Since the heart operates solely under aerobic metabolism, myocardial mitochondria must maintain an abundance of oxygen to continue oxidative phosphorylation. Heart rate, contractility, and ventricular-wall tension are the three factors that determine myocardial oxygen demand. An increase in any of these variables requires the body to adapt to sustain adequate oxygen supply to the heart.

Heart rate is thought to be the most important factor affecting myocardial oxygen demand. With an increased heart rate, the myocardium must work harder to complete the cardiac cycle more efficiently. With a shortened cardiac cycle, the time spent in diastole decreases. Because diastole ends prematurely, the amount of blood that normally fills the ventricles decreases, and oxygen-saturated hemoglobin is not allowed to reach the subendocardium. Under optimal conditions, myocardial oxygen demand will equal myocardial oxygen supply; however, when there is structural damage from a plaque that impedes flow, there can be a mismatch between supply and demand that results in ischemia.

Contractility or inotropism is the rate of increase in the intraventricular pressure during contraction at a given muscle fiber length.  Interestingly, myocytes have the innate ability to exert a contraction at any muscle length. This force is measured after the closure of the mitral valve and before the opening of the aortic valve during which time the intraventricular volume remains constant.

Contractility is impacted by a variety of intrinsic and extrinsic forces including calcium concentration. Calcium is released by the sarcoplasmic reticulum of cardiac muscle and binds to troponin C. This bond stimulates a conformational change of tropomyosin that releases it from the binding sites on the actin filament. With the release of tropomyosin, the active sites on actin are free to bind myosin which causes adenosine triphosphate (ATP) to be broken down into adenosine diphosphate (ADP) and inorganic phosphate (P). Subsequently, there is a power stroke of the myosin head which forces the actin filament centrally towards the sarcomere, and ADP and P detach from the myosin head resulting in contraction. Once ATP re-attaches to myosin, actin is freed. This cycle continues until intracellular calcium supplies are depleted, there is no longer binding between troponin C and calcium, and tropomyosin can revert to its initial confirmation to cover the binding sites on actin. Therefore, the intracellular calcium concentration is directly proportional to the contraction force [2].

Ventricular wall tension is based on the thickness of the ventricular myocardium. The law of Laplace states that ventricular wall tension is proportional to ventricular radius and intraventricular pressure. Patients with coronary artery disease will have decreased blood and oxygen supply to the myocardium. In this case, contractility will be diminished. Because the ventricle can no longer achieve adequate contraction, end systolic volume will increase. The excess blood remaining in the ventricle will cause expansion of the ventricular radius and intraventricular pressure resulting in a higher wall tension.

The oxygen-carrying capacity of the blood and flow through the coronary arteries regulate myocardial oxygen supply. Oxygen-carrying capacity can be decreased in several conditions that include either decreased red blood cell concentration or decreased oxygen saturation of hemoglobin. For example, anemia is a lower than an average number of healthy red blood cells. Even though the red blood cells may be fully saturated with oxygen, there are not enough of them to supply an adequate amount of oxygen to the muscle. Usually, it is caused by a nutritional deficiency in iron, vitamin B12, or folate which is easily correctable. However, there can be more devastating causes such as thalassemia, sickle cell anemia, and various inherent enzyme deficiencies that are more difficult to treat [1][3].

Hemoglobin is the oxygen-carrying portion of a red blood cell, and it is fully saturated when it binds four molecules of oxygen. With every molecule of oxygen that hemoglobin releases to the tissues, it binds the remaining oxygen molecules with more affinity. Usually, hemoglobin only disperses one molecule of oxygen before it returns to the lungs to become fully saturated once again. Carbon monoxide binds to hemoglobin with a much higher affinity than oxygen. When hemoglobin returns to the lungs to be re-oxygenated, it usually has usually one or two out of the total four binding spaces available [1][3].

Since carbon monoxide binds to hemoglobin with a higher affinity than oxygen, it secures the empty binding spots of hemoglobin more quickly than incoming oxygen. At this point, hemoglobin is fifty to seventy-five percent saturated with oxygen and twenty-five to fifty-percent saturated with carbon monoxide. Even though hemoglobin has oxygen molecules attached, it will not release them in the tissues. This occurs because hemoglobin’s affinity for oxygen is inversely proportional to its oxygen saturation. Therefore, the resulting hypoxia is not due to a lack of oxygen, but rather hemoglobin’s higher affinity for oxygen when only partially saturated with it [1][3].

Even though oxygen-carrying capacity can impact myocardial oxygen supply, coronary blood flow is the major determinant of supply. Coronary artery blood flow is a function of pressure divided by resistance. Myocardial oxygen consumption is equal to coronary blood flow multiplied by the arterial-venous oxygen difference. During diastole, the ventricles are receiving blood before systolic contraction. This filling phase of the cardiac cycle allows the coronary arteries to provide maximum blood flow to the heart. Additionally, this is the only phase of the cardiac cycle that allows blood to arrive at the subendocardium which is the most distal portion [1][3].

A rise in myocardial oxygen demand can become clinically significant if it exceeds myocardial oxygen supply. This can occur during the later stages of coronary artery disease (CAD). From years of poorly controlled hyperlipidemia, a patient can develop atherosclerotic plaques in the major arteries that supply blood to the heart. Once the integrity of the vasculature has been compromised, plaques can develop and begin to shorten the diameter of the coronary arteries [1].

Once the vessel has more than a seventy percent occlusion, the patient will usually begin to experience symptoms. Usually, these symptoms such as chest pain, dyspnea on exertion, and diaphoresis, present during activity or stress when the heart requires more oxygen. This is categorized as stable angina. However, once symptoms begin presenting after less physical activity or at rest, the disease has progressed to an eighty-percent occlusion, and the diagnosis of unstable angina can be made [4][5].

A person who presents to the emergency department with angina should be evaluated for a mismatch in myocardial oxygen supply and demand. The first test to determine this is a 12-lead electrocardiogram (ECG) which measures the electrical activity of the heart. The ST segment is representative of the time between ventricular depolarization and ventricular repolarization. If the ST segment is elevated upon arrival, it can be indicative of acute myocardial infarction; however, if there is a depressed ST segment, it can be representative of acute ischemia [2][4].

If the ECG is unremarkable, cardiologists may choose to perform an exercise stress test. In a controlled environment, cardiologists can monitor the patient’s blood pressure, oxygen saturation, and electrical activity of the heart. By performing exercise, the patient is causing the heart to increase its rate and contractility thus elevating the myocardial oxygen demand. If the vessels are atherosclerotic, the heart will not be able to adapt to the changes in demand thus there will be a mismatch between supply and demand which will be represented accordingly on the ECG [6][4].

Additionally, if patients have a contraindication to an exercise stress ECG, they can undergo myocardial perfusion imaging (MPI). Myocardial perfusion imaging can be used to examine the myocardium for deficits in myocardial oxygen supply due to atherosclerotic plaques from coronary artery disease. First, the patients are given an adenosine analog and a nuclear isotope which are both injected via an intravenous catheter. The adenosine analog stresses the heart and increases myocardial oxygen demand. The patient is monitored for changes in oxygen saturation, blood pressure, heart rate, and rhythm [4].

Next, the second portion of the nuclear stress test can begin. The accumulation of the nuclear isotope in the vessels allows clear images of the coronary arteries and surrounding vasculature to be obtained. Currently, the standard model includes gathering images from seventeen segments: 16 short-axis views and the long axis view of the apical segment. Cardiologists grade each view using a scale range of zero to four; 0 = normal, 1 = mildly abnormal, 2 = moderately abnormal, 3 = severely abnormal, 4 = absent. The summed perfusion score (SPS) is the total score including images from rest and stress, the summed resting score (SRS) represents the severity of myocardial infarction, and the summed stress score (SSS) reflects the extent of myocardial ischemia and infarction. To determine the severity of ischemia alone, the summed difference score (SDS) must be calculated by subtracting the SRS from the SSS [6][4].

A mismatch between myocardial oxygen supply and demand can result in myocardial ischemia or infarct. Unfortunately, infarct results in irreversible damage to the myocardium. However, ischemia and potential causes of mismatch can be controlled through a variety of pharmaceutical agents that include nitrates, beta-adrenergic-receptor blockers, and calcium-channel blockers. Each of these medication classes increases myocardial oxygen supply and decrease myocardial oxygen demand to varying degrees [1][7].

Nitrates cause a relaxation in vascular smooth muscle which causes dilatation of the coronary arteries and systemic venous circulation. When the vessels carrying de-oxygenated blood back to the heart are dilated causing the venous capacity to increase, there are corresponding decreases in cardiac preload, ventricular volume, and ventricular wall tension during systole. Because of the downward shift in workload required by the heart, myocardial oxygen demand is reduced.  Additionally, through the dilatation of coronary arteries, nitrates also increase myocardial oxygen supply. The increased radius of the vasculature supplying the heart allows blood to bypass potential plaques to provide a continuous supply of blood [8][9].

Beta-adrenergic receptor blockers inhibit the effects of catecholamines at the beta receptors. Usually, the sympathetic nervous system stimulates the release of catecholamines to bind to beta receptors causing an increase in heart rate, contractility, and blood pressure through vasoconstriction. Because beta-blockers prevent catecholamines from interacting with the beta-adrenergic receptors, there is a decrease heart rate and contractility thus diminishing myocardial oxygen demand. Additionally, the slower heart allows for a lengthened diastolic portion of the cardiac cycle. Because of this, more blood is allowed to supply the heart during the filling phase [1] .

Calcium-channel blockers prevent the entrance of calcium through voltage-gated channels. Since contractility is reliant on calcium release from the sarcoplasmic reticulum, a decreased supply of calcium will inherently cause a drop in contractility. This drop in contractility causes a decrease in myocardial oxygen demand. Additionally, the vasodilatory effects of calcium-channel blockers on vascular smooth muscle result in an increase in myocardial oxygen supply [10].