The release of adenosine from the myocardium is believed to occur when there is a reduction in myocardial oxygen tension caused by inadequate coronary blood flow, hypoxemia, or increased metabolic activity of the heart. Adenosine enters the interstitial fluid space and activates adenosine receptors, leading to vasodilation of the coronary resistance vessels. However, adenosine alone cannot explain the increased coronary flow observed during prolonged enhancement of cardiac metabolic activity as its release from cardiac muscle is temporary. Factors that can affect coronary vascular resistance are illustrated in Figure 17.35.

Diminished coronary blood flow can have significant effects on the supply of oxygen to myocardial cells. Most of the oxygen in coronary arterial blood is extracted during one passage through the myocardial capillaries. Therefore, any substantial reduction in coronary blood flow limits oxygen delivery to the myocardium since oxygen extraction is already at a maximum even under normal blood flow conditions.

A reduction in coronary flow, even if it is not severe enough to cause myocardial necrosis, can still lead to temporary dysfunction of the heart. Myocardial stunning, a condition characterized by pronounced mechanical dysfunction, can occur after a relatively brief period of severe ischemia followed by reperfusion. The pathophysiology of myocardial stunning involves intracellular calcium overload that starts during ischemia and the generation of harmful free radicals early in reperfusion. These changes impair the responsiveness of myofilaments to calcium.

In a normal human heart, there are typically no functional intercoronary channels. Therefore, abrupt occlusion of a coronary artery or its branches results in ischemic necrosis and eventual fibrosis of the affected myocardial areas. However, if a coronary artery narrows slowly over time, collateral vessels can develop to provide sufficient blood supply to the ischemic myocardium, thereby preventing or reducing the extent of necrosis. Collateral vessels may form between occluded and nonoccluded artery branches. They originate from preexisting small vessels that undergo changes in the endothelium and smooth muscle in response to wall stress and chemical agents, including vascular endothelial growth factors (VEGFs) released by the ischemic tissue. VEGFs, a group of glycoproteins, induce angiogenesis, vasodilation, and increased endothelial permeability. Vasodilation allows for perfusion of more capillaries, while increased permeability occurs through the opening of tight junctions between endothelial cells and the creation of fenestrations.

Patients who have experienced an acute coronary artery occlusion may exhibit myocardial stunning, which is prolonged ventricular dysfunction without necrosis. If the patient receives timely treatment through coronary bypass surgery or balloon angioplasty and blood flow to the ischemic region is restored adequately, the myocardial cells in that area can fully recover. However, for several days or even weeks, the contractility of the myocardium in the affected region may be significantly below normal.
According to the adenosine hypothesis, a reduction in myocardial O2 tension produced by inadequate coronary blood flow, hypoxemia, or increased metabolic activity of the heart leads to release of adenosine from the myocardium. Adenosine enters the interstitial fluid space to reach the coronary resistance vessels and induces vasodilation by activating adenosine receptors. However, it cannot be responsible for the increased coronary flow observed during prolonged enhancement of cardiac metabolic activity because release of adenosine from cardiac muscle is transitory. Factors that alter coronary vascular resistance are illustrated in
Fig. 17.35
Effects of Diminished Coronary Blood Flow
Most of the O2 in coronary arterial blood is extracted during one passage through the myocardial capillaries. Thus the supply of O2 to myocardial cells is flow limited; any substantial reduction in coronary blood flow curtails O2 delivery to the myocardium because O2 extraction is nearly maximal even when blood flow is normal.
A reduction in coronary flow that is neither too prolonged nor too severe to induce myocardial necrosis can nonetheless cause substantial (but temporary) dysfunction of the heart. A relatively brief period of severe ischemia followed by reperfusion can result in pronounced mechanical dysfunction (myocardial stunning). However, the heart eventually recovers fully from the dysfunction. The pathophysiological basis for myocardial stunning appears to be intracellular Ca++ overload, initiated during the period of ischemia, combined with the generation of OH− and superoxide free radicals early in the period of reperfusion. These changes impair the responsiveness of myofilaments to Ca++ .
In the normal human heart, there are virtually no functional intercoronary channels. Abrupt occlusion of a coronary artery or one of its branches leads to ischemic necrosis and eventual fibrosis of the areas of myocardium supplied by the occluded vessel. However, if a coronary artery narrows slowly and progressively over a period of days or weeks, collateral vessels develop and may furnish sufficient blood to the ischemic myocardium to prevent or reduce the extent of necrosis. Collateral vessels may develop between branches of occluded and nonoccluded arteries. They originate from preexisting small vessels that undergo proliferative changes of the endothelium and smooth muscle. These changes may occur in response to wall stress and to chemical agents, including vascular endothelial growth factors (VEGFs) released by the ischemic tissue. The VEGFs, of which there are at least five in mammals, are glycoproteins. The VEGFs induce angiogenesis, elicit vasodilation and increase endothelial permeability. By causing vasodilation, VEGFs enable perfusion of more capillaries and increase capillary permeability by opening tight junctions between endothelial cells and by adding fenestrations.
Myocardial stunning, prolongedventriculardysfunctionwithoutmyocardialnecrosis,maybeevidentinpatientswhohavesufferedanacutecoronaryarteryocclusion.Ifthepatientistreatedsufficientlyearlybycoronarybypasssurgeryorballoonangioplasty,andifadequatebloodflowisrestoredtotheischemicregion,themyocardialcellsinthisregionmayrecoverfully.However,formanydaysorevenweeks,thecontractilityofthemyocardiumintheaffectedregionmaybegrosslysubnormal.