is a rare syndrome with authentic cases reported in 130 males and 45 females, as reviewed in 2017[ needs update ]; however, the disorder is suspected of being commonly overlooked and therefore much more prevalent. [2] Mast cell activation and release of inflammatory cytokines as well as other inflammatory agents from the reaction leads to spasm of the arteries leading to the heart muscle or a plaque breaking free and blocking one or more of those arteries. [1] [3]

Contents

The Kounis syndrome is distinguished from two other causes of coronary artery spasms and symptoms viz., the far more common, non-allergic syndrome, Prinzmetal's angina [4] and eosinophilic coronary periarteritis, an extremely rare disorder caused by extensive eosinophilic infiltration of the adventitia and periadventitia, i.e. the soft tissues, surrounding the coronary arteries. [5] [6]

Epidemiology

Through various case observations, Kounis syndrome was noted in many different races and geographical areas. However, most cases have been found in southern Europe including Turkey, Greece, Italy, and Spain. A wide age range is observed from pediatric patients to the elderly including the ages from 2 to 90. Commonly seen comorbidities include hyperlipidemia, diabetes, smoking, hypertension, and prior allergic reactions to a precipitating factor. [7] The exact prevalence is difficult to determine given that this diagnosis is missed or under-diagnosed. There is a possibility for gene-environment interactions as a study reported all patients admitted following emergency department evaluation had a heterozygous E148Q mutation. [1]

Etiology

Many causes have been discovered to precipitate this syndrome including drugs, various health conditions, food, and environmental exposures. Any of these precipitating factors that cause IgE antibody production can contribute to this syndrome. Drugs that have been found previously include analgesics such as aspirin and dipyrone, anesthetics, multiple antibiotics, anticoagulants such as heparin and Lepirudin, thrombolytics such as TPA, anti-platelet therapy including Clopidogrel, anti-neoplastics, glucocorticoids, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and skin disinfectants. Additionally, sympathomimetics, volume expanders, antifungals, antivirals, and oral contraceptives can also trigger this syndrome. [7] Other specific common medications include Allopurinol, Enalapril, Losartan, insulin, and many more. Conditions that incriminate Kounis syndrome include bronchial asthma, Churg–Strauss syndrome, serum sickness, scombroid syndrome, angioedema, hay fever, anaphylaxis (exercise induced or idiopathic), and anisakiasis. Coronary stenting, a common procedure used in coronary artery disease patients has also been found to be a cause. Environmental exposure to poison ivy, grass, latex, and nicotine have been found to be contributory. Bites from creatures that can precipitate Kounis syndrome include spiders, snakes, scorpions, fire ants and jellyfish. Miscellaneous triggers include contrast media. Reactions to various foods that cause an allergic and inflammatory response can lead to acute coronary syndrome. [1]

Signs and symptoms

Allergic ACS is a syndrome involving two components. One component is immune mediated resulting in hypersensitivity, allergy, and an anaphylactic or anaphylactoid reaction. The second component involves cardiac signs and symptoms seen with acute coronary syndrome (ACS). Cardiac symptoms vary depending on the type of variant the patient presents with. Acute coronary syndrome is usually associated with a constrictive pain in the chest, characteristically with radiation to the neck or the left arm and often associated with pallor, sweatiness, nausea and breathlessness. Cardiac signs on exam also include cold extremities, bradycardia, tachycardia, hypotension, possible cardiorespiratory arrest, or sudden death. Just as in an allergic reaction can vary from a mild and localized reaction to something that is widespread and life-threatening, the allergic component of allergic ACS presents the same way. In allergic ACS there may also be specific symptoms relating to the underlying allergic reaction, such as swelling of the face and tongue, wheeze, hives and potentially very low blood pressure (anaphylactic shock). [2] Additional findings can include stridor, drowsiness, syncope, abdominal pain, diarrhea, vomiting, and acute pulmonary edema if severe. [7]

Myocardial infarction, acute cardiac failure, and sudden cardiac death may also be seen. As high as 13% of adult onset  sudden cardiac deaths are coupled with mast cell degranulation concluding that Kounis syndrome can involve a silent allergic reaction. [1]

Pathophysiology

In allergy, mast cells release inflammatory substances such as histamine, neutral proteases, arachidonic acid derivatives, platelet activating factor and a variety of cytokines and chemokines. These mediators can precipitate coronary artery spasm and accelerate the rupture of atheromatous plaques of the coronary arteries. This interferes with the blood flow to the heart muscle and causes symptoms otherwise indistinguishable from unstable angina. [8]

It is possible that even in people without direct evidence of allergy, the allergic response may be playing a role in acute coronary syndrome: markers of mast cell activation are found in people with ACS. [8]

The main marker of mast cell activation is inducible macrophage protein 1a (MIP-1α), which binds to mast cells when they are in close proximity to each other. [9] After allergen exposure, MIP-1α transcription and expression is induced by resident mononuclear cells in the substantia propria, which consist of CD68+ macrophages and monocytes. [10]

Diagnosis

Kounis syndrome is often missed or underdiagnosed so understanding the disease process and clinical presentation while having a high suspicion for the problem is compulsory.  It is important to focus on the duration of time between the trigger exposure and the onset of symptoms. Majority of the cases had a duration of under one hour while some had a duration of 6 hours. EKG, chest x-ray, echocardiography, and angiography are needed if suspicion for myocardial ischemia or infarction is present. [7]

Patients with systemic allergic reactions associated with clinical, electrocardiographic, angiographic, echocardiographic and laboratory findings of acute myocardial ischemia should be diagnosed as having Kounis syndrome. EKG changes can be consistent with infarction most commonly in the inferior leads, ischemia, sinus bradycardia or tachycardia, heart block, atrial fibrillation, ventricular fibrillation, ventricular ectopic beats, QRS and QT prolongation, and findings similar to digoxin toxicity. [7] Echocardiography assists with finding atherosclerotic stenosis and thrombosis. [7]

Serum tryptase, histamine, immunoglobulins (IgE), cardiac enzymes, cardiac troponins are helpful to confirm the diagnosis. In Kounis syndrome, the newer techniques such as thallium-201 single-photon emission computer tomography (SPECT) and 125I-15-(p-iodophenyl)-3-(R,S) methylpentadecanoic acid (BMIPP) SPECT have revealed severe myocardial ischemia while coronary angiography showed normal coronary arteries. Furthermore, with cardiac magnetic resonance imaging (MRI), the delayed contrast-enhanced images show normal washout in the subendocardial lesion area in patients with Kounis syndrome type I variant.

Other similar presentations to rule out include Takotsubo and hypersensitivity myocarditis. [7]

Classification

Three variants of Kounis syndrome are recognised: [8]

Management

The management of these patients may be challenging for clinicians. Although beta blockers can be beneficial in ACS, they are contraindicated in Kounis syndrome. In allergic ACS, blocking beta receptors while giving epinephrine (which is the basis of treatment of anaphylaxis) can lead to an unopposed activity of α-adrenergic receptors which would aggravate the coronary spasm. Also opioids, indicated to relieve chest pain, may induce massive mast cell degranulation which in turn will worsen the anaphylaxis. They should hence be given carefully in such patients [11]

Type I variant

Type I variant is treated based on its clinical presentation and how severe the allergic reaction is. If it is a mild reaction, then antihistamines and corticosteroids can help control the symptoms. If the patient's presentation involves anaphylaxis, intramuscular adrenaline should be given. [7]

Treatment of the allergic event alone can abolish type I variant. Giving vasodilators such as nitroglycerin or calcium channel blockers is recommended. Consequences include hypotension and worsening of anaphylaxis. [7] Antihistamine and mast cell stabilizers e.g. cromoglicate or nedocromil can be also considered. [12]

Type II variant

Acute coronary event protocol is applied and type II can be treated similarly to type I for cardiac symptom control. Glucagon may be a better option than adrenaline for acute anaphylaxis in patients with prior use of chronic beta-blockers. In addition, beta-blockers can increase coronary vasospasm and ischemia. Opiates should be used with caution. [7]

Type III variant

In addition to the application of the acute coronary syndrome protocol, thrombus aspiration, and placing a new stent is needed. [7] The use of mast cell stabilizers in association with steroids and antihistamines are recommended. Harvesting of intrastent thrombus together with histological examination of aspirated material and staining for eosinophils and mast cells should be undertaken. When allergic symptoms are present following stent implantation, desensitization measures should be applied. [13]

History

While there are several older reports associating, clinically, allergy and the heart with names such as morphologic cardiac reactions, acute carditis or lesions with basic characteristics of rheumatic carditis, the first full description of allergy-mediated acute coronary syndrome is attributed to the Greek cardiologist Nicholas Kounis, who in 1991 reported on the possible role of allergy in cases of coronary artery spasm (now, type I variant). [14] [8] Braunwald recognized the allergy induced coronary artery occlusion mediated by these spasms. Three variants of Kounis syndrome were found and a study concluded that type 1 variant was most commonly seen followed by type 2 and 3 respectively. [7]

Related Research Articles

<span class="mw-page-title-main">Angina</span> Chest discomfort due to not enough blood flow to heart muscle

Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.

<span class="mw-page-title-main">Chest pain</span> Discomfort or pain in the chest as a medical symptom

Chest pain is pain or discomfort in the chest, typically the front of the chest. It may be described as sharp, dull, pressure, heaviness or squeezing. Associated symptoms may include pain in the shoulder, arm, upper abdomen, or jaw, along with nausea, sweating, or shortness of breath. It can be divided into heart-related and non-heart-related pain. Pain due to insufficient blood flow to the heart is also called angina pectoris. Those with diabetes or the elderly may have less clear symptoms.

<span class="mw-page-title-main">Coronary thrombosis</span> Medical condition

Coronary thrombosis is defined as the formation of a blood clot inside a blood vessel of the heart. This blood clot may then restrict blood flow within the heart, leading to heart tissue damage, or a myocardial infarction, also known as a heart attack.

Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia and tissue death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or delayed cerebral ischemia is a major contributor to post-operative stroke and death especially after aneurysmal subarachnoid hemorrhage. Vasospasm typically appears 4 to 10 days after subarachnoid hemorrhage.

<span class="mw-page-title-main">Acute coronary syndrome</span> Medical condition

Acute coronary syndrome (ACS) is a syndrome due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is centrally located pressure-like chest pain, often radiating to the left shoulder or angle of the jaw, and associated with nausea and sweating. Many people with acute coronary syndromes present with symptoms other than chest pain, particularly women, older people, and people with diabetes mellitus.

<span class="mw-page-title-main">Variant angina</span> Medical condition

Variant angina, also known as Prinzmetal angina,vasospastic angina, angina inversa, coronary vessel spasm, or coronary artery vasospasm, is a syndrome typically consisting of angina. Variant angina differs from stable angina in that it commonly occurs in individuals who are at rest or even asleep, whereas stable angina is generally triggered by exertion or intense exercise. Variant angina is caused by vasospasm, a narrowing of the coronary arteries due to contraction of the heart's smooth muscle tissue in the vessel walls. In comparison, stable angina is caused by the permanent occlusion of these vessels by atherosclerosis, which is the buildup of fatty plaque and hardening of the arteries.

<span class="mw-page-title-main">Unstable angina</span> Medical condition

Unstable angina is a type of angina pectoris that is irregular or more easily provoked. It is classified as a type of acute coronary syndrome.

In medicine, collateralization, also vessel collateralization and blood vessel collateralization, is the growth of a blood vessel or several blood vessels that serve the same end organ or vascular bed as another blood vessel that cannot adequately supply that end organ or vascular bed sufficiently.

Coronary vasospasm refers to when a coronary artery suddenly undergoes either complete or sub-total temporary occlusion.

Coronary artery anomalies are variations of the coronary circulation, affecting <1% of the general population. Symptoms include chest pain, shortness of breath and syncope, although cardiac arrest may be the first clinical presentation. Several varieties are identified, with a different potential to cause sudden cardiac death.

<span class="mw-page-title-main">Coronary stent</span> Medical stent implanted into coronary arteries

A coronary stent is a tube-shaped device placed in the coronary arteries that supply blood to the heart, to keep the arteries open in patients suffering from coronary heart disease. The vast majority of stents used in modern interventional cardiology are drug-eluting stents (DES) It is used in a medical procedure called percutaneous coronary intervention (PCI). Coronary stents are divided into two broad types - drug-eluting and bare metal stents, as of 2023 drug-eluting stents were used in more than 90% of all PCI procedures. Stents reduce angina and have been shown to improve survival and decrease adverse events after a patient has suffered a heart attack - medically termed an acute myocardial infarction.

The following outline is provided as an overview of and topical guide to cardiology, the branch of medicine dealing with disorders of the human heart. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular heart disease and electrophysiology. Physicians who specialize in cardiology are called cardiologists.

<span class="mw-page-title-main">Coronary ischemia</span> Medical condition

Coronary ischemia, myocardial ischemia, or cardiac ischemia, is a medical term for a reduced blood flow in the coronary circulation through the coronary arteries. Coronary ischemia is linked to heart disease, and heart attacks. Coronary arteries deliver oxygen-rich blood to the heart muscle. Reduced blood flow to the heart associated with coronary ischemia can result in inadequate oxygen supply to the heart muscle. When oxygen supply to the heart is unable to keep up with oxygen demand from the muscle, the result is the characteristic symptoms of coronary ischemia, the most common of which is chest pain. Chest pain due to coronary ischemia commonly radiates to the arm or neck. Certain individuals such as women, diabetics, and the elderly may present with more varied symptoms. If blood flow through the coronary arteries is stopped completely, cardiac muscle cells may die, known as a myocardial infarction, or heart attack.

<span class="mw-page-title-main">Myocardial infarction</span> Interruption of blood supply to a part of the heart

A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction to the heart muscle. The most common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck or jaw. Often such pain occurs in the center or left side of the chest and lasts for more than a few minutes. The discomfort may occasionally feel like heartburn. Other symptoms may include shortness of breath, nausea, feeling faint, a cold sweat, feeling tired, and decreased level of consciousness. About 30% of people have atypical symptoms. Women more often present without chest pain and instead have neck pain, arm pain or feel tired. Among those over 75 years old, about 5% have had an MI with little or no history of symptoms. An MI may cause heart failure, an irregular heartbeat, cardiogenic shock or cardiac arrest.

<span class="mw-page-title-main">Spontaneous coronary artery dissection</span> Uncommon cause of heart attacks mostly affecting younger, healthy women

Spontaneous coronary artery dissection (SCAD) is an uncommon but potentially lethal condition in which one of the coronary arteries that supply the heart, spontaneously develops a blood collection, or hematoma, within the artery wall due to a tear in the wall. SCAD is one of the arterial dissections that can occur.

Nicholas George Kounis is professor emeritus of cardiology in the University of Patras and scientific cardiology advisor at Saint Andrews State General Hospital Patras and at the Department of cardiology of University of Patras Medical School, Patras, Greece.

<span class="mw-page-title-main">Reperfusion therapy</span> Restoring blood flow post-heart attack

Reperfusion therapy is a medical treatment to restore blood flow, either through or around, blocked arteries, typically after a heart attack. Reperfusion therapy includes drugs and surgery. The drugs are thrombolytics and fibrinolytics used in a process called thrombolysis. Surgeries performed may be minimally-invasive endovascular procedures such as a percutaneous coronary intervention (PCI), which involves coronary angioplasty. The angioplasty uses the insertion of a balloon and/or stents to open up the artery. Other surgeries performed are the more invasive bypass surgeries that graft arteries around blockages.

<span class="mw-page-title-main">Electrocardiography in myocardial infarction</span>

Electrocardiography in suspected myocardial infarction has the main purpose of detecting ischemia or acute coronary injury in emergency department populations coming for symptoms of myocardial infarction (MI). Also, it can distinguish clinically different types of myocardial infarction.

A diagnosis of myocardial infarction is created by integrating the history of the presenting illness and physical examination with electrocardiogram findings and cardiac markers. A coronary angiogram allows visualization of narrowings or obstructions on the heart vessels, and therapeutic measures can follow immediately. At autopsy, a pathologist can diagnose a myocardial infarction based on anatomopathological findings.

<span class="mw-page-title-main">Management of acute coronary syndrome</span>

Management of acute coronary syndrome is targeted against the effects of reduced blood flow to the affected area of the heart muscle, usually because of a blood clot in one of the coronary arteries, the vessels that supply oxygenated blood to the myocardium. This is achieved with urgent hospitalization and medical therapy, including drugs that relieve chest pain and reduce the size of the infarct, and drugs that inhibit clot formation; for a subset of patients invasive measures are also employed. Basic principles of management are the same for all types of acute coronary syndrome. However, some important aspects of treatment depend on the presence or absence of elevation of the ST segment on the electrocardiogram, which classifies cases upon presentation to either ST segment elevation myocardial infarction (STEMI) or non-ST elevation acute coronary syndrome (NST-ACS); the latter includes unstable angina and non-ST elevation myocardial infarction (NSTEMI). Treatment is generally more aggressive for STEMI patients, and reperfusion therapy is more often reserved for them. Long-term therapy is necessary for prevention of recurrent events and complications.

References

  1. 1 2 3 4 5 6 7 Kounis NG (1 October 2016). "Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management". Clinical Chemistry and Laboratory Medicine. 54 (10): 1545–59. doi: 10.1515/cclm-2016-0010 . PMID   26966931. S2CID   11386405.
  2. 1 2 Abdelghany M, Subedi R, Shah S, Kozman H (April 2017). "Kounis syndrome: A review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome". International Journal of Cardiology. 232: 1–4. doi:10.1016/j.ijcard.2017.01.124. PMID   28153536.
  3. ↑ Memon S, Chhabra L, Masrur S, Parker MW (July 2015). "Allergic acute coronary syndrome (Kounis syndrome)". Proceedings (Baylor University. Medical Center). 28 (3): 358–362. doi:10.1080/08998280.2015.11929274. ISSN   0899-8280. PMC   4462222 . PMID   26130889.
  4. ↑ Ahmed B, Creager MA (April 2017). "Alternative causes of myocardial ischemia in women: An update on spontaneous coronary artery dissection, vasospastic angina and coronary microvascular dysfunction". Vascular Medicine (London, England). 22 (2): 146–160. doi: 10.1177/1358863X16686410 . PMID   28429664.
  5. ↑ Séguéla PE, Iriart X, Acar P, Montaudon M, Roudaut R, Thambo JB (April 2015). "Eosinophilic cardiac disease: Molecular, clinical and imaging aspects". Archives of Cardiovascular Diseases. 108 (4): 258–68. doi: 10.1016/j.acvd.2015.01.006 . PMID   25858537.
  6. ↑ Kajihara H, Tachiyama Y, Hirose T, Takada A, Takata A, Saito K, Murai T, Yasui W (2013). "Eosinophilic coronary periarteritis (vasospastic angina and sudden death), a new type of coronary arteritis: report of seven autopsy cases and a review of the literature". Virchows Archiv. 462 (2): 239–48. doi:10.1007/s00428-012-1351-7. PMID   23232800. S2CID   32619275.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 Giovannini M, Koniari I, Mori F, Ricci S, Simone LD, Favilli S, Trapani S, Indolfi G, Kounis N, Novembre E (2020-05-28). "Kounis syndrome: a clinical entity penetrating from pediatrics to geriatrics". Journal of Geriatric Cardiology. 17 (5): 294–299. doi:10.11909/j.issn.1671-5411.2020.05.011. PMC   7276306 . PMID   32547613. Archived from the original on 2020-10-28. Retrieved 2020-10-23.
  8. 1 2 3 4 Kounis NG, Mazarakis A, Tsigkas G, Giannopoulos S, Goudevenos J (November 2011). "Kounis syndrome: a new twist on an old disease". Future Cardiology. 7 (6): 805–24. doi:10.2217/fca.11.63. PMID   22050066.
  9. ↑ Kounis, N G, Kounis, G N, Soufras, G D (April 2007). "Kounis syndrome: a potential cause of simultaneous multivessel coronary spasm and thrombosis after drug-eluting stent implantation". The Journal of Invasive Cardiology. 19 (4).
  10. ↑ Miyazaki D, Nakamura T, Toda M, Cheung-Chau KW, Richardson RM, Ono SJ (February 2005). "Macrophage inflammatory protein–1α as a costimulatory signal for mast cell–mediated immediate hypersensitivity reactions". Journal of Clinical Investigation. 115 (2): 434–42. doi: 10.1172/JCI18452 . PMC   544033 .
  11. ↑ Omri M, Kraiem H, Mejri O, Naija M, Chebili N (2017-05-23). "Management of Kounis syndrome: two case reports". Journal of Medical Case Reports. 11 (1): 145. doi: 10.1186/s13256-017-1310-7 . ISSN   1752-1947. PMC   5440976 . PMID   28532437.
  12. ↑ Kraus J (2012). "Der allergische Myokardinfarkt - Kounis-Syndrom" (PDF). Journal für Kardiologie - Austrian Journal of Cardiology. 19: 118–122.
  13. ↑ Kounis NG, Koniari I, Velissaris D, Tzanis G, Hahalis G (2019-07-11). "Kounis Syndrome—not a Single-organ Arterial Disorder but a Multisystem and Multidisciplinary Disease". Balkan Medical Journal. 36 (4): 212–221. doi:10.4274/balkanmedj.galenos.2019.2019.5.62. PMC   6636655 . PMID   31198019.
  14. ↑ Kounis NG, Zavras GM (1991). "Histamine-induced coronary artery spasm: the concept of allergic angina". The British Journal of Clinical Practice. 45 (2): 121–8. PMID   1793697.
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