Introduction
Myocardial ischemia occurs when the ability to supply oxygen and nutrients to the myocardium is exceeded by the myocardium’s oxygen and nutrient requirements. The heart is primarily an aerobic organ and has a narrow threshold for a deficit in oxygen delivery. The myocardium, and consequently the coronary circulation, must be able to adapt quickly to meet the body’s varying hemodynamic requirements. The development of acute ischemia sequentially adversely affects diastolic function, systolic function, and electrocardiographic changes and finally results in chest pain; a sequence referred to as the ischemic cascade . In the presence of chronic ischemia, a patient may develop left ventricular (LV) systolic and diastolic dysfunction and elevation of LV diastolic pressure resulting in heart failure. A patient’s clinical comorbidities, presenting clinical state, and hemodynamics determine the threshold for developing ischemia.
Myocardial Oxygen Demand
Myocardial oxygen demand is governed by three principal factors: heart rate, contractility, and wall tension. As the heart rate increases, the myocardial oxygen requirement increases, yet there is a concomitant decrease in diastolic filling period, which consequently decreases the available time for perfusion. As myocardial contractility increases, the requirement for oxygen and nutrients is also increased. Wall tension is the force generated by the myocardium at a given preload and afterload and may be calculated by the Laplace law ( Fig. 6.1 ). Wall tension is affected by afterload, chamber size (i.e., radius), and wall thickness. Clinically, chamber dimensions are decreased by interventions that reduce LV preload whereas afterload is largely determined by systolic blood pressure. The impact of afterload (i.e., increased systolic blood pressure) on myocardial oxygen demand is greater than the impact of preload or heart rate. As afterload increases, the radius of the ventricle may increase and further elevate the pressure required by the ventricle to propel blood from the heart. As wall tension increases, myocardial oxygen demand increases.
Assessment of these factors is essential in understanding an individual patient’s potential for developing myocardial ischemia ( Table 6.1 ). Moreover, each of these determinants of myocardial oxygen demand represents an important treatment target for reduction of ischemia (see Chapter 20 ).
| Total | |
| 6–8 mL/min per 100 g | |
| Distribution | |
| Basal | 20% |
| Electrical | 1% |
| Volume work | 15% |
| Pressure work | 64% |
| Effects on MVO 2 of 50% Increase In | |
| Wall stress | 25% |
| Contractility | 45% |
| Pressure work | 50% |
| Heart Rate | 50% |
Myocardial Oxygen Supply
Myocardial oxygen supply is determined by oxygen transport, oxygen delivery, and coronary arterial blood flow. Perturbations to any of these three components will decrease the ability to meet the metabolic requirements of the myocardium. Along with oxygen, the delivery of metabolic substrate to the myocardium is facilitated by normal coronary blood flow. In the normal resting state, the heart relies primarily on fatty acids, and to a lesser degree glucose, for facilitating aerobic metabolism. As supply diminishes and as demand increases—producing ischemia—the myocardium switches substrate utilization to lactate and glycogen.
Oxygen is transported in the blood bound to hemoglobin and dissociates from hemoglobin when delivered to tissues for oxidative metabolism. The transport of oxygen and the ability to deliver it to myocytes is impacted both by hemoglobin levels and factors that influence the oxygen dissociation curve ( Fig. 6.2 ). The normal oxygen dissociation curve facilitates the binding of oxygen to hemoglobin in the lungs and the dissociation within the myocardial tissue where the carbon dioxide levels are higher and pH lower. Factors that shift the curve to the left decrease oxygen release in the tissues as the hemoglobin molecule has a higher affinity for oxygen; these include hypothermia, decrease in levels of 2,3-diphosphoglycerate, increase in pH (alkalosis), decrease in CO 2 , and increases in carbon monoxide. In addition, acquired hemoglobinopathies such as methemoglobinemia shift the curve left with a net increase in the affinity for oxygen within the affected hemoglobin molecule. Clinical states including hypothermia, acid/base disorders, anemia, hypoxemia, sepsis, and hemoglobinopathies can precipitate ischemia at lower thresholds, even in the absence of epicardial coronary artery disease (CAD). By decreasing delivery of oxygen to tissues, anemia results in reduced oxygen supply. At any level of hemoglobin, oxygen delivery is further influenced by factors that govern O 2 dissociation from hemoglobin as previously described (see Fig. 6.2 ).
Coronary blood flow regulation is essential for the heart to adapt its metabolic requirements and to receive adequate oxygen and nutrients. Coronary circulation is mediated by perfusion pressure (aortic diastolic to LV diastolic pressure), arterial tone (autoregulation), metabolic activity, sympathetic/parasympathetic activity, and the endothelium. The regulation of coronary blood flow occurs via neural pathways, metabolic mediators, myogenic control, and extravascular compressive forces ( Table 6.2 ). Exogenous medications, including α- and β-adrenergic agonists/antagonists, adenosine, and dipyridamole, impact blood flow via coronary epicardial and resistance vessels.
| Normal Coronaries | Atherosclerosis | |
|---|---|---|
| Myogenic Response | ||
| Pressure and flow-based dilation/constriction, resistance vessels | Dilation or constriction | Dilation or constriction |
| Metabolic Mediators | ||
| Adenosine | Dilation of resistance vessels | Attenuated dilation |
| Sympathetic | ||
| Norepinepherine | ||
| α 1 | Constriction | Constriction |
| β 2 | Dilation | Attenuated dilation |
| Parasympathetic | ||
| Acetylcholine | Dilation | Constriction of conduit vessels |
| Attenuated dilation of resistance vessels | ||
Coronary autoregulation maintains a relatively constant perfusion pressure over a broad range of aortic mean pressures (40 to 130 mm Hg). The epicardial vessels do not contribute to resistance unless clinically significant stenoses are present. In the absence of coronary artery stenoses, the majority of resistance is provided by prearteriolar, arteriolar, and intramyocardial capillary vessels ( Fig. 6.3 ). At rest, the capillaries are responsible for 25% of the microvascular resistance, which increases to 75% during periods of hyperemia. In normal individuals, coronary flow can increase 3- to 5-fold under conditions of maximal hyperemia. This ability to augment coronary blood flow is termed coronary flow reserve (see Chapter 5 ). Abnormalities in coronary flow reserve occur in many pathologic states, including diabetes mellitus, hypertension, dyslipidemia, myocardial infarction, aortic stenosis, and idiopathic dilated cardiomyopathies.
Clinical Predisposition
An individual’s health and risk factors impact his/her ability to increase coronary blood flow to meet the substrate requirements of the myocardium. The coronary epicardial and resistance vessels must be able to dilate to augment coronary blood flow. Factors that inhibit the normal coronary flow reserve will increase the propensity for developing myocardial ischemia. The common underlying mechanisms include endothelial cell dysfunction and a decrease in myocardial capillary density. Common conditions that adversely impact endothelial cell function include increasing age, obesity, hypertension, dyslipidemia, diabetes mellitus, hyperhomocysteinemia, and in women a history of preeclampsia and/or a postmenopausal state. In addition, risk factors including smoking, sedentary lifestyle, and poor nutrition also promote endothelial cell dysfunction. These risk factors and clinical conditions decrease the production of vasodilators such as nitric oxide (NO) and prostacyclin while increasing the production of potent vasoconstrictors including endothelin-1. Over time, this produces a prothrombotic environment and stimulates the formation of atherosclerosis, which may precipitate ischemia. In the presence of endothelial dysfunction, stimuli that normally result in vasodilation may paradoxically cause coronary vasoconstriction and precipitate myocardial ischemia.
Specific Environmental Factors
Hypoxemia
Individuals frequently develop hypoxemia secondary to medical conditions such as acute or chronic pulmonary diseases or exposure to high-altitude environments including airline travel and residing or visiting high-altitude locales. In addition to the direct effects of hypoxemia on oxygen delivery, individuals who are acutely hypoxemic develop tachycardia and an increase in rate pressure product. In the absence of epicardial CAD, the coronary physiology adapts to hypoxemia by epicardial coronary vasodilation and an increase in coronary flow reserve. In the presence of epicardial coronary disease, hypoxemia-induced epicardial coronary vasodilation may not occur; when studied in individuals with greater than 50% stenoses in at least one major epicardial vessel, vasoconstriction occurred, leading to a decrease in overall myocardial blood flow. As a result, individuals with comorbidities such as hypertension may develop myocardial ischemia at a lower peak rate pressure product, which may limit their functional capacity. An understanding of the normal response to hypoxemia and the alterations that occur in patients with CAD is critical in directing patient management during critical illnesses to minimize the risk for myocardial ischemia. This should be assessed with an understanding of the impact the patient’s overall clinical condition is having on the oxygen dissociation curve as this may also adversely impact the threshold for developing ischemia.
Hyperglycemia
The prevalence of diabetes mellitus is increasing and impacts a significant proportion of the general population. Individuals with metabolic syndrome or with diabetes mellitus have an increased incidence of myocardial ischemia and myocardial infarction. For patients hospitalized with acute illnesses, hyperglycemia in the absence of diabetes is often noted. The presence of hyperglycemia, independent of diabetes, is now known to adversely affect coronary physiology. In a study of 104 patients without diabetes (fasting blood glucose of <126 mg/dL, hemoglobin A 1c <6.5%), cardiac catheterization and assessment of coronary blood flow, coronary artery diameter, and coronary vascular resistance were performed. Hyperglycemia did not impact endothelium-dependent epicardial vessel dilation but was associated with impaired endothelial function in resistance coronary vessels. In addition, hyperglycemia was associated with increased coronary vascular resistance. These effects on coronary physiology may contribute to the increased risk for developing myocardial ischemia. Whether acute treatment of hyperglycemia decreases the risk of developing myocardial ischemia is unknown and requires further investigation. Diabetes, much like hypertension, plays a key role in the development of atherosclerosis, as well as myocardial ischemia. Diabetes mellitus leads to the development of oxygen free radicals, inflammation, and impaired vascular tone. Hyperglycemia causes a down-regulation of the endogenous nitric oxide synthase, inhibiting endogenous vasodilation via NO, as well as decreasing NO-related inhibition of platelet aggregation. Insulin resistance leads to an increase in free fatty acids, thereby promoting free radical generation and inflammation. Diabetes also leads to an upregulation in endothelin-1 as well as angiotensin II, known vasoconstrictors and catalysts for atherogenesis. Diabetes contributes to an alteration in collagen synthesis, leading to a weakened fibrous cap. Along with its vascular effects, diabetes can elevate the prothrombotic nature of platelets, leading to further ischemic events.
Hypercapnia
In the absence of respiratory disease, carbon dioxide, a product of aerobic cellular respiration, is maintained within a range of 35 to 45 mm Hg. Levels of carbon dioxide are known to impact the oxygen dissociation curve and coronary blood flow; the regional production of carbon dioxide is crucial to the metabolic control of myocardial blood flow. Systemic hypercapnia is often accompanied by acidosis and changes in hemodynamic states. Together these often increase coronary blood flow, primarily via decreases in coronary vascular resistance. Depending on the degree of sympathetic activation, the decrease in coronary vascular resistance may be blunted. In addition, the ability of hemoglobin to bind oxygen and transport it to the tissue is impaired when systemic carbon dioxide is elevated and the patient has acidosis. Consequently, patients can develop ischemia at a lower peak rate pressure product or when the perfusion pressure is adversely impacted, especially in the presence of concomitant CAD.
Acidosis
The presence of acidosis shifts the oxygen dissociation curve to the right, which promotes the dissociation of oxygen from hemoglobin at the tissue level. In the presence of systemic acidosis, however, this decreases the oxygen-carrying capacity of hemoglobin and may contribute to a lower ischemic threshold. Furthermore, in vitro studies have shown that acidosis has a profound inhibitory effect on the production of cellular cyclic GMP synthesis, which is further impaired when coupled with the presence of hypoxemia.
Hypothermia
Hypothermia is now commonly applied to out-of-hospital cardiac arrest patients who have been successfully resuscitated and who have impaired neurologic function. In canine models, both mild (32°C) and moderate (27°C) surface-induced hypothermia did not adversely impact coronary autoregulation. Therapeutic hypothermia reduces heart rate, may decrease the magnitude of vasopressor requirements, and may minimally improve systolic function. In contrast to the favorable hemodynamic effects, therapeutic hypothermia activates platelets and may be associated with an increase in the risk of stent thrombosis. There is no evidence, however, that it changes the threshold for ischemia (see Fig. 6.2 ).
Specific Cardiovascular Conditions
Hyperlipidemia
Elevated levels of low-density lipoprotein (LDL) confer an increased risk for atherosclerosis and myocardial ischemia, and treatment with lipid-modifying agents decreases this risk. Mechanisms for the development of both ischemia and atherosclerosis are multiple, including inflammation-driven development of lipid-laden plaques, oxidation of LDL increasing inflammation, and decreased response to vasodilation through direct inhibition of endothelium-dependent vasodilation. Improvements in levels and various treatments of hyperlipidemia have been shown to decrease recurrent ischemic events, furthering the understanding of the direct and indirect relationship between hyperlipidemia and myocardial ischemia.
Hypertension
Hypertension is an important contributor to myocardial ischemia with effects on both myocardial oxygen demand and supply. Even without the longstanding adaptive mechanism of LV hypertrophy, hypertension itself leads to both endothelial dysfunction and a maladaptive response to appropriate endogenous nitrate-driven coronary vasodilation. Increased levels of angiotensin II directly affect atherosclerosis and endothelial dysfunction, through upregulation of proinflammatory cytokines such as interleukin-6, NF-κB, and reactive oxygen species. Chronic hypertension disables normal endogenous mechanisms by which coronary arteries augment flow, mainly through endothelial NO and its effects on smooth muscles cells. Management of hypertension, especially with inhibitors of the renin-angiotensin-aldos-terone system, has a significant impact in decreasing myocardial ischemia.
Hypotension
Systemic hypotension, with its many causes, leads to reduced tissue perfusion including that in the myocardium. A decrease in the coronary perfusion pressure occurs, which decreases myocardial oxygen delivery. An increase in production of lactic acid further worsens delivery of oxygen to the myocardium. This scenario is common in cardiogenic shock where worsening hypotension leads to an increase in systemic vasoconstriction, LV diastolic pressure, and worsening acidosis, which collectively decrease myocardial oxygen delivery. The presence of coexisting CAD will further impair myocardial tissue perfusion.
Coronary Artery Disease
The development of CAD predisposes the patient to developing ischemia at lower peak rate pressure products, which may limit functional capacity. Daily experiences and activities including emotional stressors such as anger, tobacco use, and exercise can trigger ischemia. Abnormalities in endothelial cell function may result in paradoxic vasoconstriction to stimuli including cold temperatures, exercise, hypoxemia, and emotional stressors, which can lead to angina. As coronary stenoses increase in severity, the coronary microcirculation dilates in an effort to maintain adequate blood flow ( Fig. 6.4 ). The development of epicardial stenoses results in increased resistance to blood flow. The pressure gradient that develops across the lesion is described by the Bernoulli equation ( Fig. 6.5 ). The pressure gradient is influenced by lesion length in a linear fashion but is exponentially increased by the reduction in cross-sectional area. Thus, small changes in cross-sectional area may have profound hemodynamic effects given that the pressure gradient is inversely proportional to the fourth power of the lumen reduction. Whereas resting blood flow is maintained at normal levels until epicardial coronary stenoses exceed approximately 85% of the normal vessel diameter, maximal hyperemic coronary blood flow is impaired once the epicardial stenoses exceed approximately 50% ( Fig. 6.6 ).
