Disorders of coronary vessels

Source and dominance

Adequate and continuous blood supply to the heart is one of the most crucial requirements on the human body. It is quite ironic that the heart is required to supply itself with blood so that it can continue to supply the rest of the body. The coronary arteries are a pair of vessels arising from the root of the aorta that branch and supply the heart with oxygenated, nutrient-rich blood.

The coronary arteries are named after the aortic sinus (of Valsalva) from which they originate. The right coronary artery originates from the right aortic sinus (of Valsalva), while the left coronary artery arises from the left aortic sinus (of Valsalva). There is a third sinus that does not give rise to any vessel; it is referred to as the non-coronary (or posterior) sinus.

As each vessel emerges from the base of the ascending aorta, they tend to travel in the subepicardial space. However, there are instances where the vessels may be covered by pericardial fat or bridging myocardial fibers. The left coronary artery is the larger of the two vessels. However, the size of the vessel does not always translate to the territory it covers. In most cases, the right coronary artery is dominant based on the fact that it gives off the posterior interventricular branch that supplies the posterolateral part of the left ventricle and the posterior third of the ventricular septum. In other instances, this vessel arises from a branch of the left coronary artery, and therefore the left coronary artery will be the dominant vessel. Co-dominance is also a possible (albeit infrequent) phenomenon where both left and right coronary arteries share this territory.

Right coronary artery

The right coronary artery can be subdivided into proximal, middle, and distal parts. After emerging from the anterior sinus of Valsalva, three vessels branch off from the proximal part of the right coronary artery. These are the right conus, right anterior ventricular, and right atrial branches of the right coronary artery. The middle portion of the right coronary artery then gains access to the right side of the atrioventricular groove. It then gives rise to the right marginal and right posterior descending arteries. The branches of the proximal part supply the right atrium, the subdivisions of the right marginal supply the anterior part of the right ventricle, and the right posterior descending supplies parts of the posterior wall and the diaphragmatic surface of the heart.

Left coronary artery

Unlike the right coronary artery, the proximal part of the left coronary artery has no branches. After leaving the left posterior sinus of Valsalva, the left coronary artery accesses the left side of the atrioventricular groove. It then branches into the left circumflex and left anterior descending arteries. The former travels to the diaphragmatic surface of the heart and gives several branches to supply the left atrium and majority of the left ventricle, while the latter supplies the interventricular septum and parts of the sternocostal surface of the heart.

Coronary sinus and cardiac veins

Venous blood leaves the myocardium via numerous venous tributaries. The coronary venous system is more eclectic than the arterial division. The coronary sinus is the main vein of the heart. It receives venous supply from the majority of the cardiac veins, except the Thebesian vessels (which drain directly into all four chambers of the heart) and anterior cardiac veins (which drain directly into the right atrium). The coronary sinus is fed by the great cardiac, middle cardiac, small cardiac and oblique veins. The sinus then opens into the right atrium, adjacent to the ostium of the inferior vena cava and the vestibule of the tricuspid valve.

Outgrowth theory

There is much debate regarding the development of the coronary vasculature. More specifically, there is some uncertainty regarding the cellular origin and details of the molecular pathways responsible for coronary formation. Previous theories postulated that the vessels are derived from angiogenic events (i.e. budding of new vessels from pre-existing veins), while others suggest that the vessels arise de novo during development (i.e. vasculogenesis takes place). 

Older schools of thought proposed that the coronary arteries grew out from the aortic roots and the cardiac veins that were derived from a systemic venous structure. However, this theory has largely been disproven since coronary arteries have been identified in embryonic hearts prior to the formation of the coronary ostia in the aortic sinuses. Therefore, the outgrowth theory was traded in for the ingrowth theory. 

Ingrowth theory

Recall that systemic vasculogenesis outside of the heart relies on the differentiation of mesenchymal tissue under the influence of vascular endothelial growth factor (VEGF) and other inductive agents. However, the primitive heart is only covered by the false. Eventually, there is a migration of coelomic cells initially found at the venous aspect of the cardiac tube to the surface of the heart. This proepicardium spreads out to form a monolayer of cells over the previously bare, primitive myocardium. While the majority of the proepicardium will mature to form the epicardium, the underlying myocardium and nearby hematopoietic progenitor cells initiate a phenotypic transformation of some of the primitive cells. Consequently, there is a shift from the epithelial tissue of the epicardium, to a highly invasive mesenchymal tissue known as epicardial-derived cells (EPDCs). These cells are considered extremely important in the formation of the coronary vascular tree.

By the middle of the 4th gestational week (around day 25), vasculogenesis results in the formation of primitive vessels between the myocardium and epicardium. They coalesce as time progresses to give rise to a diffuse vascular plexus in the subepicardial space. Spatially and temporally coordinated inductive factors (including, but not limited to VEGF, connexion 43, perlecan, and neural crest cells) promote the growth of some of these branches toward the root of the aorta. Here, at least two vessels will penetrate the aortic root to give rise to the coronary arteries. The vessels are instantly exposed to a rush of blood, which further promotes smooth muscle migration and maturation of the vessel wall (via cellular rearrangement and apoptosis). 

The jury is still out regarding several aspects regarding the coronary vasculature. However, it is important to understand how these vessels are formed, as abnormalities related to these vessels have deleterious effects.

Ectopic coronary vessels

The two major concerns of ectopic coronary arteries refer to those arising from the incorrect sinus of Valsalva, and those arising from the wrong great vessel. A right coronary artery arising from the left posterior sinus (anomalous right coronary artery) and a left coronary artery arising from the anterior sinus (anomalous left coronary artery) have both been described. Additionally, the left circumflex artery has also been seen arising from the anterior sinus as well (anomalous left circumflex artery).

In terms of frequency, the anomalous left circumflex artery occurs more commonly, followed by the anomalous right and anomalous left coronary arteries. The concerns with the ectopic coronary arteries are that when they arise from the contralateral sinus, their proximal ostia tend to be slit-like instead of oval. Therefore, the amount of blood that passes through the vessel is slightly reduced. Additionally, the vessels tend to travel in abnormal routes, as seen with the anomalous left coronary artery passing in the transverse cardiac sinus (between the pulmonary artery and root of the aorta). Consequently, this segment of the vessel is likely to be compressed with each ventricular contraction, resulting in interrupted blood flow to the myocardium. Hence, these patients are at an increased risk for fatal hypoxic injuries to the heart muscles.

A coronary artery arising from the pulmonary artery is an extremely rare, yet life-threatening congenital defect. Only occurring in about 1 in 300,000 cases, this deformity often affects the left coronary artery. Patients tend to present with dilated cardiomyopathies, mitral insufficiency, and congestive cardiac failure during early life. Not surprisingly, these symptoms arise on the basis that only one coronary artery would be delivering oxygenated blood to the myocardium. However, they may develop significant collateral circulation that minimizes their symptoms later on. Surgical management is the gold standard in treating ectopic coronary arteries. However, the risk to benefit ratio should be considered especially in patients who are asymptomatic at rest and during stressful events.

Internal defects of the coronary arteries

Very rarely, the ostium of the coronary artery may be stenotic, or even atretic. Consequently, the lumen of the vessel may be partly or completely absent. These patients usually present during the first year of life. The left coronary is often affected, with angiographic analysis revealing obliteration of the vessel prior to its division. However, there are typically collateral vessels arising from the right coronary circuit that may provide temporizing relief; but it may be insufficient in the long run.

Abnormal communication of coronary vessels

Normally the coronary vessels travel within the subepicardial space, covered by pericardial fat. Occasionally, there are bridges of myocardium that may overlap the vessel for short distances. The problem with the relationship between the coronary artery and the myocardium arises when the vessels travel within the myocardium for variable distances. The incidence of this phenomenon ranges widely from 15 – 85% of hearts at autopsy (0.5 – 40% clinically). Therefore, this suggests that some of these sub-myocardial coronary arteries may actually be benign. However, symptomaticity is more often than not, related to ischaemia. The middle part of the left anterior descending is most commonly affected, followed by the right coronary and the left circumflex arteries.

The other abnormality of coronary communication can be both congenital and acquired. The coronary artery fistula is another rare complication that accounts for only 0.4% of all coronary abnormalities, but they can also follow traumatic or iatrogenic injuries. It is most often seen with the right coronary artery communicating directly with the right atrium or ventricle, the pulmonary vessels, or the superior vena cava ; but drainage into the left cardiac chambers can also occur. Symptoms of angina, associated shortness of breath, fatigue, and subsequently congestive heart failure can arise as a result of the size of the fistula and the severity of the shunt. Trans-catheter fistula obliteration has taken precedence over a surgical approach to rectify this anomaly. 

Kawasaki disease

Kawasaki disease is an acute inflammatory disorder affecting small to medium-sized vessels such as the coronary arteries. It more commonly affects children less than 5 years old, with a marginal male predilection. The prevalence of the disease tapers off in older populations, as it is almost never seen in patients over 18 years old. It is characterized as a clinical constellation of mucocutaneous manifestations that present in a specific temporal sequence, and can be readily recognized by the astute physician. They commonly present with an abrupt, high grade, febrile illness, with irritability that exceeds the scope of the fever. The fever usually lasts for 1 – 2 weeks (but can go up to 3 – 4 weeks), occasionally remits and relapses, but does not respond to antipyretic drugs. During the initial phases, the patients are also likely to have an associated bilateral conjunctivitis, swollen and hyperaemic hands and feet, and the classical strawberry tongue. A better way to remember the symptoms of Kawasaki disease is with the acronym FEBRILE:

• Fever – >102-104°F (39-40°C)
• Enanthem – redness of the mouth and throat, crusting and fissuring of the lips, strawberry tongue
• Bulbar conjunctivitis – bilateral and non-exudative
• Rash – globally distributed papulosquamous patches
• Internal organ involvement – particularly coronary artery aneurysm (not clinically apparent)
• Lymphadenopathy – usually limited to cervical lymph nodes, unilateral, and >1.5 cm
• Extremity changes – membranous desquamation of the palms and soles that was preceded by oedema and erythema

While the overall infection that causes Kawasaki disease tends to be self-limiting, the associated vasculitis affecting the coronary vasculature is the most concerning aspect of the disease. However, keep in mind that the vascular inflammation occurs throughout the body and is responsible for many of the symptoms. The early part of the vasculitis is characterized by vessel wall oedema extending into the tunica media layer of the vessel.

About a week to nine days after the fever begins, neutrophils and cluster of differentiation 8 (CD8=) migrate to the vessel walls and proliferate. The inflammatory mediators begin to produce numerous interleukins (particularly IL-1, IL-4, and IL-6), cytokines (including VEGF, TNF, and chemotactic agents), as well as matrix metalloproteinases (mostly MMP3 and MMP9). Not only do the cytokines and interleukins propagate the elevated body temperature, but they also result in injury to the elastic layer of the vessel walls. The damage can be so severe that the muscular layer of the vessel wall becomes necrotic.

This weakness between the external and internal elastic layers of the vessel wall creates an environment that is susceptible to coronary aneurysms.
A clinical diagnosis of Kawasaki disease can be made in the setting of a febrile illness lasting for more than four days with at least four of the clinical signs outlined by the AHA (see FEBRILE acronym; excluding internal organ involvement). All patients suspected of having Kawasaki disease should be admitted and have an adequate workup completed. The main aim of therapy is to limit or prevent damage to the coronary vasculature. The primary medical regime used in treating this disorder is intravenous immunoglobulin (IVIG) given in a single dose infusion, as well as a high dose of aspirin given orally.

Coronary vasospasm

Prinzmetal or variant angina are disorders of the coronary arteries characterized clinically by acute chest pain, ST-elevation (on echocardiogram) and, pathologically by spasmodic contractions of the smooth muscle layer of the coronary arteries. These disorders have been associated with the manifestation of atherosclerosis, ventricular arrhythmias, myocardial infarctions, and sudden cardiac death. While the exact cause of the vasospasms remain enigmatic, they can result in partial or complete obstruction of the coronary arteries; giving rise to the aforementioned complications. 

Gender predilection of Prinzmetal angina tends to vary in different regions. However, the common age of presentation is during the 6th decade of life. Retrosternal pain that radiates to the neck and left arm (as seen in angina) are typical complaints of patients with coronary vasospasms. Most patients have a normal threshold for exercise and only experience cyclical chest pain. However, there are identifiable triggers of angina episodes, including (but not limited to) tobacco, hyperventilation, and some drugs like histamine, serotonin, and acetylcholine.

Because the symptoms of Prinzmetal angina are so close to unstable angina, it is important to carry out a full cardiac workup on these patients when they present. Nitroglycerin is most often given via the sublingual route (but can also be given intravenously) to promote vasodilation until coronary artery disease is ruled out. These patients are also started on other pharmacological agents commonly used for patients with unstable angina or myocardial infarction. Long-term therapies include calcium channel blockers and longer acting nitrates often help to reduce the recurrence of spasmodic episodes.

Coronary artery disease

Coronary artery disease is an umbrella term used to describe a group of non-communicable disorders that result from an ischaemic insult to the myocardium as a result of arterial obstruction. Across the world, coronary artery disease is a common cause of mortality among both men and women. There is a strong male preponderance for the development of these disorders, with about 33% of men and 25% of women meeting their demise as a result of coronary disease. The vast majority of cases are long term complications from atherosclerosis. However, there are other causes of medium to large vessel vasculitis that can also result in coronary artery disease (e.g. polyarteritis, aortitis, and some connective tissue diseases).

The risks of developing coronary artery disease can be grouped based on whether or not they can be modified on a day to day basis. The non-modifiable risk factors include ethnicity, age, and family history. 

• Age: Like most non-communicable diseases, the risk of developing coronary artery disease increases with age. This is mostly due to the degenerative processes that result from aging, leading to reduced vascular compliance and thus an increased risk of a cardiac event. 
• Ethnicity: In the Western world, individuals of African or Caribbean descent have an increased risk of developing coronary artery disease when compared to their age and gender-matched counterparts of other ethnicities. 
• Family History: A positive family history of coronary artery disease is one in which there is a first-degree male relative (father or brother), or female relative (mother or sister), was diagnosed with coronary artery disease prior to their 55th or 65th (respectively) birthday.

The modifiable risk factors (which include, but are not limited to the following) predispose the patients to developing atherosclerosis; which is the leading cause of coronary artery disease:

• Diabetes mellitus 
• Essential hypertension 
• Physical inactivity 
• Obesity
• Dyslipidemia
• Smoking

Atherosclerotic plaques are abnormal lipid deposits within the intimal layer of the blood vessels. These plaques may remain fixed, but occlude the lumen of the vessel to variable degrees. Myocardial ischaemia due to a fixed plaque is known as stable angina. The classical angina-type chest pain (described earlier) often presents when the supply of oxygen to the myocardium does not match the amount that is demanded.

If the plaque ruptures, erodes, or migrates, then the situation changes from stable angina (where symptoms are only present with physical activity) to unstable angina, where the symptoms are present even at rest. If the blood supply to the heart is inefficient for a prolonged period of time, tissue death and subsequent necrosis will ensue. Myocardial infarction is associated with severe morbidity and mortality; survivors generally require lifetime therapy. Over time, patients who have had a heart attack may also have associated arrhythmias and may progress to developing heart failure, which is a constellation of symptoms resulting from reduced cardiac function.

Treatment of coronary artery disease depends on the degree of occlusion and should be tailored for each patient. Special attention should be paid to those presenting with acute events, as early intervention is likely to improve the patient outcome.

Electrocardiography

Electrocardiography detects the electrical depolarization that spreads across the precordium associated with myocardial depolarization. The impulses are detected, amplified, transduced, and reproduced (either printed or displayed on a monitor) as a graph known as an electrocardiogram. The electrocardiogram has characteristic waves, segments, and intervals that correspond to different phases of the cardiac cycle.

The P wave corresponds to the atrial contraction; however, the waves corresponding to atrial repolarization are buried in the ventricular activity. The QRS complex represents ventricular contraction and normally follows each P wave. The intervals begin at the beginning of a preceding wave and end at the beginning of a subsequent wave. Segments, on the other hand, begin at the end of a preceding wave and ends at the end of a subsequent wave. 
The standard electrocardiograph is generated with twelve electrodes (i.e. 12 leads). The leads can be subdivided into limb leads (I, II, and III), augmented limb leads (aVR, aVL, and aVF), and precordial leads (numbered V1 - V6). Each set of leads displays the electrical activity across a region of the heart:

• The inferior surface - supplied by the inferior interventricular artery (more commonly arising from the right coronary artery) - is monitored by leads are II, III and aVF.
• The anteroseptal region - mostly supplied by the anterior interventricular artery - is monitored by leads V1 and V2.
• The anterior wall - mostly supplied by the anterior interventricular artery - is monitored by leads are V3 and V4.
• The high lateral and low lateral walls - supplied by branches of the left interventricular artery - are monitored by leads I and aVL, and V5 and V6, respectively.

When abnormal depolarization and repolarization occurs within the ischaemic or infarcted tissue, there is usually elevation of the ST segment with concurrent pathological Q wave changes. The leads that these changes occur in suggest the vessels that are obstructed. For example, ST elevation in leads V1 and V2 suggest obstruction of the anterior interventricular artery.

Cardiac biomarkers

Like every cell within the body, there are numerous proteins that are important for cellular function. There are certain proteins that are specific to some cells. Proteins such as creatine kinase -muscle/brain (CK-MB), lactate dehydrogenase (LDH), and isoenzymes of troponin (Tn I and Tn T) are elevated in the serum following cardiac injury.

All the cardiac enzymes are elevated following the injury. CK-MB has the fastest rise (reaching its peak within 6 to 8 hours of the injury) and is cleared within 24 hours. Therefore, while it is good as an acute biomarker, the lack of specificity (CK-MB also found in brain tissue) and the rapid degradation makes it less reliable. Although LDH remains elevated longer than other biomarkers, it has a slow rise, low specificity, and does not peak until three days following the injury. These factors also make it a less reliable biomarker. The troponin proteins are highly specific for myocardiocytes. They peak within 12 to 24 hours of the injury and remain elevated for up to four days. Therefore, it is the preferred biomarker for identifying an acute myocardial infarction.