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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 Angina, also known as angina pectoris, is chest pain or pressure, usually caused by ischemia, insufficient blood flow to the Cardiac muscle, heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typical ...
(cardiac chest pain). Variant angina differs from
stable angina 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. Angina is typically the result of obstru ...
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 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 de ...
, a narrowing of the
coronary arteries The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ of ...
due to contraction of the
heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
's
smooth muscle tissue Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
in the vessel walls. In comparison, stable angina is caused by the permanent occlusion of these vessels by
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
, which is the buildup of fatty plaque and hardening of the arteries.


Signs and symptoms

In contrast to those with
angina Angina, also known as angina pectoris, is chest pain or pressure, usually caused by ischemia, insufficient blood flow to the Cardiac muscle, heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typical ...
secondary to
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
, people with variant angina are generally younger and have fewer risk factors for coronary artery disease with the exception of
smoking Smoking is a practice in which a substance is burned and the resulting smoke is typically breathed in to be tasted and absorbed into the bloodstream. Most commonly, the substance used is the dried leaves of the tobacco plant, which have bee ...
, which is a common and significant risk factor for both types of angina. Affected people usually have repeated episodes of unexplained (e.g., in the absence of exertion and occurring at sleep or in the early morning hours) chest pain, tightness in throat, chest pressure, light-headedness, excessive sweating, and/or reduced exercise tolerance that, unlike atherosclerosis-related angina, typically does not progress to
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
(heart attack). Unlike cases of atherosclerosis-related
stable angina 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. Angina is typically the result of obstru ...
, these symptoms are often unrelated to exertion and occur in night or early morning hours. However, individuals with atherosclerosis-related
unstable angina Unstable angina (UA), also called crescendo angina, is a type of angina pectoris that is irregular. It is also classified as a type of acute coronary syndrome (ACS). It can be difficult to distinguish unstable angina from non-ST elevation (non-Q ...
may similarly exhibit night to early morning hour symptoms that are unrelated to exertion. Cardiac examination of individuals with variant angina is usually normal in the absence of current symptoms. Two-thirds of these individuals do have concurrent
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
of a major
coronary artery The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ of ...
, but this is often mild or not in proportion to the degree of their symptoms. Persons who have atherosclerosis-based occlusion that is ≥70% in a single coronary artery or that involves multiple coronary arteries are predisposed to develop a variant angina form that has a poorer prognosis than most other forms of this disorder. In these individuals but also in a small percentage of individuals without appreciable atherosclerosis of their coronary arteries, attacks of coronary artery spasm can have far more serious presentations such as
fainting Syncope, commonly known as fainting, or passing out, is a loss of consciousness and muscle strength characterized by a fast onset, short duration, and spontaneous recovery. It is caused by a decrease in blood flow to the brain, typically from ...
,
shock Shock may refer to: Common uses Collective noun *Shock, a historic commercial term for a group of 60, see English numerals#Special names * Stook, or shock of grain, stacked sheaves Healthcare * Shock (circulatory), circulatory medical emergen ...
, and
cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...
. Typically, these presentations reflect the development of a
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...
and/or a potentially lethal
heart arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
; they require immediate medical intervention as well as consideration for the presence of, and specific treatment regimens for, their disorder. Variant angina should be suspected by a
cardiologist Cardiology () is a branch of medicine that deals with disorders of the heart and the cardiovascular system. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular hear ...
when a) an individual's symptoms occur at rest or during sleep; b) an individual's symptoms occur in clusters; c) an individual with a history of angina does not develop angina during treadmill stress testing (variant angina is exercise tolerant); d) an individual with a history of angina shows no evidence of other forms of cardiac disease; and/or e) an individual without features of coronary artery atherosclerotic heart disease has a history of unexplained fainting. Complaints of chest pain should be immediately checked for an abnormal electrocardiogram (ECG). ECG changes compatible but not indicative of variant angina include elevations rather than depressions of the
ST segment In electrocardiography, the ST segment connects the QRS complex and the T wave and has a duration of 0.005 to 0.150 sec (5 to 150 ms). It starts at the J point (junction between the QRS complex and ST segment) and ends at the beginning of the T ...
or an elevated ST segment plus a widening of the
R wave The QRS complex is the combination of three of the graphical deflections seen on a typical electrocardiogram (ECG or EKG). It is usually the central and most visually obvious part of the tracing. It corresponds to the depolarization of the ri ...
to create a single, broad QRS complex peak termed the "monophasic curve". Associated with these ECG changes, there may be small elevations in the blood levels of cardiac damage marker enzymes, especially during long attacks. Some individuals with otherwise typical variant angina may show depressions, rather than elevations in the ST segments of their ECGs during angina pain; they may also show new
U wave The 'U' wave is a wave on an electrocardiogram (ECG). It comes after the T wave of ventricular repolarization and may not always be observed as a result of its small size. 'U' waves are thought to represent repolarization of the Purkinje fibers. ...
s on ECGs during angina attacks. A significant percentage of those with variant angina have symptom-free episodes of coronary artery spasm. These episodes may be far more frequent than expected, cause myocardial ischemia (i.e. insufficient blood flow to portions of the heart), and be accompanied by potentially serious abnormalities in the rhythm of heart beats, i.e. arrythmias. The only evidence of the presence of totally asymptomatic variant angina would be detection of diagnostic changes on fortuitously conducted ECGs.


Risk factors

The intake of certain agents have been reported to trigger an attack of variant angina. These agents include: * recreational agents (e.g.
nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
in tobacco and other forms, alcoholic beverages,
marijuana Cannabis, also known as marijuana among other names, is a psychoactive drug from the cannabis plant. Native to Central or South Asia, the cannabis plant has been used as a drug for both recreational and entheogenic purposes and in various tra ...
,
cocaine Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...
); *
catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a subst ...
-like stimulants (e.g.
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
,
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
, various
amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
s); * the uterus-contracting drug,
ergonovine Ergometrine, also known as ergonovine and sold under the brand names Ergotrate, Ergostat, and Syntometrine among others, is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used ei ...
; *
parasympathomimetic drug A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because acet ...
s (e.g.
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
,
methacholine Methacholine (International Nonproprietary Name, INN, United States Adopted Name, USAN) (trade name Provocholine), also known as Acetyl-β-methylcholine, is a synthetic choline ester that acts as a non-selective muscarinic receptor agonist in the ...
); * anti-migraine drugs (e.g. various
triptan Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual headaches, th ...
s); *
chemotherapeutic Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
drugs (e.g.
5-fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancrea ...
,
capecitabine Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth. Comm ...
); * high consumption of energy drinks have been associated with variant angina. In addition, hyperventilation and virtually any stressful emotional or physical (e.g. cold exposure) event that is suspected of causing significant rises in the blood levels of
catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a subst ...
s may trigger variant angina.


Mechanism

The mechanism that causes such intense vasospasm, as to cause a clinically significant narrowing of the coronary arteries is so far unknown, but there are three relevant hypotheses: # Enhanced contractility of coronary vascular smooth muscle due to reduced nitric oxide bioavailability caused by a defect in the endothelial nitric oxide synthetase enzyme which leads to endothelial function abnormalities. #*
Acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
is normally released by the
parasympathetic nervous system The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...
(PSNS) at rest, and causes dilation of the coronary arteries. While acetylcholine induces vasoconstriction of vascular smooth muscle cells through a direct mechanism, acetylcholine also stimulates endothelial cells to produce
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
(NO). NO then diffuses out of the endothelial cells, stimulating relaxation of the nearby smooth muscle cells. In healthy arterial walls, the overall indirect relaxation induced by acetylcholine (via nitric oxide) is of greater effect than any contraction that is induced. #* When the endothelium is dysfunctional, stimulation with acetylcholine will fail to produce, or produce very little, nitric oxide. Thus, acetylcholine released by the PSNS at rest will simply cause contraction of the vascular smooth muscle. #
Thromboxane A2 Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by act ...
,
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
,
histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
, and
endothelin Endothelins are peptides with receptor (biochemistry), receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when gene ex ...
are vasoconstrictor which activated platelets release and/or cause to be released. Abnormal platelet activation (e.g. by
lipoprotein(a) Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart ...
interference with
fibrinolysis Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other c ...
by competing with
plasminogen Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encode ...
to thereby impair fibrinolysis and promote platelet activation) results in the release of these mediators and coronary vasospasm. # Increased
alpha-adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
activity in epicardial coronary arteries or the excessive release of the "flight or fight" catecholamines (e.g.
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
) that activate these receptors may lead to coronary vasospasm. Other factors thought to be associated with the development of variant angina include: intrinsic hypercontractility of coronary artery smooth muscle; existence of significant atherosclerotic coronary artery disease; and reduced activity of the
parasympathetic nervous system The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...
(which normally functions to dilate blood vessels).


Diagnosis

Although variant angina has been documented in between 2% to 10% of angina patients, it can be overlooked by cardiologists who stop further evaluations after ruling out typical angina. Individuals who develop cardiac chest pain are generally treated empirically as an "
acute coronary syndrome Acute coronary syndrome (ACS) is a syndrome (a set of signs and symptoms) 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 loca ...
", and are immediately tested for elevations in their blood levels of enzymes such as
creatine kinase Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phosp ...
isoenzymes or
troponin image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; magenta = troponin T.; ; rendered with PyMOL Troponin, ...
that are markers for cardiac damage. They are also tested by ECG which may suggest variant angina if it shows elevations in the
ST segment In electrocardiography, the ST segment connects the QRS complex and the T wave and has a duration of 0.005 to 0.150 sec (5 to 150 ms). It starts at the J point (junction between the QRS complex and ST segment) and ends at the beginning of the T ...
or an elevated ST segment plus a widening of the
R wave The QRS complex is the combination of three of the graphical deflections seen on a typical electrocardiogram (ECG or EKG). It is usually the central and most visually obvious part of the tracing. It corresponds to the depolarization of the ri ...
during symptoms that are triggered by a provocative agent (e.g.
ergonovine Ergometrine, also known as ergonovine and sold under the brand names Ergotrate, Ergostat, and Syntometrine among others, is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used ei ...
or
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
). The electrocardiogram may show depressions rather than elevations in ST segments but in all diagnosable cases clinical symptoms should be promptly relieved and ECG changes should be promptly reversed by rapidly acting sublingual or intravenous
nitroglycerin Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating g ...
. However, the
gold standard A gold standard is a monetary system in which the standard economic unit of account is based on a fixed quantity of gold. The gold standard was the basis for the international monetary system from the 1870s to the early 1920s, and from the la ...
for diagnosing variant angina is to visualize coronary arteries by
angiography Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins, and the heart chambers. Modern angiography is performe ...
before and after injection of a provocative agent such as
ergonovine Ergometrine, also known as ergonovine and sold under the brand names Ergotrate, Ergostat, and Syntometrine among others, is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used ei ...
,
methylergonovine Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and in the treatment of migraine. It reportedly produces ...
or
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
to precipitate an attack of vasospasm. A positive test to these inducing agents is defined as a ≥90% (some experts require lesser, e.g. ≥70%) constriction of involved arteries. Typically, these constrictions are fully reversed by rapidly acting nitroglycerin. Individuals with variant angina may have many undocumented episodes of symptom-free coronary artery spasm that are associated with poor blood flow to portions of the heart and subsequent irregular and potentially serious
heart arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
s. Accordingly, individuals with variant angina should be intermittently evaluated for this using long-term ambulatory cardiac monitoring.


Prevention

Numerous methods are recommended to avoid attacks of variant angina. Affected individuals should not smoke tobacco products. Smoke cessation significantly reduces the incidence of patient-reported variant angina attacks. They should also avoid any trigger known to them to trigger these attacks such as emotional distress, hyperventilation, unnecessary exposure to cold, and early morning exertion. And, they should avoid any of the recreational and therapeutic drugs listed in the above
signs and symptoms Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
and
risk factors In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection. Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...
sections as well as blockers of beta receptors such as
propranolol Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anx ...
which may theoretically worsen vasospasm by inhibiting
beta-2 adrenergic receptor The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catechola ...
's vasodilation effect mediated by these receptors' naturally occurring stimulator i.e.
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
. In addition, aspirin should be used with caution and at low doses since at high doses it inhibits the production of the naturally occurring vasodilator,
prostacyclin Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. When used as a drug, it is also known as epoprosteno ...
.


Treatment


Acute attacks

During acute attacks, individuals typically respond well to fast-acting sublingual, intravenous, or spray
nitroglycerin Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating g ...
formulations. The onset of symptom relief in response to intravenous administration, which is used in more severe attacks of angina, occurs almost immediately while sublingual formulations of it act within 1–5 minutes. Spray formulations also require ~1–5 minutes to act.


Maintenance

As maintenance therapy, sublingual
nitroglycerin Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating g ...
tablets can be taken 3-5 min before conducting activity that causes angina by the small percentage of patients who experience angina infrequently and only when doing such activity. For most affected individuals,
antianginal An antianginal is a drug used in the treatment of ''angina pectoris'', a symptom of ischaemic heart disease. Examples Drugs used are nitrates, beta blockers, or calcium channel blockers. Nitrates Nitrates cause vasodilation of the venous capaci ...
s are used as maintenance therapy to avoid attacks of variant angina.
Calcium channel blocker Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...
s of the dihydropyridine class (e.g.
nifedipine Nifedipine (3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate), sold under the brand name Adalat and Procardia, among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Ra ...
,
amlodipine Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure and coronary artery disease. It is taken by mouth. Common side effects include swelling, feeling tired, ab ...
) or non-dihydropyridine class (e.g.
verapamil Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be used ...
,
diltiazem Diltiazem, sold under the brand name Cardizem among others, is a calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used ...
) are regarded as first-line drugs to avoid angina attacks. Long-acting nitroglycerins such as
isosorbide dinitrate Isosorbide dinitrate is a medication used for heart failure, esophageal spasms, and to treat and prevent chest pain from not enough blood flow to the heart. It has been found to be particularly useful in heart failure due to systolic dysfunction ...
or intermittent use of short-acting nitroglycerin (to treat acute symptoms) may be added to the calcium channel blocker regimen in individuals responding sub-optimally to the channel blockers. However, individuals commonly develop tolerance, i.e. resistance, to the efficacy of continuously used long-acting nitroglycerin formulations. One strategy to avoid this development is to schedule nitroglycerin-free periods of between 12 and 14 hours between doses of long-acting nitroglycerin formulations. Individuals whose symptoms are poorly controlled by a calcium blocker may benefit from addition of a long-acting nitroglycerin and/or a second calcium channel blocker of a different class than the blocker already in use. Nevertheless, about 20% of individuals fail to respond adequately to the two-drug calcium blocker plus long-acting nitroglycerin regimen. If these individuals have significant permanent occlusion of their coronary arteries, they may benefit by
stent In medicine, a stent is a metal or plastic tube inserted into the lumen of an anatomic vessel or duct to keep the passageway open, and stenting is the placement of a stent. A wide variety of stents are used for different purposes, from expandab ...
ing their occluded arteries. However, coronary stenting is contraindicated in drug- refractory individuals who do not have significant organic occlusion of their coronary arteries. For the latter individuals, other, less fully investigated drugs may provide symptom relief.
Statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low- ...
s, e.g.
fluvastatin Fluvastatin is a member of the statin drug class, used to treat hypercholesterolemia and to prevent cardiovascular disease. It was patented in 1982 and approved for medical use in 1994. It is on the World Health Organization's List of Essenti ...
, while not evaluated in large-scale double-blind studies, are reportedly helpful in reducing variant angina attacks and should be considered in patients when calcium channel blockers and nitroglycerin fail to achieve good results. There is also interest in using rho-kinase inhibitors, such as
fasudil Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator. Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage, as well as to improve the cognitive decline seen ...
(available in Japan and China but not the USA), and blocker of alpha-1 adrenergic receptors such as
prazosin Prazosin is an α1 blocker medication primarily used to treat high blood pressure, symptoms of an enlarged prostate, and nightmares related to post-traumatic stress disorder (PTSD). It is a less preferred treatment of high blood pressure. Other ...
(which when activated cause vasodilation) but studies are needed to support their clinical utility in variant angina.


Emergency

Individuals with certain severe complications of variant angina require immediate therapy. Individuals presenting with potentially lethal irregularities in the rhythm of their heart beating or a history of episodic fainting spells due to such arrhythmias require implantation of an internal defibrillator and/or
cardiac pacemaker 350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart. The_muscle_contraction.htm ...
to stop such arrhythmias and restore normal heart beating. Other rare but severe complications of variant angina viz.,
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
, severe
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, and
cardiogenic shock Cardiogenic shock (CS) is a medical emergency resulting from inadequate blood flow due to the dysfunction of the ventricles of the heart.Textbooks of Internal MedicinHarrison's Principles of Internal Medicine 16th Edition, The McGraw-Hill Compan ...
require the same immediate medical interventions that are used for other causes of these extremis conditions. In all of these emergency cases,
percutaneous coronary intervention Percutaneous coronary intervention (PCI) is a non-surgical procedure used to treat narrowing of the coronary arteries of the heart found in coronary artery disease. The process involves combining coronary angioplasty with stenting, which is the ...
to
stent In medicine, a stent is a metal or plastic tube inserted into the lumen of an anatomic vessel or duct to keep the passageway open, and stenting is the placement of a stent. A wide variety of stents are used for different purposes, from expandab ...
areas where coronary arteries evidence spasm is only useful in individuals who have concomitant coronary atherosclerosis on coronary angiogram.


Prognosis

Most individuals with variant angina have a favorable prognosis provided they are maintained on calcium channel blockers and/or long-acting nitrates; five-year survival rates in this group are estimated as over 90%. The Japanese Coronary Spasm Association established a clinical risk scoring system to predict outcomes for variant angina. Seven major factors (i.e. history of out of hospital
cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...
core = 4 Core or cores may refer to: Science and technology * Core (anatomy), everything except the appendages * Core (manufacturing), used in casting and molding * Core (optical fiber), the signal-carrying portion of an optical fiber * Core, the central ...
smoking, angina at rest, physically obstructive coronary artery disease, and spasm in multiple coronary arteries
core = 2 Core or cores may refer to: Science and technology * Core (anatomy), everything except the appendages * Core (manufacturing), used in casting and molding * Core (optical fiber), the signal-carrying portion of an optical fiber * Core, the central ...
and presence of ST segment elevations on ECG and history of using
beta blockers Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage cardiac arrhythmia, abnormal heart rhythms, and to protect the heart from a second myocardial infarction, heart attack after a first heart ...
core = 1 Core or cores may refer to: Science and technology * Core (anatomy), everything except the appendages * Core (manufacturing), used in casting and molding * Core (optical fiber), the signal-carrying portion of an optical fiber * Core, the central ...
where assigned the indicated scores. Individuals with scores of 0 to 2, 3 to 5, and ≥6 experienced an incidence of a major cardiovascular event in 2.5, 7.0, and 13.0% of cases.


History

Dr.
William Heberden William Heberden FRS (13 August 171017 May 1801) was an English physician. Life He was born in London, where he received the early part of his education at St Saviour's Grammar School. Full text at Internet Archive (archive.org) At the end of ...
is credited with being the first to describe in a 1768 publication the occurrence of
chest pain 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 n ...
attacks (i.e.
angina pectoris 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. Angina is typically the result of obstru ...
) that appeared due to pathologically occluded coronary arteries. These attacks were triggered by exercise or other forms of exertion and relieved by rest and
nitroglycerin Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating g ...
. In 1959, Dr.
Myron Prinzmetal Myron Prinzmetal (February 8, 1908 – January 8, 1987) was an American cardiologist. He studied hypertension and heart arrhythmias among many other topics, and was the first to describe Prinzmetal's angina, Prinzmetal angina. Early life Myron P ...
described a type of angina that differed from the classic cases of Heberden angina in that it commonly occurred in the absence of exercise or exertion. Indeed, it often woke patients from their normal sleep. This variant angina differed from the classical angina described by Dr. Heberden in that it appeared due to episodic
vasospasm 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 de ...
of coronary arteries that were typically not occluded by pathological processes such as
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
,
emboli An embolism is the lodging of an embolus, a blockage-causing piece of material, inside a blood vessel. The embolus may be a blood clot (thrombus), a fat globule ( fat embolism), a bubble of air or other gas (gas embolism), amniotic fluid (amniot ...
, or spontaneous dissection (i.e. tears in the walls of coronary arteries). Variant angina had been described twice in the 1930s by other authors and was referred to as
cardiac syndrome X Microvascular angina, previously known as cardiac syndrome X, is Angina pectoris, angina (chest pain) with signs associated with decreased blood flow to heart tissue but with normal coronary artery, coronary arteries. The use of the term CSX can l ...
(CSX) by Kemp in 1973, in reference to patients with exercise-induced angina who nonetheless had normal coronary angiograms. CSX is now termed
microvascular angina Microvascular angina, previously known as cardiac syndrome X, is angina (chest pain) with signs associated with decreased blood flow to heart tissue but with normal coronary arteries. The use of the term CSX can lead to the lack of appreciation of ...
, i.e. angina caused by disease of the heart's small arteries. Some key features of variant angina are chest pain that is concurrently associated with elevations in the
ST segment In electrocardiography, the ST segment connects the QRS complex and the T wave and has a duration of 0.005 to 0.150 sec (5 to 150 ms). It starts at the J point (junction between the QRS complex and ST segment) and ends at the beginning of the T ...
on
electrocardiography Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the hear ...
recordings, that often occurs during the late evening or early morning hours in individuals who are at rest, doing non-strenuous activities, or asleep, and that is not associated with permanent occlusions of their coronary vessels. The disorder seems to occur more often in women than men, has a particularly high incidence in Japanese males as well as females, and affects individuals who may
smoke Smoke is a suspension of airborne particulates and gases emitted when a material undergoes combustion or pyrolysis, together with the quantity of air that is entrained or otherwise mixed into the mass. It is commonly an unwanted by-product ...
tobacco products but exhibit few other cardiovascular risk factors. However, individuals exhibiting angina symptoms that are associated with depressions in their electrocardiogram ST segments, that are triggered by exertion, and/or who have atherosclerotic coronary artery disease are still considered to have variant angina if their symptoms are caused by coronary artery spasms. Finally, rare cases may exhibit symptom-free coronary artery spasm that is nonetheless associated with cardiac muscle
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
(i.e. restricted blood flow and poor oxygenation) along with concurrent ischemic electrocardiographic changes. The term vasospastic angina is sometimes used to include all of these atypical cases with the more typical cases of variant angina. Here, variant angina is taken to include typical and atypical cases. For a portion of patients, variant angina may be a manifestation of a more generalized episodic
smooth muscle Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
-contractile disorder such as
migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
,
Raynaud's phenomenon Raynaud syndrome, also known as Raynaud's phenomenon, eponymously named after the physician Auguste Gabriel Maurice Raynaud, who first described it in his doctoral thesis in 1862, is a medical condition in which the spasm of small arteries cau ...
, or
aspirin-induced asthma Aspirin exacerbated respiratory disease (AERD), also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inf ...
. Variant angina is also the major complication of eosinophilic coronary periarteritis, an extremely rare disorder caused by extensive eosinophilic infiltration of the
adventitia The adventitia () is the outer layer of fibrous connective tissue surrounding an organ. The outer layer of connective tissue that surrounds an artery, or vein – the tunica externa, is also called the ''tunica adventitia''. To some degree, its ...
and periadventitia, i.e. the soft tissues, surrounding the
coronary arteries The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ of ...
. Variant angina also differs from the
Kounis syndrome 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. It is a rare syndrome with au ...
(also termed allergic acute coronary syndrome) in which coronary artery constriction and symptoms are caused by
allergic Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
or strong immune reactions to a drug or other substance. Treatment of the Kounis syndrome very much differs from that for variant angina.


See also

*
Angina pectoris 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. Angina is typically the result of obstru ...
: the most common form of coronary artery spasm; it is due to atherosclerosis. *
Kounis syndrome 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. It is a rare syndrome with au ...
: coronary artery spasm due to an allergic reaction. * Eosinophilic coronary periarteritis: a very rare form of coronary artery spasm; it is due to non-allergic infiltration of coronary arteries by eosinophils.


References


External links

* {{Circulatory system pathology Ischemic heart diseases