Continuing Education Activity

Coronary artery vasospasm (CAVS) is a constriction of the coronary arteries that can cause complete or near-complete occlusion of the vessel. In 1959, Dr. Myron Prinzmetal described a different entity of angina than the classic Heberden angina which was originally described in 1772. This vasospastic disease can cause acute ischemia and present anywhere along the spectrum of angina from stable angina to acute coronary syndrome. CAVS appears to be a heterogeneous disease but does not follow the traditional risk factors in the development of coronary artery disease. This activity reviews the evaluation and management of coronary artery vasospasm and highlights the role of the interprofessional team in evaluating and improving care for patients with this condition.

Objectives:

• Describe the pathophysiology of coronary artery vasospasm.
• Review the presentation of coronary artery vasospasm.
• Summarize the treatment of coronary artery vasospasm.
• Outline the clinical evaluation of coronary artery vasospasm and explain the role of the interprofessional team in coordinating the care of patients with this condition.

Introduction

Coronary artery vasospasm (CAVS) is a constriction of the coronary arteries that can cause complete or near-complete occlusion of the vessel. In 1959, Dr. Myron Prinzmetal described a different entity of angina than the classic Heberden angina which was originally described in 1772. This vasospastic disease can cause acute ischemia and present anywhere along the spectrum of angina from stable angina to acute coronary syndrome. CAVS appears to be a heterogeneous disease but does not follow the traditional risk factors in the development of coronary artery disease.[1][2][3][4]

Etiology

The development of coronary artery vasospasm (CAVS) is multifactorial and can be influenced by the autonomic nervous system, inflammation, oxidative stress, endothelial dysfunction, smooth muscle cell hypercontractility, genetic predisposition, and lifestyle choices. Prinzmetal et al. published their study in 1959, which was conducted on 25 dogs where they noticed the changes that took place by occluding and releasing a large epicardial artery. They found clinical symptoms of pain and angina, electrocardiographic changes consistent with ischemia in the corresponding region, and systolic ballooning of the ischemic region. They postulated this as the course of a vasospastic epicardial coronary artery.[5][6][7][8]

Epidemiology

The prevalence of coronary artery vasospasm (CAVS) is highest between the ages of 40 and 70 and tends to decrease after 70 years. The distribution is varied throughout the world with the highest incidence noted in the Japanese population when compared to the Western population. Furthermore, the frequency of multiple spasms noted on provocative testing is also higher in the Japanese population (23%) than those in Caucasians (7.5%). A German study found that every fourth patient with suspected obstructive coronary artery disease (CAD) had no culprit lesion; of these patients tested with acetylcholine, 50% were confirmed to be due to CAVS.

Pathophysiology

The pathogenesis of coronary artery vasospasm (CAVS) remains to be multifactorial. Originally the autonomic nervous system was thought to play an important role in the development of CAVS. However, later endothelial dysfunction, oxidative stress load, magnesium deficiency, and respiratory alkalosis were also elucidated to contribute to the pathogenesis. Most recently, genetic mutations that may play a role have also been discovered. Nevertheless, the coronary vessel's smooth muscle hypertonicity and reactivity play a pivotal role in the development of CAVS.

• Autonomic Nervous System: An increase in both the parasympathetic and sympathetic activity had been found to play a role in inducing CAVS. CAVS usually occurs during the night when the parasympathetic nervous system is activated. Also, acetylcholine has been shown to induce CAVS, which supports the notion that parasympathetic activity can induce CAVS. However, studies have shown CAVS at night frequently occurs during rapid eye movement when there is a reduction in vagal tone with a surge in adrenergic activity. Furthermore, clinical studies have also shown that elevated catecholamine levels can also induce CAVS. Thus, the autonomic nervous system relationship with CAVS is complex and something that is still being investigated.
• Endothelial Dysfunction: Dysfunctional endothelial nitric oxide (NO) synthase and the decreased release of NO have been associated with the development of CAVS. Acetylcholine, serotonin, and histamine induce endothelium-dependent vasodilatation by releasing NO from normal endothelium but they can provoke CAVS in the presence of endothelial dysfunction. However, endothelial dysfunction is not always seen in patients with CAVS. Thus, other factors are also likely associated with manifesting CAVS.
• Oxidative Stress: Oxidative stress is known to have a detrimental effect on vascular wall health. The reactive oxygen species (ROS) cause inflammation, endothelial damage, and vasoconstriction. Thus increased levels of ROS lead to vascular dysfunction and remodeling. Smoking has been shown to reduce acetylcholine-endothelium-dependent relaxation, which means NO can be destroyed by ROS. However, the role of this relationship in the development of CAVS is complex as not all patients with CAVS have endothelial NO deficiency or dysfunction.
• Smooth Muscle Cell Hypercontractility: Shimokawa et al. discovered that enhanced myosin light-chain phosphorylation plays a central role in CAVS.  They further elucidated hydroxyfasudil-sensitive Rho-kinase-mediated pathway may be responsible for the enhanced myosin light-chain phosphorylation. Thus, a Rho-kinase inhibitor can potentially inhibit vasospastic activity. Further studies have shown other pathways, which may impact CAVS such as in K mutant or SUR2 K knockout mice. Loss of function of K channels has been shown to cause smooth muscle cell hyper contraction in the absence of atherosclerotic disease. These studies have opened pathways to understand the implication of smooth muscle hypercontractility in developing CAVS in humans.
• Genetics: No direct genetic link has been uncovered to date linking CAVS to genetic polymorphism. However, mutations or polymorphisms in the endothelial NO synthase gene and paraoxonase I gene have been seen in patients with CAVS. Other genetic mutations in adrenergic and serotoninergic receptors, angiotensin-converting enzyme, and inflammatory cytokines have also been described. However, the direct genetic link has yet to be discovered in all CAVS cases.

Histopathology

Increased inflammation has been associated with coronary artery vasospasm (CAVS). Inflammation in CAVS histologically can present with the infiltration of inflammatory cells such as mast cells. Mast cells have been reported at the site of CAVS, in the adventitia, and in the plaque of coronary arteries in patients with CAVS.

History and Physical

About 20% to 30% of those complaining of chest pain who are evaluated for obstructive coronary artery disease with a coronary angiogram have normal coronary arteries. These patients may or may not present with symptoms. If symptoms are present, they may include typical anginal complaints during the episodes of vasospasm. Coronary artery vasospasm (CAVS)-induced pain can appear at rest and particularly between night and early morning and can be accompanied by low exercise tolerance, especially in the morning. A patient can describe this pain as crushing, substernal chest pain with features such as radiation to the jaw or arm, and pain relieved by sublingual nitroglycerin. The physical examination should consist of a thorough cardiovascular exam, beginning with noting the vitals and ensuring hemodynamic stability, and then auscultating for the heart sounds. Providers should pay attention to the rhythm, rate, murmurs, and extra heart sounds such as S3 or S4, as well as the pulmonary exam particularly paying attention to the development of crackles which could indicate pulmonary edema.

Evaluation

An electrocardiogram (ECG) should be recorded during the episode. Changes that can be seen are ST-elevation corresponding to the occlusion of the culprit lesion with ST depression in the contralateral leads. A diagnosis can be made if the patient is given a fast-acting nitrate during the episode and ECG findings resolve. In some cases, only ST depression can be seen in the contiguous leads. Other findings on ECG may include the development of negative T waves in the culprit lesion territory during recovery from ischemia and the development of negative U waves during an active spasm.

Blood can also be checked for the release of cardiac biomarkers including troponin I or C and creatinine kinase. However, these biomarkers are not always elevated in patients with coronary artery vasospasm (CAVS)-induced chest pain.

Coronary angiography with provocative testing is the only definitive test that can confirm CAVS disease. Provoked CAVS is defined as luminal narrowing of 50%, 70%, 75%, or 90% with accompanying symptoms and ECG changes. This is then followed by intracoronary administration of nitroglycerin to dissipate the vasospastic changes on the vessel. Currently, in the United States, methylergonovine (a form of ergonovine) and acetylcholine are used in provocative testing that causes vasoconstriction in coronary arteries that have endothelial dysfunction.

Treatment / Management

Medical therapy with risk factor modification is the cornerstone of the treatment and management of this patient population. Treatment initially consists of administering nitrates or calcium channel blockers. Nitrates cause relaxation of vascular muscle by activating the guanylate cyclase to increase the production of cGMP. Coronary artery vasospasm (CAVS) should also be treated with calcium channel blockers that lower the calcium intake into the vascular smooth muscle. Alternative therapies that have been studied include nicorandil (a nitrate and K-channel activator), statins, fasudil (a rho kinase inhibitor), aspirin, magnesium, vitamins C and E, iloprost, alpha-receptor blockade, selective serotonin receptor inhibitors, and selective thromboxane A2 synthetase inhibition.[9][10] While these alternative options may have some success, the variable and limited success reported in the literature warrants that they must be further studied before they can be considered generalized mainstay treatment options like nitrates and calcium channel blockers. Beta-blockers should be avoided as they can result in vasospastic angina.

Usually, CAVS can be relieved by vasodilatation. However, there are instances when the vasospastic disease is resistant to drug therapy including long-acting medications. This scenario is met in approximately 20% of the patients with CAVS. In these cases, percutaneous balloon angioplasty has not led to favorable results. The percutaneous coronary intervention has also been studied with the continuation of medications as long-term. However, some of these patients have recurrent vasospasm in another location. Thus, coronary stenting with long-term medical therapy should only be considered in patients who have significant stenosis from CAVS.

The application of implantable cardioverter-defibrillators in patients with CAVS who present with ventricular tachycardia or ventricular fibrillation remains unknown. However, there have been reports of favorable outcomes in implanting the device in patients who survive fatal ventricular arrhythmias due to CAVS.[11][12]

Differential Diagnosis

Due to the heterogeneous presentation of coronary artery vasospasm (CAVS), it can initially be mistaken for multiple other cardiac pathologies. CAVS may or may not present with chest pain, ECG changes, and elevated cardiac biomarkers. Thus, obstructive atherosclerotic coronary artery disease, pericarditis or myopericarditis, primary arrhythmias, and stress-induced cardiomyopathy, should always be on the differential.

Prognosis

Recurrent episodes of angina are usually seen in 4% to 19% of the patients. Advanced age and impaired left ventricular function have been identified as factors for poor prognosis in patients who present with acute coronary syndrome due to coronary artery vasospasm (CAVS). In addition, elevated hs-CRP levels predict a higher risk of death, non-fatal myocardial infarction, and recurrent angina requiring repeat coronary angiography. However, the prognosis is usually favorable as long as the patients are maintained on calcium channel blockers and risk factors such as smoking are addressed.

Complications

Complications of coronary artery vasospasm (CAVS) include:

• Life-threatening arrhythmias
• Myocardial infarction
• Sudden cardiac death

Deterrence and Patient Education

Patients should be counseled to modify risk factors that can precipitate coronary artery vasospasm (CAVS) such as smoking. Treatment should be targeted in initiating and maintaining maximum tolerated doses of calcium channel blockers. Patients should be encouraged about medication compliance and the risks of recurrent CAVS that can occur with medication non-compliance.

Pearls and Other Issues

Due to the heterogeneity of symptoms upon presentation, coronary artery vasospasm (CAVS) should be on a differential when a patient is presenting with symptoms. It is important to recognize CAVS when compared to obstructive atherosclerotic coronary artery disease due to different approaches to treatment. Due to patients having recurrent symptoms resulting from CAVS further research needs to be implemented to better understand the pathogenesis and impact of treatment options.

Enhancing Healthcare Team Outcomes

Once a patient has been diagnosed with coronary artery vasospasm (CAVS), the role of the primary care provider and the nurse practitioner cannot be overstated. These professionals need to educate the patient on atherosclerosis and reduce the modifiable risk factors for coronary disease. Patients should be counseled to modify risk factors that can precipitate CAVS such as smoking, and monitored for sustained medication use to prevent future CAVS attacks. Due to patients having recurrent symptoms resulting from CAVS further research needs to be implemented to better understand the pathogenesis and impact of treatment options. Close monitoring is required because the recurrence of coronary vasospasm is common, which in some patients can prove fatal. (Level V)