Cardiac Syndrome X

Etiology

Although the etiology and pathogenesis of CSX or microvascular angina is not entirely understood, different mechanisms and theories of the condition have been reported. One of the predominant etiologies is microvascular dysfunction of the coronary vessels limiting blood flow resulting in ischemia or typical/atypical angina. Another commonly hypothesized etiology is heightened cardiac pain sensitivity, termed "hyperalgesia." It is considered in patients with typical anginal chest pain and microvascular dysfunction of the coronary vessels after stressors such as exercise, which did not exhibit any evidence of ischemia of the myocardium.[2][3] 

Microvascular dysfunction and heightened cardiac pain sensitivity could also occur in some patients, while other subjects with CSX may have distinct underlying etiologies. Subjects who have established CSX have a 30% greater probability of presenting with underlying metabolic comorbid conditions when compared to the general population (8%). Potential contributing factors to the pathogenesis of CSX and coronary microvascular dysfunction include insulin resistance and hyperglycemia, enhanced sodium-hydrogen exchange in red blood cells (RBC), chronic inflammation with elevated C-reactive protein levels (CRP), and vascular or nonvascular smooth muscle dysfunction.[5][6]

Epidemiology

The true prevalence of CSX is unknown but is reported to be more common in women (70%) when compared to men.[5]  It occurs commonly in perimenopausal or postmenopausal females between the ages of 45 to 55, with a mean age of 48.5.[2][3] 

Approximately 10 to 20% of subjects receiving a coronary angiography are reported to have CSX. A large study conducted in 886 subjects with chest pain suspecting a myocardial infarction received a coronary angiography; 41% of females demonstrated non-significant findings of the coronary vessels, significantly greater than men, which showed 8%.[7]

History and Physical

The diagnosis of CSX is mainly of exclusion. Patient presentation is typical of recurring anginal-type chest pains and no evidence of lesions more than 50% on imaging. Chest pains can present during activities such as exercise, and continued chest discomfort may occur after. Chest pain may also occur during rest and has been characterized as retrosternal, which may radiate towards the left arm. A thorough history and physical should be conducted prior to non-invasive and invasive testing, and patients should be carefully assessed for the potential pathophysiology of their manifestations. Chest pain from all non-cardiac causes, including psychological possibilities, should be differentiated. The patient's risk factors for coronary artery disease should also be thoroughly assessed.[8][9]

Evaluation

Evaluating CSX should begin with a history and physical followed by noninvasive tests. Before invasive procedures, an exercise tolerance test (ETT) or dobutamine stress echocardiogram (DSE) should be conducted. Patients are reported to exhibit ST-segment depression on exercise stress tests and may also demonstrate transient ST depression on Holter monitoring.

Severe angina during DSE with the exhibition of ST-segment depressions and the lack of contractile anomalies of the left ventricle are distinctive of endothelial dysfunction and may indicate CSX. ETT can also be done again following administration of short-acting sublingual nitrates as they may reveal ST-segment changes in some patients. Although effective in alleviating symptoms in CAD patients, the short-acting sublingual nitrates have also been reported to be ineffective in relieving chest pain in CSX patients.

Coronary angiography can provide an accurate measure of obstruction to the coronary vessels. The conventional characterization of coronary artery disease is defined as 50% or more significant stenosis of the left coronary artery (LCA) or 70% or greater stenosis of a coronary artery greater than 2 mm on coronary angiography. CSX is primarily a diagnosis of occlusion. Patients present with typical or atypical anginal chest pain, ST depression, and no evidence of coronary vessel obstruction greater than 50% on angiography.

An invasive diagnostic modality to assess the endothelial function of coronary flow reserve (CFR) is accomplished by cardiac catheterization and Doppler guide-wire. This procedure measures the increases in the blood flow of the coronary arteries after administering adenosine and acetylcholine. Noninvasive modalities such as brachial artery reactivity and peripheral arterial tonometry may also be employed to evaluate endothelial function.[8]

Treatment / Management

The management of patients suspected of having CSX is challenging and complex as its etiology is not entirely understood. To date, there are no specific guidelines to treat CSX, and management should be initiated on a case by case basis. Treatment modalities include pharmacologic management with anti-ischemic agents, analgesics for pain management, non-pharmacological management, and lifestyle modifications. Conventional anti-ischemic agents include beta-blockers, statin therapy, calcium channel blockers, ACE inhibitors, and antianginal agents such as ranolazine.

Patients with CSX and anginal chest pain should be initiated on therapy with sublingual nitrates. Although no studies have reported the effectiveness of the vasodilatory effects of nitrates on the small coronary vessels in subjects with established CSX, nitrates alongside beta-blockers are currently the mainstay of treatment.[8] Beta-blockers (propranolol, nebivolol, and carvedilol) have been reported with 75% effectiveness in patients suffering from CSX and have been shown to improve exercise tolerance and symptoms. Newer third-generation better blockers like nebivolol and carvedilol also exert their effects by endothelium vasodilatory activity and are reported to be potentially more effective than conventional beta-blockers.(B3)

Calcium channel blockers (nifedipine, verapamil, diltiazem) may be an alternative therapy to beta-blockers if a therapeutic response is not achieved.[10] Although calcium channel blockers increase exercise tolerance and minimize the episodes of angina, they are reported to be not as effective as beta-blockers in patients with CSX. Ranolazine, a recent antianginal indicated for chronic angina used in patients with refractory angina, has also been reported to be an effective alternative for therapy. Ranolazine's function to regulate neuronal voltage-gated sodium channels plays a role in managing potential neuropathic pain in patients with CSX. A Seattle Angina Questionnaire reported ranolazine as a beneficial agent in females with anginal symptoms and no reported evidence of coronary artery obstruction.[11]

Statins enhance the endothelium's vasodilatory effects and may be effective in patients with CSX. ACE inhibitors have also been reported to be beneficial. They impede endothelial bradykinin degradation, which results in vasodilatory effects.[10] These effects may further regulate the microvascular tone of the coronary vessels.

Based on the hypothesis of altered pain perception in patients with CSX, analgesic pharmacotherapy may be effective. Agents such as xanthine derivatives (adenosine receptor blockers), aminophylline, and neural electrical stimulation have been proposed in select patients. Neural electrical stimulation procedures target increased pain sensitivity in CSX and are utilized in subjects resistant to pharmacotherapy. Procedures include spinal cord stimulation and transcutaneous electrical nerve stimulation (TENS). The therapeutic effects reportedly enhance parasympathetic activity, further improving endothelial dysfunction and pain sensitivity. Other reported actions include increasing blood flow in the coronary vessels by spinal cord stimulation.

Other agents proposed for therapy include antidepressants such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Imipramine has been reported to decrease the frequency of chest pain by roughly 50%. TCAs action of serotonin and noradrenaline reuptake inhibition exerts analgesic action; hence their proposed benefits in patients with CSX. Imipramine is also advised by the American College of Cardiology for CSX patients unresponsive to beta-blockers, calcium channel blockers, and nitrates. Imipramine, used in the management of CSX, has been controversial due to its adverse effects.

Alongside pharmacological therapy, lifestyle modifications should be advised. Adjustments include exercise training, smoking cessation, weight loss, and dietary changes. Lifestyle changes have shown to have beneficial effects on endothelial function, which plays a significant role in reducing adverse cardiovascular events and CSX.[12]

Differential Diagnosis

Once the clinical manifestations suggest cardiac origin, imaging modalities such as an echocardiogram may be utilized to investigate structural and inflammatory etiologies. If a coronary vessel dysfunction is suspected, a large and small vessel dysfunction should be thoroughly analyzed and specified. Vasospastic angina is a common large vessel dysfunction of the myocardium that typically presents with anginal chest pain at rest.

Coronary spasms may be induced with ergonovine or acetylcholine. They may also occur involuntarily during angiography. Mechanical irritation from catheter introduction into the coronary vessels may result in catheter-induced spasms. Exhibition of non-ischemic changes such as reversible ST-elevations can be detected on an electrocardiogram (ECG).[2] 

For patients reporting cardiac pain during catheterization of the coronary vessels, catheter-induced spasm is highly likely, and a diagnosis of vasospastic angina is probable. Appropriate management with epicardial vasodilators like nitroglycerin may be initiated. It is vital to distinguish the presence of ostial atherosclerosis from catheter-induced spasms, as damped or ventricularized coronary arterial pressure waveforms may appear due to narrowing of ostial diameter.[13]

Patients with clinical characteristics of cardiac ischemia without evidence of obstructive coronary artery disease on angiography indicate microvascular dysfunction of the coronary vessels and require assessment as a potential cause for chest pain. All other ailments associated with microvascular dysfunction of the coronary vessels such as heart disease attributed to hypertension, amyloid induced cardiac disease, Takotsubo heart disease, Anderson Fabry disease, coronary slow-flow phenomenon (CSFP), also known as cardiac syndrome Y, a no-reflow phenomenon during a percutaneous coronary intervention (PCI) should be ruled out prior to concluding a CSX diagnosis.[14]

Non-cardiac origins of chest pain should also be ruled out. Differentials include psychological (anxiety and depressive illnesses), gastrointestinal disease, hepatic causes, pulmonary ailments, musculoskeletal causes, and other entities such as Tietze syndrome.

Prognosis

Long-term outcomes of CSX may be determined by typical disease characteristics such as chest pain, poor intracoronary microvascular response to acetylcholine (Ach), the severity of endothelial dysfunction, and ischemia of the myocardium.[3][5] Endothelial dysfunction of the coronary vessel wall and intracoronary microvascular response to Ach are vital predictors of prognosis. Severe dysfunction poses a significant risk for atheroma formation and acute coronary syndrome (ACS). Patients with established CSX often tend to have unfavorable cardiovascular events, leading to recurring hospitalizations, decreased quality of life, and poor prognostic outcomes.

The intensity of CSX symptoms is reported to reduce in 30% of subjects but may progressively worsen in approximately 20% of patients over time.[3][5] A study conducted on a cohort of female subjects reported 45% of individuals with chest pain and no evidence of coronary artery obstruction by imaging (angiography) reported ongoing typical or atypical chest pain persisting greater than 12 months. The study also reported subjects to have twice the risk for adverse cardiovascular events (myocardial infarction, stroke, CHF, and cardiovascular mortality).

Progressive disease comprises regular and lengthy anginal chest pains that manifest at decreased exertion levels and may even occur at rest. Some subjects may also experience a disease course resistant to pharmacological management, which further diminishes the quality of life. Patients with a progressive disease course may require drastic diagnostics that could lead to functional disability.[3]

Complications

CSX was previously thought to be a benign condition. Recent literature has associated females with anginal chest pain and no evidence of stenosis on imaging with adverse cardiovascular events. Such occurrences include MI, stroke, cardiac death, all-cause mortality, and hospitalization for heart failure.[15]

CSX further causes a prominent decline in a patient's quality of life and difficulties in daily activities. The diagnosis of CSX is one of exclusion which further prompts extensive workup and assessment that can be costly and time-consuming. The challenge of achieving therapeutic efficacy from pharmacotherapy also poses additional barriers as traditional therapy for managing anginal chest pain is often unsuccessful. This often prolongs CSX symptoms, prompts hospital admissions, restraining daily activities, and inability to attend work.

Although the prognosis of CSX is exemplary, the high prevalence rate results in periodic hospitalization from recurring episodes of chest pain. Clinical manifestations are reported to reduce in roughly 30% of patients and progressively worsen in 10 to 20%. Patients who suffer from a deteriorating disease course often face diagnostic challenges and procedures, potentially causing disability.[16]